Post on 11-Feb-2022
Consiglio di Amministrazione
Seduta del
- 5 DIC 2013
SAPIENZA UNIVERSITAgrave DI ROMA
Nellanno duemilatredici addigrave 5 dicembre alle ore 1550 presso il Salone di rappresentanza si egrave riunito il Consiglio di Amministrazione convocato con nota rettorale prot n 0070666 del 29112013 per lesame e la discussione degli argomenti iscritti al seguente ordine del giorno
bullbull OMISSIS bull
Sono presenti il rettore prof Luigi Frati il prorettore vicario prof Antonello Biagini i consiglieri profssa Antonella Polimeni prof Maurizio Barbieri prof Bartolomeo Azzaro prof Michel Gras Sig Domenico Di Simone dottssa Angelina Chiaranza sig Luca Lucchetti sigra Federica Di Pietro il direttore generale Carlo Musto DAmore che assume le funzioni di segretario
Egrave assente giustificato dottssa Francesca Pasinelli
Il presidente constatata lesistenza del numero legale dichiara ladunanza validamente costituita e apre la seduta
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Universitagrave degli Studi di Roma La Sapienza
SAPIENZA UN1VER5lTAgrave DI ROMA
Consiglio 0 AfTnigravenistrazione
Seduta de
- 5 DIC 2013 RATIFICA DELL ACCORDO PER LA CREAZIONE DELLINTERNATIONAL ASSOCIATED LABORATORY (LlA)
Il Presidente sottopone al Consiglio di Amministrazione la relazione predisposta dall Area per llnternazionalizzazione relativa allapprovazione a ratifica dellaccordo tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Ulle - Ulle 1 e lIstituto Neuromed giagrave approvata dal Senato accademico nella seduta del 26 novembre 2013
LAccordo giagrave firmato da tutte le parti egrave stato proposto dal prof Nencini Direttore del Dipartimento di Farmacologia e Fisiologia e si inserisce nel quadro della pluriennale collaborazione scientifica tra Italia e Francia nell ambito delle Neuroscienze noncheacute piugrave in particolare della collaborazione tra il laboratorio di Farmacologia della Sapienza e vari team di ricerca francesi
LAccordo egrave finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases Lo scopo del LlA egrave quello di realizzare un progetto di ricerca (descritto nellAnnex 1 dellAccordo allegato come parte integrante alla presente relazione) in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
1 LlA non ha status o capacitagrave legale LAccordo non comporta e non puograve in alcun modo essere interpretato come finalizzato alla formazione la creazione limplementazione di una societagrave comune o di un rapporto di agenzia societagrave gruppo di interesse o di qualsiasi altro tipo di raggruppamento commerciale o ente o societagrave di fatto tra le Parti
I LlA saragrave coordinato congiuntamente da due co-Direttori la profssa Stefania Maccari per la Francia e il prof Ferdinando Nicoletti per lItalia
LAccordo ha durata quadriennale rinnovabile solo una volta
Ciograve premesso il Presidente sottopone allapprovazione del Consiglio di amministrazione lapprovazione a ratifica dellaccordo
Allegato parte integrante
Moo Universitagrave degli Studi di Roma la Sapienza
SAPIENZA UNIVERSITAgrave DI ROMA
Consglio d Ammirlstrazione
del
- 5 DIC 2013
- Accordo tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et
- technologies de Lille - Lille 1 e lIstituto Neuromedfinalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Mcd Universitagrave degli Studi di Roma La Sapienza
SAPIENZA UNIVERSITAgrave DI ROMA
bullbullbullbullbull OMISSIS Consiglio di Amministrazione
DELIBERAZIONE N 288113
Seduta del IL CONSIGLIO DI AMMINISTRAZIONE
5 DIC 2013 bull Letta la relazione istruttoria bull Visto lAccordo culturale tra 1ltalia e la Francia del 41111949 bull Visto lAccordo di Cooperazione scientifica e tecnologica tra il
Governo della Repubblica francese e il Governo della Repubblica italiana del 29012001
bull Visto lAccordo di collaborazione culturale e scientifica bilaterale tra Sapienza Universitagrave di Roma e lUniversiteacute des sciences et technologies de Lille del 150212007
bull Considerato linteresse e lopportunitagrave di creare llnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases avente come scopo quello di realizzare un progetto di ricerca in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
bull Vista la necessitagrave di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e lIstituto Neuromed finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
bull Vista la delibera del Senato accademico n 438113 del 26 novembre 2013
bull Presenti 11 votanti 9 con voto unanime espresso nelle forme di legge dal rettore e dai consiglieri Polimeni Barbieri Azzaro Gras Di Simone Chi aranza Lucchetti e Di Pietro
DELIBERA
di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e llstitutt Neuromed finalizzato alla creazione delllntemational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Letto approvato seduta stante per la sola parte dispositiva
IL SE RETARIO ILP~~~Cari Musto DAmore LUii~ bullbullbull OMISSIS bull
Universitagrave degli Studi digrave Roma La Sapienza ModO(
LlAPSND
AGREEMENTTOCREATE THE INTERNATIONAL ASSOCIATED LABORATORY
Prenatal stress and neurodegenerative diseases (LIAPSND)
The Cenue National de la Rechetche Scientifique (French Narional Center for Scienrific Research) hereinafter referred to as CNRS a public scienrific and technological organizarion headquartered at 3 me Michel-Ange 75794 Paris cedex 16 (France) represented by its President Professor Alain FUCHS
And
The Universiteacute des sciences et technologies de Lille hereinafter referred to as Lille 1 a public insritution of higher education and research headquartered Citeacute Scientifique 59655 Villeneuve dAscq Cedex (France) represented by its President Professor Philippe ROLLET
acting in their own names and joindy on behalf of the following joiot research urut
Uniteacute de g1ycobiologie sttucturale et fonctionnelle UMR 8576 (CNRS - lille 1) directed by Dr Christophe DHULST
And
The Sapienza Universitagrave di Roma hereinafter referred to as Sapienza a public iosritution of academic education and research headquartered 5 Piazzale Aldo Moro 00185 Roma (Italy) represented by its President Professor Luigi FRATI
Acting in its own name and 00 behalf of
Department ofPhysiology and Pharmacology laquov Erspamer directed by Pro Paolo NENCINI
And
The Neuromed Institute hereinafter referred to as Neuromed a private institurioo of research clinical studies and education recognized by the ltalian Ministty of Health as Hospital aod Clinical Insriturion with Scientific Purpose (IRCCSS) headquartered at Via Atinense 18 86077 Pozzilli (IS) (Italy) represented by its President Professor Erberto MELARAGNO
Acring io its own name and on behalf of
Laboratory ofMolecular NeuroPharmacology (MNP) directed by Pro Ferdinando NICOLETTI
Hereinafter referred to collectivelyas the Parties or iodividually as the Party
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
UAPSND
and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
SAPIENZA UN1VER5lTAgrave DI ROMA
Consiglio 0 AfTnigravenistrazione
Seduta de
- 5 DIC 2013 RATIFICA DELL ACCORDO PER LA CREAZIONE DELLINTERNATIONAL ASSOCIATED LABORATORY (LlA)
Il Presidente sottopone al Consiglio di Amministrazione la relazione predisposta dall Area per llnternazionalizzazione relativa allapprovazione a ratifica dellaccordo tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Ulle - Ulle 1 e lIstituto Neuromed giagrave approvata dal Senato accademico nella seduta del 26 novembre 2013
LAccordo giagrave firmato da tutte le parti egrave stato proposto dal prof Nencini Direttore del Dipartimento di Farmacologia e Fisiologia e si inserisce nel quadro della pluriennale collaborazione scientifica tra Italia e Francia nell ambito delle Neuroscienze noncheacute piugrave in particolare della collaborazione tra il laboratorio di Farmacologia della Sapienza e vari team di ricerca francesi
LAccordo egrave finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases Lo scopo del LlA egrave quello di realizzare un progetto di ricerca (descritto nellAnnex 1 dellAccordo allegato come parte integrante alla presente relazione) in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
1 LlA non ha status o capacitagrave legale LAccordo non comporta e non puograve in alcun modo essere interpretato come finalizzato alla formazione la creazione limplementazione di una societagrave comune o di un rapporto di agenzia societagrave gruppo di interesse o di qualsiasi altro tipo di raggruppamento commerciale o ente o societagrave di fatto tra le Parti
I LlA saragrave coordinato congiuntamente da due co-Direttori la profssa Stefania Maccari per la Francia e il prof Ferdinando Nicoletti per lItalia
LAccordo ha durata quadriennale rinnovabile solo una volta
Ciograve premesso il Presidente sottopone allapprovazione del Consiglio di amministrazione lapprovazione a ratifica dellaccordo
Allegato parte integrante
Moo Universitagrave degli Studi di Roma la Sapienza
SAPIENZA UNIVERSITAgrave DI ROMA
Consglio d Ammirlstrazione
del
- 5 DIC 2013
- Accordo tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et
- technologies de Lille - Lille 1 e lIstituto Neuromedfinalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Mcd Universitagrave degli Studi di Roma La Sapienza
SAPIENZA UNIVERSITAgrave DI ROMA
bullbullbullbullbull OMISSIS Consiglio di Amministrazione
DELIBERAZIONE N 288113
