Document:

Exhibit 10.14

 

Confidential Materials omitted and filed separately with the 
 Securities and Exchange Commission.  Double asterisks denote omissions.

 

	    

    	
 
    
	
 
    	
 
    
	
INSTITUT PASTEUR
    	
(1)
    
	
 
    	
 
    
	
and
    	
 
    
	
 
    	
 
    
	
AMSTERDAM MOLECULAR THERAPEUTICS (AMT) BV
    	
(2)
    
	
 
    	
 
    
	    

    	
 
    
	
 
    	
 
    
	
DEVELOPMENT and MANUFACTURING
    	
 
    
	
AGREEMENT
    	
 
    
	
 
    	
 
    
	    

    	
 
    

 

 

 

THIS DEVELOPMENT AND MANUFACTURING AGREEMENT (this “Agreement”) is effective as of January 7th, 2011 (“Effective Date”).

 

BY AND BETWEEN

 

ON THE ONE HAND

 

(1)                                 INSTITUT PASTEUR a non profit private foundation organized under the laws of France with offices at 25-28 rue du Docteur Roux, 75 724 Paris Cedex 15, France, VAT FR 65 775 684 897 (“Institut Pasteur”), acting herein in the name and behalf of the Consortium (“Consortium” and each designated individually as “Consortium Member”) which has been organized under an agreement by and between the following members:

 

L’INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE, Etablissement Public à caractère Scientifique et Technologique, organized under the laws of France, having its principal offices at 101 rue de Tolbiac, 75013 Paris, (“INSERM),”

 

INSERM TRANSFERT, Société Anonyme, organized under the laws of France, registered under RCS Paris n° 434 033 619 having its principal offices at 7, rue Watt - 75013 Paris, (“INSERM-TRANSFERT”),

 

L’ECOLE NATIONALE VETERINAIRE ET DE L’AGROALIMENTAIRE ET DE L’ALIMENTATION DE NANTES ATLANTIQUE, centre d’expérimentation sur l’animal en thérapie génique et cellulaire, organized under the laws of France, having its principal offices at Atlanpole - La Chantrerie - 44 307 NANTES, (“ONIRIS”),

 

INSTITUT PASTEUR a non profit private foundation organized under the laws of France with offices at 25-28 rue du Docteur Roux, 75 724 Paris Cedex 15, France, VAT FR 65 775 684 897 (“INSTITUT PASTEUR”),

 

L’ASSOCIATION FRANCHISE CONTRE LES MYOPATHIES, l’Association Française contre les Myopathies, an association governed by the law of July 1, 1907, reconnue d’utilité publique de droit privé, organized and existing under the laws of France, having its principal office at l’lnstitut de Myologie, 47-83 boulevard de l’Hôpital, 75651 Paris Cedex 13, (AFM)

 

(“the Consortium represented herein by “Institut Pasteur”)]

 

And

 

ON THE OTHER HAND

 

(2)                                 AMSTERDAM MOLECULAR THERAPEUTICS (AMT) BV a company incorporated under the laws of the Netherlands, with offices at P.O.Box 22506 - 1100 DA Amsterdam, The Netherlands, (“AMT”).

 

(each, a “Party” and together the “Parties”)

 

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BACKGROUND:

 

(A)                               Sanfilippo Syndrome IIIB (“Sanfilippo B”) is a lysosomal storage disorder caused by a deficiency of the enzyme a-N-acetylglucosaminidase (NaGlu), resulting in a severe degenerative pathology of central nervous system.

 

(B)                               Institut Pasteur, acting herein in the name and behalf of the Consortium which has been organized to execute a program of research and development relating to Sanfilippo B, according to an agreement by and between INSTITUT PASTEUR, INSERM, INSERM-TRANSFERT, ONIRIS and AFM.  In this context, Institut Pasteur intends to carry out Phase I/II and Phase II/III clinical trials for the gene therapy treatment of Sanfilippo B with Product (as defined below) that has been manufactured by AMT in accordance with AMT’s proprietary manufacturing technology.

 

(C)                               This Agreements sets out the terms and conditions on which AMT will develop the manufacturing process for the Product and supply one or two clinical Batches to Institut Pasteur.

 

IT IS NOW AGREED AS FOLLOWS:

 

1                                         Definitions

 

1.1                               The following capitalized terms, whether used in the singular or plural, shall have the meanings assigned to them below for purposes of this Agreement:

 

1.2                               “Acquisition Cost” means the actual price paid by AMT to any Third Party (net of any discounts, rebates, credits or the like) for any Raw Materials, Consumables, Wearables used in the manufacture of the Product under this Agreement, plus [**] percent ([**]%) of such actual price to cover AMT’s acquisition and storage costs for such materials together with all shipping and handling costs and customs duties incurred and paid by AMT to that Third Party in connection with the acquisition of such materials.