Seduta del IL CONSIGLIO DI AMMINISTRAZIONE
5 DIC 2013 bull Letta la relazione istruttoria bull Visto lAccordo culturale tra 1ltalia e la Francia del 41111949 bull Visto lAccordo di Cooperazione scientifica e tecnologica tra il
Governo della Repubblica francese e il Governo della Repubblica italiana del 29012001
bull Visto lAccordo di collaborazione culturale e scientifica bilaterale tra Sapienza Universitagrave di Roma e lUniversiteacute des sciences et technologies de Lille del 150212007
bull Considerato linteresse e lopportunitagrave di creare llnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases avente come scopo quello di realizzare un progetto di ricerca in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
bull Vista la necessitagrave di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e lIstituto Neuromed finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
bull Vista la delibera del Senato accademico n 438113 del 26 novembre 2013
bull Presenti 11 votanti 9 con voto unanime espresso nelle forme di legge dal rettore e dai consiglieri Polimeni Barbieri Azzaro Gras Di Simone Chi aranza Lucchetti e Di Pietro
DELIBERA
di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e llstitutt Neuromed finalizzato alla creazione delllntemational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Letto approvato seduta stante per la sola parte dispositiva
IL SE RETARIO ILP~~~Cari Musto DAmore LUii~ bullbullbull OMISSIS bull
Universitagrave degli Studi digrave Roma La Sapienza ModO(
LlAPSND
AGREEMENTTOCREATE THE INTERNATIONAL ASSOCIATED LABORATORY
Prenatal stress and neurodegenerative diseases (LIAPSND)
The Cenue National de la Rechetche Scientifique (French Narional Center for Scienrific Research) hereinafter referred to as CNRS a public scienrific and technological organizarion headquartered at 3 me Michel-Ange 75794 Paris cedex 16 (France) represented by its President Professor Alain FUCHS
And
The Universiteacute des sciences et technologies de Lille hereinafter referred to as Lille 1 a public insritution of higher education and research headquartered Citeacute Scientifique 59655 Villeneuve dAscq Cedex (France) represented by its President Professor Philippe ROLLET
acting in their own names and joindy on behalf of the following joiot research urut
Uniteacute de g1ycobiologie sttucturale et fonctionnelle UMR 8576 (CNRS - lille 1) directed by Dr Christophe DHULST
And
The Sapienza Universitagrave di Roma hereinafter referred to as Sapienza a public iosritution of academic education and research headquartered 5 Piazzale Aldo Moro 00185 Roma (Italy) represented by its President Professor Luigi FRATI
Acting in its own name and 00 behalf of
Department ofPhysiology and Pharmacology laquov Erspamer directed by Pro Paolo NENCINI
And
The Neuromed Institute hereinafter referred to as Neuromed a private institurioo of research clinical studies and education recognized by the ltalian Ministty of Health as Hospital aod Clinical Insriturion with Scientific Purpose (IRCCSS) headquartered at Via Atinense 18 86077 Pozzilli (IS) (Italy) represented by its President Professor Erberto MELARAGNO
Acring io its own name and on behalf of
Laboratory ofMolecular NeuroPharmacology (MNP) directed by Pro Ferdinando NICOLETTI
Hereinafter referred to collectivelyas the Parties or iodividually as the Party
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
UAPSND
and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
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The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
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Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
SAPIENZA UNIVERSITAgrave DI ROMA
Consglio d Ammirlstrazione
del
- 5 DIC 2013
- Accordo tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et
- technologies de Lille - Lille 1 e lIstituto Neuromedfinalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Mcd Universitagrave degli Studi di Roma La Sapienza
SAPIENZA UNIVERSITAgrave DI ROMA
bullbullbullbullbull OMISSIS Consiglio di Amministrazione
DELIBERAZIONE N 288113
Seduta del IL CONSIGLIO DI AMMINISTRAZIONE
5 DIC 2013 bull Letta la relazione istruttoria bull Visto lAccordo culturale tra 1ltalia e la Francia del 41111949 bull Visto lAccordo di Cooperazione scientifica e tecnologica tra il
Governo della Repubblica francese e il Governo della Repubblica italiana del 29012001
bull Visto lAccordo di collaborazione culturale e scientifica bilaterale tra Sapienza Universitagrave di Roma e lUniversiteacute des sciences et technologies de Lille del 150212007
bull Considerato linteresse e lopportunitagrave di creare llnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases avente come scopo quello di realizzare un progetto di ricerca in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
bull Vista la necessitagrave di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e lIstituto Neuromed finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
bull Vista la delibera del Senato accademico n 438113 del 26 novembre 2013
bull Presenti 11 votanti 9 con voto unanime espresso nelle forme di legge dal rettore e dai consiglieri Polimeni Barbieri Azzaro Gras Di Simone Chi aranza Lucchetti e Di Pietro
DELIBERA
di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e llstitutt Neuromed finalizzato alla creazione delllntemational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Letto approvato seduta stante per la sola parte dispositiva
IL SE RETARIO ILP~~~Cari Musto DAmore LUii~ bullbullbull OMISSIS bull
Universitagrave degli Studi digrave Roma La Sapienza ModO(
LlAPSND
AGREEMENTTOCREATE THE INTERNATIONAL ASSOCIATED LABORATORY
Prenatal stress and neurodegenerative diseases (LIAPSND)
The Cenue National de la Rechetche Scientifique (French Narional Center for Scienrific Research) hereinafter referred to as CNRS a public scienrific and technological organizarion headquartered at 3 me Michel-Ange 75794 Paris cedex 16 (France) represented by its President Professor Alain FUCHS
And
The Universiteacute des sciences et technologies de Lille hereinafter referred to as Lille 1 a public insritution of higher education and research headquartered Citeacute Scientifique 59655 Villeneuve dAscq Cedex (France) represented by its President Professor Philippe ROLLET
acting in their own names and joindy on behalf of the following joiot research urut
Uniteacute de g1ycobiologie sttucturale et fonctionnelle UMR 8576 (CNRS - lille 1) directed by Dr Christophe DHULST
And
The Sapienza Universitagrave di Roma hereinafter referred to as Sapienza a public iosritution of academic education and research headquartered 5 Piazzale Aldo Moro 00185 Roma (Italy) represented by its President Professor Luigi FRATI
Acting in its own name and 00 behalf of
Department ofPhysiology and Pharmacology laquov Erspamer directed by Pro Paolo NENCINI
And
The Neuromed Institute hereinafter referred to as Neuromed a private institurioo of research clinical studies and education recognized by the ltalian Ministty of Health as Hospital aod Clinical Insriturion with Scientific Purpose (IRCCSS) headquartered at Via Atinense 18 86077 Pozzilli (IS) (Italy) represented by its President Professor Erberto MELARAGNO
Acring io its own name and on behalf of
Laboratory ofMolecular NeuroPharmacology (MNP) directed by Pro Ferdinando NICOLETTI
Hereinafter referred to collectivelyas the Parties or iodividually as the Party
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
UAPSND
and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
SAPIENZA UNIVERSITAgrave DI ROMA
bullbullbullbullbull OMISSIS Consiglio di Amministrazione
DELIBERAZIONE N 288113
Seduta del IL CONSIGLIO DI AMMINISTRAZIONE
5 DIC 2013 bull Letta la relazione istruttoria bull Visto lAccordo culturale tra 1ltalia e la Francia del 41111949 bull Visto lAccordo di Cooperazione scientifica e tecnologica tra il
Governo della Repubblica francese e il Governo della Repubblica italiana del 29012001
bull Visto lAccordo di collaborazione culturale e scientifica bilaterale tra Sapienza Universitagrave di Roma e lUniversiteacute des sciences et technologies de Lille del 150212007
bull Considerato linteresse e lopportunitagrave di creare llnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases avente come scopo quello di realizzare un progetto di ricerca in materia di impatto dello stress nei primi anni di vita sulle malattie neurologiche da adulti
bull Vista la necessitagrave di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e lIstituto Neuromed finalizzato alla creazione delllnternational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
bull Vista la delibera del Senato accademico n 438113 del 26 novembre 2013
bull Presenti 11 votanti 9 con voto unanime espresso nelle forme di legge dal rettore e dai consiglieri Polimeni Barbieri Azzaro Gras Di Simone Chi aranza Lucchetti e Di Pietro
DELIBERA
di ratificare lAccordo giagrave sottoscritto tra Sapienza Universitagrave di Roma il Centre National de la Recherche Scientifique - CNRS lUniversiteacute des sciences et technologies de Lille - Lille 1 e llstitutt Neuromed finalizzato alla creazione delllntemational Associated Laboratory (LlA) Prenatal stress and Neurodegenerative Diseases
Letto approvato seduta stante per la sola parte dispositiva
IL SE RETARIO ILP~~~Cari Musto DAmore LUii~ bullbullbull OMISSIS bull
Universitagrave degli Studi digrave Roma La Sapienza ModO(
LlAPSND
AGREEMENTTOCREATE THE INTERNATIONAL ASSOCIATED LABORATORY
Prenatal stress and neurodegenerative diseases (LIAPSND)
The Cenue National de la Rechetche Scientifique (French Narional Center for Scienrific Research) hereinafter referred to as CNRS a public scienrific and technological organizarion headquartered at 3 me Michel-Ange 75794 Paris cedex 16 (France) represented by its President Professor Alain FUCHS
And
The Universiteacute des sciences et technologies de Lille hereinafter referred to as Lille 1 a public insritution of higher education and research headquartered Citeacute Scientifique 59655 Villeneuve dAscq Cedex (France) represented by its President Professor Philippe ROLLET
acting in their own names and joindy on behalf of the following joiot research urut
Uniteacute de g1ycobiologie sttucturale et fonctionnelle UMR 8576 (CNRS - lille 1) directed by Dr Christophe DHULST
And
The Sapienza Universitagrave di Roma hereinafter referred to as Sapienza a public iosritution of academic education and research headquartered 5 Piazzale Aldo Moro 00185 Roma (Italy) represented by its President Professor Luigi FRATI
Acting in its own name and 00 behalf of
Department ofPhysiology and Pharmacology laquov Erspamer directed by Pro Paolo NENCINI
And
The Neuromed Institute hereinafter referred to as Neuromed a private institurioo of research clinical studies and education recognized by the ltalian Ministty of Health as Hospital aod Clinical Insriturion with Scientific Purpose (IRCCSS) headquartered at Via Atinense 18 86077 Pozzilli (IS) (Italy) represented by its President Professor Erberto MELARAGNO
Acring io its own name and on behalf of
Laboratory ofMolecular NeuroPharmacology (MNP) directed by Pro Ferdinando NICOLETTI
Hereinafter referred to collectivelyas the Parties or iodividually as the Party
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
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INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
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and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
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1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
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The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
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A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
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from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
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Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LlAPSND
AGREEMENTTOCREATE THE INTERNATIONAL ASSOCIATED LABORATORY
Prenatal stress and neurodegenerative diseases (LIAPSND)
The Cenue National de la Rechetche Scientifique (French Narional Center for Scienrific Research) hereinafter referred to as CNRS a public scienrific and technological organizarion headquartered at 3 me Michel-Ange 75794 Paris cedex 16 (France) represented by its President Professor Alain FUCHS
And
The Universiteacute des sciences et technologies de Lille hereinafter referred to as Lille 1 a public insritution of higher education and research headquartered Citeacute Scientifique 59655 Villeneuve dAscq Cedex (France) represented by its President Professor Philippe ROLLET
acting in their own names and joindy on behalf of the following joiot research urut
Uniteacute de g1ycobiologie sttucturale et fonctionnelle UMR 8576 (CNRS - lille 1) directed by Dr Christophe DHULST
And
The Sapienza Universitagrave di Roma hereinafter referred to as Sapienza a public iosritution of academic education and research headquartered 5 Piazzale Aldo Moro 00185 Roma (Italy) represented by its President Professor Luigi FRATI
Acting in its own name and 00 behalf of
Department ofPhysiology and Pharmacology laquov Erspamer directed by Pro Paolo NENCINI
And
The Neuromed Institute hereinafter referred to as Neuromed a private institurioo of research clinical studies and education recognized by the ltalian Ministty of Health as Hospital aod Clinical Insriturion with Scientific Purpose (IRCCSS) headquartered at Via Atinense 18 86077 Pozzilli (IS) (Italy) represented by its President Professor Erberto MELARAGNO
Acring io its own name and on behalf of
Laboratory ofMolecular NeuroPharmacology (MNP) directed by Pro Ferdinando NICOLETTI
Hereinafter referred to collectivelyas the Parties or iodividually as the Party
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
UAPSND
and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LlA PSND
TABLE OF CONTENTS
IN ACKNOWLEDGMENT OF PREAMBLES
TITRE 1- CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA Artide 1- Creanon and Term Artide 2 - Purpose
Artide 3 - Composinon
Artide 4 - Type of cooperanon
TITRE II - ORGANlZATION Artide 5 - Co-cIirectors Artide 6 - Steering Committee
61 Composition 62 Chairperson 63 Meetings and decisions 64 Role
Artide 7 - Sciennfic evaluanon
TITRE III - FINANCIAL AND HUMAN RESOURCES Artide 8 - Funcling provisions
Artide 9 - Personnel Artide 10 - Facilines and equiprnent
Artide 11- Research contracts
TITRE IV - PUBLICATIONS CONFIDENTIALITY INTELLECTUAL PROPERTY AND VALORISATION
Artide U - Mutuai inforrning and Publicanons
Artide 13 - Non-disclosure Artide 14 - lntellectual Property
Defininons 141 Ownership of Results 142 Patent protection of LlA Results 143 Appointment ofa sole Administrator 144 Patent infringement actions 145 Rights of access 146 CommerciaI exploitation ofJoint Results
TITRE V - MISCELLANEOUS PROVISIONS Artide 1S - Renewal
Artide 16 - Modificanon - Membership Artide 17 - Cancellanon Artide 18 - Interna communicanon between Parties
Artide 19 - Liability
Artide 20 - Fina provisions
ANNEX 1- RESEARCH PROGRAM ANO INDIVIDUAL PROJECTS ANNEX 2- COMPOSITION OFTHELIAAS OFJANUARY 1ST 2013 ANNEX 3 - CONSOLIDATED PROJECTED BUDGET AS OFJANUARY 1ST2013 ANNEX4-FAC~ITIESANDEQU~MENT ANNEX 5 - PROPRIETARY RESULTS EXCLUDED FROMTRE PURPOSES OF LlA PNSD AS OF JANUARY 1ST 2013
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
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and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
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1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
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The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
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A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
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TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
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if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
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144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
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from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
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Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
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Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
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ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
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Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
INACKNOWLEDGMENT OF
_The Cultura agreement between French and ltalian govemments signed on the 4th ofNovember 1949
_The Scientific agreement of cooperation between the govemment of the French Republic and tbe govemment of tbe Italian Republic signed on the 29th ofJanuary 2001
_The cultura and scientific frame agreement on the bilatera collaboration between the University ofIllle 1 and the Sapienza signed on the 151h February 2007
- The agreement between CNRS and Lille 1
_The French decree n02009-645 ofJune 9 2009 on the management between the French public institutions of the industriai property of the results ampom research conducted by French state-employees and which determines a French public mandatary responsible far the protection and exploitation of said results
- The constirutive agreement of the Intemational Scientific Coordination Network entided Early Programming ofModem Diseases (abbreviated as GDRE EPMD) (2009-2012) signed on the 17th ofMarch 2010
PREAMBLE
The scienIgravefic collaboration on neurosciences between France and Italy started more than 20 years ago In particu1ar the collaboration between the laboratory of Pharmacology at Sapienza University of Rome and French research teams from Bordeaux started in October 1988 SeveraI grants for mobility were obtained in tbe framework of several national and intemationaI progtanls sucb as the Partenariat Hubert Cunen (pHq Galileo and the ERASMUS program short fellowship from the European Union and private grants Etom industries Severa PhD students took their PhD and Italian students became Researchers or Professors in France such as S Maccan herself who became first Assistant Professor at the University of Bordeaux 2 and after Professor at the University of Lille 1 A new collaboration was created between Lille and the Institute of Neurosciences in Rome (CNR) Afrarne agreement was also signed between University of Lille 1 and the Sapienza University of Rome in 2007This agreement pemlitted the nomination of Frencbresearcbers as Visiting Professors at the Sapienza University of Rome and in rerum the nomination of ltalian researcbers as Visiting Professors at the University of Li1le 1 Furthermore mobility of PhD srudents and Postdocs was improved thanks to this agreement which supported the annua summer scbools of neurosciences organised by S Maccari A financial support for the summer schools was obtained Etom the Federation of European Neurosciences Societies (FENS) In 2008 a two-day meeting on Progtamming and Epigenetic was organized in Lille funded by the French Neurosciences Society
Thanks to the support of CNRS an Intemational Scientific Coordination Network the GDRE 691 Early programming of modero diseases (EPMD) was created in 2009 by the Parties Consiglio Nazionale delle Ricercbe (CNR) and Universitagrave Cattolica del Sacro Cuore with S Maccari (for France) and Dr A Moles (for ltaly) as coordinators Aim of EPMD was to consolidate the intemational network around bebavioura1 epigenetics an innovative theme of neurosciences This consortium grouped high level researchers intemationally recognized in different neuroscience fields prenatal stress animal model of depression (PRS) (S Maccan) animal models of neurodegenerative diseases (F Nicolettigrave and B Bioulac) and antidepressant action on plasticity (A Daszuta) eating disturbancies (A Moles V Preacutevot) and CIgravelcadian disorders (p Pevet J Mairesse) proteomics and epigenetics (S Morley-Fletcher A Benecke)
In particular the GDRE has supported a bilatera collaboration between S Maccari and F Nicoletti interoationally acknowledged as experts of the neurobiology of prenatal stress and of neurodegenerative disorders respectivdy
Very recent results obtained in this bilateral cooperation indicate that PRS can induce a latent state of Park1nsonism raising the interesting possibility tbat thls pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain cbaracterized by slowness of movement
UAPSND
and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
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from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
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Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
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Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
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ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
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vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
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ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
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Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
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ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
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ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
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and locomotion (bradykinesia rigidity and tremor) lt is one of tbe most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in tbe US Tbe average age of clinical onset is about 60 Dopamine is involved in tbe control of motor programming Parkinsons disease occurs when tbe dopaminergic neurons are slowly degenerated Depletion in dopamine alters nigro-striata motor patbway This leads to a deep alteration of motor planning Tbe damage gets worse over rime Nowadays tbe reasons of this important cell deatb are poorly known Qur studies suggest tbat early life events can induce changes in tbe dopaminergic motor system during tbe adult life affecting behavior and neurochemical transm1ssion These researches also highlight tbe importance to detect tbe early signs of a latent parkinsonism
Based on tbese encouraging scientific results tbe Partles recognize tbe quality of tbe research collaboration emerged tbanks to tbe GDRE EPMD and decided to support tbis successful bilatera cooperation through a structuring partnership allowing a long term development of further joint research activity on prenata stress and neurodegenerative diseases
Consequently tbe Partles agree on tbe basis of this Agreement to form an Intemational Associated Laboratory - UA devoid oflega status and govemed by tbe following provisions
TITLE I - CREATION TERM NAME PURPOSE AND COMPOSITION OF THE LlA
Article 1 - Creation and term
The Intemational Associated Laboratory (IlA) Prenatal stress and Neurodegenerative Diseases abbreviated as PSND hereinafter referred to as LIA or lteLIA PSND shall be effective on 1 January 2013 for a term of four (4) years renewable once
Article 2 bull Purpose
The purpose of tbe UA is to carry out tbe research project desccibed in Annex 1 attached hereto in tbe field of impact of early life stress on neurologica adult diseases
Artide 3 bull Composition
The UA PSND consists of tbe following laboratones
bull Neuroplasticity Team headed by Pro Stefania MACCARl - Uniteacute de glycobiologie structurale et fonctionnelle UMR 8576 (CNRS Universiteacute Lille 1) directed by Dr Christophe DHUIST
bull Psychopharmacology Group headed by Pro Ferdinando NlCOLETTI - Department of Physiology and Pharmacology V Erspamer Sapienza directed by Pro Paolo NENCINI
bull Laboratory of Molecular NeuroPharmacology IRCCSS NEUROtv1ED directed by Pro Ferdinando NICOLETTI
The personnel and teams list (hereinafter referred to as LIA Members) as ofJanuary lmiddott 2013 1S set out in Annex 2
According to tbe research program realised in tbe fiamework of tbe LIA researchers from otber laboratones can participate in tbe LIA research Tf deemed necessary tbeir participation will be subject to a specific Agreement or to an Amendment to tbe Agreement according to art 16
Artide 4 - Type of cooperation
The LIA has no lega status or capacity
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1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
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The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
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A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
lIAPSND
1bis Agreement neither sets out to nor results in nor should anything in it be constru~d as either fo~g creating implementing or recognizing the creation of a joint company agency relattonshlp c~rporatton interest group or any other type of commerciaI grouping or entity or de facto company by the Pames
TITLE II - ORGANIZATION
Artide 5 - Co-directors
The LIA 1S mn by two co-directors The management of tbe LIA is joindy provided by
- Pro Stefania MACCARI for France - Pro Ferdinando NICOLETTI for ltaly
hereinafter referred to as Co-directors
In accordance witb the practice of their home institutions tbe Co-directors joindy assume responsibility for tbe scientific program and each one individually manages bis part of tbe LIA As necessary they shall establish tbe bylaws of tbe LIA
The Co--directors shall prepare tbe research program provisional budget and annua financial and scientific reports to be submitted to tbe Steering Committee and to the Parties
The directors of the French Joint Research Units (UMR) participating in the LIA are solely responsible administrative1y witb regard to staff management and use of funding resources allocated to tbe LIA vis-agrave-VIgrave5 the Parties overseeing tbeir unito
The Co-directors may take advice from a Scientific Advisory Board composed of scientific experts not involved in the LIA whose names are listed in Annex 2B
Artide 6 - Steering Committee
61 - Composition
A Steering Committee for the LIA PSND is constituted 1bis Committee shall be composed of 2 representatives per country chosen from outside the staff of those laboratones making up tbe LIA
- 2 representatives of French Parties - the Director of the Institute of Biologica Sciences of CNRS or bisher representative - the Vice President for Research ofLille 1 or hisher representative
- 2 representatives ofItalian Parties the President ofSapienza or hlsher representative
- tbe President ofNeuromed or hlsher representative
Al members possess equal voting rights
Subject to the execution of a nondisclosure agreement all Parties may invite members of tbeir administrative organization andor outside parties to attend tbe steering committee meetings Such invited guests shall sit in a consultative capacity The li~t of representatives as ofJanuary 1st 2013 is set out in Annex 2C
The LIA Co-directors shall attend tbe Steering Committee meetings in a consultative capacity
62middot Cbairperson
The Parties appoint one of the Steering Committee members as Chairperson in rotation for two years in order to preside the Steering Committee
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
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Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
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ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
UAPSND
The Chairperson as ofJanuary 1 SI 2013 is tbe Director of tbe Institute of Biological Sciences of CNRS or
bisher representative
63 - Meetings and decisions
The Steering Committee shalI meet at least once every WO (2) years and at tbe initiative of its Chairperson md at tbe request of hs members or the Co-dUectors as often as required by the interests of the LlA
Decisions require the unanirnity of members either present or represented the quorum being reached at of its members In the event of practical impossibility of a physical meeting the Steering Committee may meet via telecooferencing or any other means
64 - Role
The Steering Committee - formulates recommendations 00 the project presented by tbe Co-directors and tbe state aod d1rectioo of tbe research carried out by tbe LLA - approves tbe fuoding oecessary to run tbe LLAi - may make recommeodatioos or propose reonentations - defines tbe collaboration policy of tbe LLA taking into account tbe Parties interests - defmes tbe Party in charge of negotiatioo - provides an opinioo 00 any modificatioo of tbe LLA structure and on tbe admission of new laboratories or Parties to tbe LLA - provides an advice as to tbe renewal of the LLA based on tbe evaluatioo reporti - may also study any matter relating to tbe LLA
Meeting minutes for alI Steering Committee meetings shalI be provided by tbe Chairperson to alI Parties within 30 days
Artide 7 - Scientific evaluation
The LLA activities shall be assessed regularly and in any case before its ex-piration date by tbe relevant autborities ofbotb parties in accordance witb tbe applicable procedures of tbese bodies Tbe Parties may also propose to fonn an Ad Hoc Committee particularly pnor to LLA renewal in order to evaluate its scientific activities aod issue recommendations 00 tbe LLA scientific onentatioo and functioning Evaluation reports shall be addressed to tbe Steering Committee and tbe Parties
TITLE III - FlNANClAL AND HUMAN RESOURCES
Artide 8 - Funding provisions
Every calendru yeat tbe budget required to cacry out tbe LLA research is prepared and submitted by tbe ilA Co-d1rectors to tbe Steering Committee for approvalo
Annex 3 attached hereto sets out tbe projected budget allocated by tbe Parties as of tbe date tbe LlA enters into effect This budget is updated annually by tbe LLA Co-directors following a vote by tbe Steering Committee
Each LLA Party shall manage its respective resources such as the internai budget allocation for the LlA purposes or extemal resources
Resources obtained joindy within tbe framework of agreemeots concluded 00 behalf of tbe LlA shall be shued and managed by tbe Parties in accordance witb tbeir participation in such projects
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
A report is provided annually by each Party to the others on the resources it allocated over the past year (including equipmeot premises and teoured or temporary personnel)
Moreover the funds allocated to the LIA and managed by bOth LIA Co-direc~ors are subject to the customary monitoring mechanisms in their respective countries to verify their legitimate use in relation to the purpose of this Agreement
Artide 9 - Personnel
Personnel assigned to contribute to the UA shall remain administratively dependent on their originai institution and unit and shall carry out its work under the administrative supervision of their unit director
Annex 2 summarizes the schedule and extent of the participation of personnel in the joint scieotific project
The exchange of personnel (secondment etc) is subject to execution of an agreement setting out terms md conditions of compensation ownership of results and suborcllnation
While on assigrunent visitors are subject to the by1aws and procedures of the hosting laboratory
Artide 10 - Facilities and equipment
UA members shall have access to the facilities mdior equipment listed in Annex 4 throughout the term of this Agreement for putposes of carrying out the research project described in Annex 1
The Party in whose possession the facilities andor equipmeot are Iocated remains liable therefore
For information purposes the amount of depreciation allowance for facilities md equipment made availab1e to the LIA must be provided (according to the terms in effect for each Party)
The use of facilities mdior equipment is subject to the safety and security rules in force
The Parties premises are made availab1e to LIA use subject to compliance with the bylaws and procedures of the owner Party andthe execution ofa hosting agreemeot In the event of a 10an or rentai of facilities and equipment a 10an agreement shall be executed by the Parties concemed including reference to the purpose and term any applicable fees the Parties liabiliries and the terms of mainteoance and return of the property
Artide 11- Research contraets
All research contracts that the LIA shall execute with third-party bodies public or private require approvai of and signature by all Parties and are subject to the paragraph 64 on the role of the Steering Committee
They shall be negotiated by the Party having express authority to so act followigraveng the Co-directors proposition and recommendations of the Steering COmnllttee and with the agreement of the other Parties The authorized Party shall keep the other Parties informed of the results of all negotiations The latter shall dispose of fifteen (15) days to respond after which the negotiation is deemed approved
The use of LIA PSND ride by the Parties must include that LIA is devoid of legai personality and the LIA Partles are financia1ly md legaliy independent and separate liable partners
The nondisclosure clauses included in such research contracts must not preclude the concemed researchers from induding tbeir research in activity reports or tbe students to defend their PhD dissertation
The contracts shall make explicit provisions for reimbursing overheads associated with activities developed under said contracts which have been paid by me Party involved in the research The corresponding amounts determined by agreement between the Parties shall be allocated to the budgetary contribution of said Party
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LlA PSND
TITLE IV - PUBUCATIONS CONFIDENfIALITY INfELLECTUAL PROPERTY AND VALORISATION
Artide 12 - Mutuai informing and Publications
Each Party undertakes to share with the other Part1es all information needed to cany out the joint research work The publication of scientific results shall be made according the usual custom and practice of the scientific commuruty Part1es recommendations on scientists affiliation and with prior consent of ali scientific contributors to the results and entitled Part1es
Publications related to the joint research efforts of the ilA research project shali include reference to the ilA Parties or other French overseeing authorities and bearing the mandatory statement Researcb conducted in tbe scope oftbe PSND International Associated Laboratory (LIA)
Throughout the term of the LIA and for a subsequent period of two (2) years each Party shall request the consent of the other Party for its own publication related to the LIA Such consent may not be unreasonably withheld
In any case a publication cannot be delayed beyond nineteen (19) months from the date of receipt of a notice by the Parties Where a publication or paper contains important information of an industriaI commercial or strategie nature related to the activities of certain Parties the decision regarding the nature and term of nondiselosure shall be taken by thegrave Steering Committee (allowed activity reports by personnel closed session dissertation defenses) The Steering Committee shall make its decision known within a maxigravemum period of one (1) month as from the receipt date of the enquiry This decision can consist in
a) Accepting the publication unreservedly or b) Requesting that the publication or commurucations project be postponed owing to rea and serious reasons in particular if specific information must be subject to protection under intel1ectual property provisions In such case the Parties agree to either remove the objecting Partys Confidential Information or to delay the planned publication for a period of up to a maximum of eighteen (18) months after objectionto allow for protection or other appropriate steps
Article 13 - Non-disc1osure
Within the framework of information exchange necessary to carry out the ioint research work the Part1es shall refrain from diselosure protection (patent) or exploitation of commercial or industria nature of any confidential information belonging to the other Party
Information (of any kind contained in any medium) is confidential when explicitly identified as confidential
The period of confidentiality runs for the term of the LIA and a subsequent 5-year periodo
Parties are responsible for ensuring compliance with duty of non-disclosure by their employees durlng LIA and following expiration of its term or following terminatioti of their employment as wel1 as by hosted personnel
However this clause shall not impede CNRS researchers from fulfilling their obligation of producing an activity report which shall not consti tute disclosure within the meaning of the laws goveming industriaI property nor students ftom defending their doctoral thesis or intemship report relating to the work conducted under this cooperative activity If necessary the exarnination may take pIace behind closed doors
Exceptions in which the Confidentiality obligations shall not apply if the confidential information becomes publicly available by means other than a breach of the recipients confidentiality obligations
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIA PSND
if the disclosing party subsequendy infonns the recipient that the confidential infonnation is no
longer confidential if the confidential information is communicated to the recipient without any obligation of confidence by a third party who is in lawful possession thereof and under no obligation of confidence to the
disclosing party if the confidential information at any rime was developed by the recipient completdy independendy of any such disclosure by the disclosing party or if the confidential information was already known to the recipient prior to disclosure if a Party is required to disclose confidential information in order to comp~y with applicable law~ ~r regulations or with a court or adrninistrative order provided however that lt shall to the extent lt 1S
lawfully able to do so prior to any such disclosure o notify the owning party and o comply with the owning partys reasonable instructions to protect the confidentiality of the
information
Article 14 - Intellectual Property
Definitions
laquoProprietary Results Results including software and databases which may or may not be protected by intellectual property rights and belonging to one of the Parties obtained prior to joining the present Agreement or simultaneous to and independent of the scope of LIA activities
laquoJoint Results Results including software and databases which may or may not be protected by intellectual property rights to which two or more Parties joindy contributed in a substantial or inventive manner and which are a direct or indirect result of the LIA activities
laquoQualified Know-How Ali practical results unprotected by intellectual property rights which are (a) confidential (b) substantial ie significant and useful for the magraveriufacture of paiticulagraver prodticts and (c) identified ie descrlbed in such a way as to be understandable and adequate to confinn the dements of (a) and (b)
141 - Ownership of Results
Proprietary Results remain the property of the owning Party Proprietary Results or Qualified Know-how that are not free of access for the purposes of LIA are set out in Annex 5 which shall be regularly updated by the Parties Ali Proprietary Results which are not listed in Annex 5 are free of access for the purposes ofLIA
Joint Results are the joint property of the entided Parties (hereinafter referred to as Joint Owners) which shall hold such rights in the following proportions - 50 to CNRS and Lille 1 (in their names and in the narne and on behalf of other LIA Members employers unless theses employers explicidy waive their rights) - 50 to Sapienza and Neuromed
The above allocation shall be the default in cases ofJoint Results but the Parties may negotiate however from case to case a more appropriate allocation of share according to the inventive contributions if such contributions are substantially not comparable In case of disagreement between the parties regarding to such contributions the share should be discussed in an amicable way in the framework of the Steering Committee In case of persisting disagreement such share shall be determined by an extemal independent patent attomey
Any transfer of ownership grant of license or similar right over the Joint Results shall require the prior written consent of the other Joint Owners
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
UA PSND
The Joint Owners agree to negotiate in good faitb an Inter-Institutional-Agreement CIIA) settling their rights and duties with regard to any Joint Result
To the extent possible such IlA shall be based on the terms and conditions with regard to the regulation the administratioti and the commercial exploitation of the Joint Result agreed by the Joint Owners and specified in this section
A result obtained in the framework of the LIA activities (hereinafter the ceLIA Resulf) which is not a J oint Result shall be sole1y owned by the Party who obtained it and shalI not be subject to tbe provisions regarding the ]oint Results
142 - Patent protection ofJoint Results
Inventors of a J oint Result shall infOlm both Co-directors and the Steering Committee and declare their invention to each of the entided Parties which shall evaluate any interest in protecting said invention
The J oint Owners shall jointly decide whether or not to patent a J oint ResUlt In the event a patent is filed they shalI jointly decide on the countries or regions to be covered by the registration Patent applications shall be filed in the names and for the joint benefit of the Joint Owners the name(s) of the inventor(s) shall be mentioned pursuant to hishertheir rights
One or more Joint Owner(s) have the right to file a patent in its (their) name and at its (their) expense if one or more]oint Owners expressly waive and assign their tights to do so The J oint Owner who waived and assigned bis right should take alI steps andor execute alI documents necessary morder to give full force and effect to any such assignment Such J oint Owner shall be entided however to assign its rights m the Jomt Result to its mventors without obtaining the other Partys approva provided that the inventors hashave undertaken in writing to the other Party to be bound by the provisions of this Agreement
The remaining Joint Owners has the right to recover the patent rights in their name(s) if during the term of protection one of the Joint OWners decides to withdraw its involvementmiddotfrom the patent Such Jomt OWner shall be entided however to assign 1ts rights in the Jomt Result to its inventors without obtaining the other Partys approva provided that the Inventors hashave undertaken m writing to the other Party to be bound by the provisions of this Agreement
A Jomt Owner who does not join in protecting a J oint Result or who withdraws its involvement m the patent protection shalliose its rights (including the right to remuneration or compensation in respect of SUch patent rights or such assignment) save for the right to use the Joint Results for internal research purposes
The J oint Owners involved in such protection shall be the sole beneficiaries of the income generated froro commercia1 exploitation of the patent in the corresponding countries
Each Jomt Owner involved in the protection of a J omt Result is solely liable for ensuring compliance with duties relative to its ernployees rights over the mvention
143 - Appointment of an Administrator
Tbe Jomt Owner most able to valome or exploit one or more Jomt Results of the LIA identiEied by mutuaI agreeroent between the Parties upon recommendation by the Steering Comrnittee and subject to the French decree n02009-645 shall administer the protection and exploitation of the(se) Jomt Results (hereinafter the Adrninistrator)
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIA PSND
144 - Patent infringement actions
In the event that one of the Jomt Owners leams of 30 alieged infringement of a patent owned jomtly by the Parties or of 30 application pending or a patent be10nging to a third party 30d mterfering With ~e patent he1d jointly the Parnes the information shali be immediately commurucated between the JOlnt Owners
The ]oint Owners mvolved m the protection of a ]omt Result shali mutualiy agree on measures to be taken in the event of mfringement The Aclministtator who shali be veacutested With ali specific powers m relation thereto is responsible for such measures he shali take ali necessary steps in order to take cognizance of 30d put a stop to the infringing action
The legaI fees costs damages 30d mterest shali be shared betweenamong the Joint Owners acting jomtly according to their share m the ownership J oint Owners who do not participate m the action shali not collect any sums resulting ampom legaI recourse
145 - Rights of access
Each Party holds subject to third-party rights a non-exclusive non-transferable right to use the LIA Results - including those that are not Jomt Results - 30d the Proprietary Results except for those listed m Annex 5 free of charge for purposes of the LIA research
Each Jomt Owner holds a non-exclusive non-transferable right to use the Jomt Results - mcluding the structure and content of Jomt software 30d databases - free of charge for their own mtema1 research needs With the exception of 30y activity which is of 30 mdusttial or commercial nature and necessitates execution of 30 agreement defining the scope terms 30d conditions oflicensmg
Third-party acces to ]omt Results mcluding software 30d databases is 5ubject to the prior consent of the Joint Owners aod subject to a wntten agreement
146 - Commerciai exploitation ofJoint Results
The consent of ali Jomt Owners 15 required to grantthird-party rights as licenses to useand exploit 30y ] omt Result
The ]oint Owners shall agree With regard to each commercial negotiation With a third pagraverty 00 the principal financial tenns wruch shali form part of the commercial agreement With such third party m adv30ce (hereinafter the Term Sheet)
Express powers are granted to the Administrator by other Jomt Owners to act 30d undertake ali activities to commercially exploit the Jomt Results
The Administtator shali regularly mform the J oint Owners of the progress and conclusion of negotiations
The ]omt Owners agree that after the Term Sheet shali be agreed upon by them the Administrator shall be entitled to negotiate license and other commercialization agreements on the Jomt Owners behalf m respect of the Jomt Results based on the terms of the Term Sheet and the provisions set out be10w (Additional Tenns) The Jomt Owners shali jointly execute 30y such agreements 30d shall not be entitled to Withhold their signature thereon provided the Administtator has complied With the terms hereof
In addition to the specific terms of the Term Sheet that shali be agreed by the Jomt Owners as aforesaid an Agreement for 30y license granted in respect of the Jomt Results shall include inter alia
a definition of the products for which the Jomt Results may be used for their development manufacture and sale
terms securlng full mdemnificatioo Without exception and holding harmless of the Parties 30d those employed by them against 30d from 30y claim damage or expense of 30y kind resulting
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
from any use the Licensee or those authomed by the Licensee may make of the Joint Results or
other licensed informatioo _ a disdaimer as to any representations andor warranties in respect of the Joint Results their potential
use exploitability andor that it does npt infringe third partys rigbts _ the license agreement may not be sublicensed transfetted or assigned without the prior written
consent of the Joint Owners - financial terms in retum for the license agreement the Joint Owners sball get financial retum as
royalties (m the form of percentage from sales) part of any consideration other than from sales received in connection with a grant of sub-license an annuallicense fee and an equity (in start-up companies) The exact mixture of the above and the terms securing it will be negotigraveated
_ specific undertakings of commercialization of the licensee (such as but not limited to achieving milestones for developing and sale of the products (to avoid shelving of the technology) receiving prior approval before the grant ofany sub-license etc)
- limitation on the use of the names of the Inventors CNRS Lille 1 Sapienza NEUROMED and their employees
paymentreimbursement of past and future patent expenses by the licensee - patent prosecution and maintenance shall be done by the Adrninisttator
Notwithstanding anything to the conttary herein in the event that a potentigraveallicensee rejects any of the above terms the Joint owners sball in good faith seek solutions that will be subject to ali Joint Owners written approval to be advised timeously and not to be unreasonably withheld
Licensmg agreements shall require signature of ali Jomt Owners
The Adrninisttator shall ttansfer to the Jomt Owners their share of the royalties from the license granted over the Result(s) according to their share in the Result(s) after having deducted the Adrninisttators commercial development fees capped at 10 of said royalties For the avoidance of doubt research funding received from a licensee by either Party shall not be regarded as payment from commercialization of the Invention andor the Patents
TITLE V - MISCElLANEOUS PROV1SIONS
Article 15 - Renewal
This Agreement may be renewed once for a second term of foUI (4) years by amendrnent executed by the Parties following a decision by the Parties on advice from the Steering Committee the relevant evaluating bodies of the Parties and the LlA Co-directors
Artide 16 - Modification - Membership
All modifications to the present Agreement require the mutuaI consent of all Parties by Amendrnent
All additions of members to the LIA including that of a new laboratory of one of the Parties require the unanimous consent of the Steering Committee
Any adrnissIgraveon of a new laboratory under the authority of a Party requires the update ofAnnexes m particular Annexes 2 and 3 to be provided by the Co-directors to ali Parties
The addition of new parties to the ilA shall require an amendrnent to this Agreement All adrnissIgraveon amendments to this Agreement shall be signed by the new parties and CNRS authorized by this Agreement to so act on behalf of the other Parties The sole purpose of an adrnission amendrnent is to join new Parties to the LIA It in no way modifies the scope of the presegravent Agreement
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
UAPSND
Article 17 - Cancellation
In the event of an unresolved dispute the Parties following consultation with the Steering Cornrnittee and the LlA Co-directors may mutually consent to canceling the present Agreement before the expiration of its term upon six (6) months notice In such a case the Parties shall eoncludejoint acttons undertaken prior to norice given
Tbe decision to caneel shall be taken by the Parcles following consultanon with the Steecing Committee and the LIA Co-directors
The withdrawaI of a Party prior to term notified to the other Parties with S1x months norice shall terminate the present Agreement
Non-disclosure publication intellectual property and exploitation provisions shall continue to apply for their respecttve terms
Artide 18 - Internai commumcation between Parties
Internai commurucation between Parties shall be done in writing (registered letter with acknowleclgement of receipt sent via postal or eIectronic means facsimile etc)
The names and addresses are the followmg
atCNRS
Dr Florence NobIe Deputy Scientific Director INSB 3 me Michel-Ange 75794 Pans ceda 16 France TeI +33 1 44 96 45 85 Fax +33 144964927 e-mail flotencenoblecnrs-dirfr
at Uruversity of Lille l
Pro Philippe Rollet President Citeacute Scientifique 59650 Villeneuve dAscq France TeI +33 (0)3 20434301 Fax +33 (0)3 2043 43 58 e-mail philipperolletuniv-liIlelfr
at Sapienza
Pro Luigi Frati President Piazzale aldo Moro 5 00185 Rome Italy TeI +39 064958568 e-mail luigifratiuniromalit
atNeuromed
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
__1LJr
LlAPSND
Pro Erberto Melaragno Via Atinense 18 94038 Pozzilli (lS) ltaIy Tel +39 08 65 929636 e-mail euprojectsneuromedit
Artide 19 - Liability
Each Party remains liable without right of action against the other Parties except in case of gross or intentional negligence for repairing damage to igravets own property dwing and owing to the igravemplementation of this Agreement Should damage be caused to physical assets acquired by the Parties under this Agreement the latter shall pay repair or replacement charges for said assets on a pro rata basis of their respective financial contrigravebutions to the acquisigravetion thereof According to the rules of ordinary law each Party is liable for damage 10ss of any natwe caused to thigraverd parties dwing the igravemplementation of this Agreement
Artide 20 - Finai provisions
The Parties undertake to settle their disputes out of court Failing that disputes arising out of or in connection with this Agreement which cannot be solved amicably shall be finally settled under the Rules of Arbitration of the lntemational Chamber of Commeree by one arbitrator appointed in accorrlance with thesaid Rules The pIace of arbitration shall be Paris or Rome at the defendants totaI discretion
Done in 4 (Cour) originai copies
Lille on the 9th of October 2013
The National Center ofScientific Research The Sapienza University of Rome
Alain Fuchs Luigi FratiL n r A President President ~ tt-( ~-
By delegation Franc Pattus Deputy Director Institute of Biologicai Sciences
University ofLiDe 1 Neuromed
Erberto Melar President
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
ANNEXl
RESEARCH PROGRAM AND INDIVIDUAI PROJECTS
Prenatal stress and neurological disorders (PSND)
Prenatally restraint stressed (PRS) rats (ie the adult offspring of mothers exposed to chronicrestraint ~tr~ss during pregnancy develop a pathological epigenetic programming that mainly targets syna~t1c transffi1S~lOn and plasticity in hippocampus and striatum Alterations induced by PRS comp~se an a~xlOus depressiveprofile related to a dysfunction of the hypothatatno-p~tuitary~adren~ ax1S ~ disorgaruzat1~n of circadian rhythms and the sleep-wake cycle an age-dependent lmpamnent ID spatiallearrung and reductlon of bippocampal neurogenesis With this purpose we opened ~e ~DRE with the lecture of Pr F Turek Wlth whom S Maccaris team has collaborated for long cime on orcadianrhythms and related mood disturbances
We have proven evidence of the validity of PRS as a model of epigenetic programming that recapitulates some aspects of depression Chronic treatment with different classes of antidepressants (imipramine tianeptine or agomeiatine a novel antidepressant that behaves as a mixed MT1MT2 melatorun receptor agonist5-HT2c serotorun receptor anragonist) reversed biochetnical and behavioural changes including anxietydepression and sleep alterations (Morley-Fletcher et al 2011 Mairesse et al 2012) Abnormalities of synaptic transtnission and plasticity in the hippocampus represent an integra part of the altered progtamming triggered by early life stress We have also shown that glutamate transtnission in particular at the levels of metabotropic glutamate receptors mGlu 23 and mGlu5 is persistently impaired by PRS since infancy (Laloux et al 2012) that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress (Matrisciano et al 2011) A very recent study of our GDRE (Marroccoet al ]oumal ofNeuroscience 2012) shows that an impairment of glutamate release in the ventral hippocampus is a key component of the neuroplastic program induced by PRS and that strategies aimed at enhancing glutamate release in the ventral hippocampus correct the anxious phenotype caused byearly life stress
Prenata restraint stress (PRS) in rats programs the offspring to develop a pathological behavioral phenotype associated with abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis (Damaudery and Maccari 2008) Chronic systetnic treatment of PRS rats with the oxytocin receptor agonist carbetocin normalized the HPA response to a mild stress and the related changes in the expression of corticosteroid receptors in the hippocampus Ali pathological behaviors of PRS rats (anxiety- and depressive-like behavior and impaired social behavior and social memory) were corrected by carbetocin treatment The negative correiation between anxiety-like behavior and social behavior in the entire cohort of rats suggested that reduction of anxiety lies at the core of the therapeutic effect of carbetocin in PRS rats Carbetocin treatment also corrected the defect of depolarization-evoked glutamate release in ventral hippocampal synaptosomes of PRS rats a neurochetnical parameter that showed a tight correlation with both anxiety and social behavior Remarkably carbetocin had little if any effect in unstressed control rats suggesting that its action was disease dependent (Mairesse et al subtnitted) Thus at least in this particular setting activation of oxytocin receptors had no impact on normal brain functiorung but corrected the pathological program induced by early life stress Activation of oxytocin receptors in the SNC is a new potential strategy in the treatment of psychiatric disorders lnvolving emotions and social behavior These data strongly encourage the use of oxytocin receptor agonists in the treatment of stress-related disorders
Very recently joint research indicates that PRS can induce a latent state of parkinsonism r31SIDg the interesting possibility that this pathology can be programmed by stressful events occurring in early life Parkinsons disease is a disorder of the brain characterized by slowness of movement and locomotion (bradykinesia rigidity and tremor) It is one of the most common nervous system disorders of the elderly Parkinsons disease has an incidence of about 50000 new cases per year in the US The average age of clinical onset is about 60 Dopamine is lnvolved in the controi of motor programming Parkinsons disease occurs when the dopatninergic neurons are slowly degenerated Depletion in dopamine alters nigro-striatal motor pathway This leads to a deep alteration of motor planning The damage gets worse over rime Nowadays the reasons of this important cell death are poorly known To investigate the possible causes of
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
UAPSND
vulnerability to Pruldnsons disease we stUdied the effect of PRS in rats on dopamine neurons This animal mode has been proven for the study of brain adaptation occurring in response to eruly life stress Male adult PRS rats (Le the adult offspring of mothers exposed to repeated episodes of restraint stress during pregnancy) showed impainnent in behavioral tests (active avoidance the grip strength test and the pastashymatrix) that reflect the function of the rugro-striatal motor activity Remarkably PRS rats showed a mruked reduction in dopamine release within these brain regions OUI studies suggest that eruly life events can induce changes in the dopaminergic motor system during the adult life affecting behavior and neurochemical transmission These reseruches also highlight the importance to detect the early signs of a latent palcinsonism Indeed subject at risk to develop Prukinsons disease could undergo clinical analysis of the dopaminergic system (ie by PET staining with 18F-DOPA) to establish whether they can benefit of neUIoprotective drugs despite the lack of motor symptoms Finally the identiJication of risk factors for Parldnsons disease may be of great help for the selection of patients that rue eligible to an early neuroprotective tteatment Furthermore we would like to extend OUI reseruches higraveghlighting mechanisms of neuroprotection that can be altered in Alzheigravemers bramo Among the risk factors that might increase the vulnerability to develop Alzheigravemers disease glucose metabolism impairments have a predominant role We will focus on a post-ttanslational glycosylation that is directly dependent on the neuronal ability to metabolize glucose O-linked Nshyacetylglucosaminylation (O-GlcNAc) Triggering O-GlcNAc dynarnics may pave the way for a generation of new therapeutic sttategies against AD
These results pave the way of reseruch project of the PSND French-ltalian associated laboratory based upon the ex~hanges with and thc expertise of the ltalian Partner Pro Ferdinando Nicoletti (Sapienza UruversltyNEU~tO~D InStltute) and French Partner Pro Stefania Maccari (University of Lille 1 UMR 8576 CNRS) Wlth this purpose GDRE has been clotured and opened to ilA with the lecture of Pr McEwen in the last October 2012 in New Orleans with whom S Maccaris and F Nicolettis teams collaborate since a long rime on stress induced alterations in brain
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
llAPSND
ANNEX2
bull COMPOSITION OF TRE LIA AS OF JANUARY 12013
UAMembers
COUNTRY INSTITUTION ABORATORYTEAM PERSONNELTITLE
Ptrmanent
Stefania MACCARI Pro Lillel
Sara MORLEY-FLETCHER MdC Ullel
Gilles V AN CAMP MdC Lille 1
Hammou BOUWALERH lE Lille 1
Temporary
Francesco MA TRISClANO MD PhD
Jerome MAIRESSE PostDoc
JOldan MARROCCO PostDoc
Marie-Line REYNAERT PhD student
Eleonora GATTA PhD student
Lucie DERUYTER Technician
FRANCE CNRS and Lillel UMR8576
Neuroplasticity Team
ITALY Sapienza
and
Neuromed
Psychophatmacology GIOUp
and
Labotatory of Molecular NeuroPhatmacology (MNP)
Permanml
Fetdinando NICOLETTI Pro
Valeria BRUNO Pro
Temporary
Giuseppe BATTAGLIA CR
Richatd Teke NGOMBA CR
Carla BUSCETI CR
Francesca BIAGIONI PostDoc
Milena CANNEUA CR
Gemma MOLINARO PostDoc
Composition oEtbe UA PSND SciendBc Advisory Board
INSTITUTIONLABORATORIES NAME CITY COUNIRY
CNRS - Collegravege de France Franccedilois TRONCHE Pans France
CNRS Bernud BIOULAC Bordeaux France
Rockfeller University I Bruce MCEWEN New York City USA
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
Leiden University RonDEKLOET Leiden the Netherlands
Consiglio Nazionale delle Ricerche Anna MOLES Romeltaly
(CNR)
I University oCMilan Maurizio POPOLI Milanltaly
Composition oE tbe LlA PSND Steeting Committee
l INSTITUTION TlTLE NAME FUNCTION CITY COUNrRY
CNRS - Dr Catherine JESSUS Director oflNSB Paris France
Lille 1 - Pro Philippe ROllET President Lille France
Sapienza - Pro Luigi FRATI Rector RomeItaly
Neuromed - Pro Erberto MELARAGNO President Pozzilli (lS) ltaly
President for the first turo-year mandate
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
i
LIAPSND
ANNEX3
CONSOUDATED PROJECTED BUDGET FOR 2013
A Specific aUocations for the LIA PSND
Tbe UA P SND rhall be supported IY tbe ahcation oJearmarkedfinancia contribution ofeacb ParY mainy devoted fo cover mobiliti expenres (rhort-term rtqyr and meeting) in additioTJ fo otber rerourns fa wbich tbe relevant rerearcb teams bave accef
AMOUNT (euro or FIE)TYPE OF RESOURCESLABORATORYCOUNTRY IINSTITUTlON ALLOCATED TO THE
LIAPSND TEAM
bull Total amount 15000 euroSpecific funding Team neuroplasticity UMR8576CNRSFrance
Total amount 10000 euroSpecific funding i Team neuroplasticity
UMR8576Lille1
Total amount 2000 euro Group
Specific funding PsychophatmacologySapienzaItaly
T otal amount 15000 euro N euroPhatmacology (MNP)
Specific funding Laboratory of MolecularNeuromed
i i
Additionalspeagraveflcfund sueh as co-spmIised PhDfundin~ inuited professorpositions Master rtutUnlsfondin~ subjea lo annua tendNs
B Preexisting staamp effort devoted to the LIA PSND
TYPE OF RESOURCES AMOUNT (FIE)I COUNTRY I INSTITUTlON LABORATORY ALLOCATED TO THE LIAi I TEAM
Lille 1 UMR8576 Laboratofy Statr Neuroplasticity Team
France
Permanenl RMeorccedilhm 1 Technicianr 02
Non-pmttantnl PhDrtmktJ 09 PbD SfIItknt MD 03 Port-Docs 06
i Tebniagraveon 1I Sapienza Psycbopharmacology Laboratory Statr
Group ItaIy
bull 075i Permanenl
Neuromed Laboratory of Moleltular Laboratory Star NeuroPharmacology l
NonptrmtJnent(MNP) 08RtrtanhersI1 03Post-Doa I I
The st4Jing need ~the LL4 an cakulated based on the full lime equivalent (FTE) IJ its memberr
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIA PSND
ANNEX4
FACILITIES ANO EQUIPMENT
France
CNRS-Lille 1 - UMR 8576
Behavioural and proteomic platfonns
Italy
Sapienza
Psychopharmacolgy platfonn
Neuromed
Molecular neuropharmacology platform
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None
LIAPSND
ANNEX5
PROPRlETARY RESULTS EXCLUDED FROM THE PURPOSES OF ilA PSND
France
None
ltaly
None