 

1.3                               “Additional Services” means any service that is not contained in this Agreement and that requires a Change Order according to Section 3.6(c) in order to authorize AMT to commence the same or any service specifically identified as an Additional Service in this Agreement, for which the Parties will determine in good faith the amount to be paid for the performance of such Additional Services according to the prices specified in Exhibit A.

 

1.4                               “Affiliate” means, with respect to either Party, any other corporation or business entity that directly, or indirectly through one or more intermediaries, controls, is controlled by or is under common control with such Party.  For purposes of this definition, the term “control” means direct or indirect ownership of more than fifty percent (50%) of the securities or other ownership interests representing the equity voting stock or general partnership or membership interest of such entity or the power to direct or cause the direction of the management or policies of such entity, whether through the ownership of voting securities, by contract, or otherwise.

 

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1.5                               “AMT Confidential Information” means the MPR, the Batch Disposition Documentation, any Manufacturing Documentation, the Manufacturing Information, the AMT Background Information and all elements of the Manufacturing Process provided from time to time by AMT to Institut Pasteur together with all technical and other information, whether patented or unpatented, relating to the AMT Facility and/or AMT processes, methods, operations, technologies, forecasts and business information and all other data and information that is disclosed or supplied to, or used on behalf of, Institut Pasteur by AMT pursuant to this Agreement, or of which Institut Pasteur may become aware through the presence of its employees or agents at AMT offices or at the AMT Facility, including, without limitation, trade secrets, know-how, processes, concepts, experimental methods and results and business and scientific plans and information and facility layout.  All portions of documents and records describing or relating to AMT Intellectual Property shall be deemed to be AMT Confidential Information.

 

1.6                               “AMT Facility” means the facilities operated by AMT at Meibergdreef 45 and 61, 1105 BA Amsterdam, The Netherlands.

 

1.7                               “AMT Background Information” means all technical know-how and information known to AMT and all AMT Intellectual Property (including all AMT Confidential Information) (a) which is incorporated into the Manufacturing Process, or (b) that is necessary to the practice of the Manufacturing Process and/or for the utilisation of the Deliverables.

 

1.8                               “Batch” means a specific quantity of Product or other material produced from a single Run.

 

1.9                               “Batch Disposition Documentation” means the following documentation associated with the production and testing of a given Clinical Batch: batch production records, Release Statements, the Certificate of Analysis and the Certificate of Compliance.  Such documentation shall be deemed to be AMT Confidential Information disclosed to Institut Pasteur pursuant to Section 17, except under the provisions of Sections 11.8 and 14.3.

 

1.10                        “Certificate of Analysis” means a document prepared by AMT listing in relation to each Batch the tests performed by AMT or approved Subcontractors, the specifications and test outcomes.

 

1.11                        “Certificate of Compliance” means a document prepared by AMT:  (i) listing the manufacturing date, unique Batch number, and quantity of Product in such Batch, (ii) certifying that such Batch was manufactured in accordance with the Master Production Record and cGMP and (iii) certifying that all Investigative and Corrective Action Reports are completed and approved.  The Parties shall from time to time agree upon a format or formats for the Certificate of Compliance to be used under this Agreement.

 

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1.12                        “cGMP” means the regulatory requirements for current good manufacturing practices in EC Directives 2003/94/EC and 2005/28/EC, as applicable to the responsibilities specified in the Quality Agreement, the agreed upon Project Plan or this Agreement, as well as any applicable ICH (International conference on harmonization) guidelines, as well as any additional regulatory agency requirements needed to seek registration in the EU, such as Part II of Volume IV of the EU Guide to Good Manufacturing Practice, as any of the foregoing may be amended from time to time and anything which replaces or supersedes the same from time to time.

 

1.13                        “Change Order” means a document mutually approved in writing by both Parties in accordance with the procedures set forth in Section 3.6 that describes in detail an amendment or modification to the Project and/or the Project Plan.

 

1.14                        “Clinical Batch” means a Batch product from a Clinical Run.

 

1.15                        “Clinical Run” means a Run manufactured in accordance with the Master Production Record and cGMP and used to create Product for use in human clinical trials.

 

1.16                        “Confidential Information” means Institut Pasteur Confidential Information and/or AMT Confidential Information, as the context requires.

 

1.17                        “Conforming Product” means Product that conforms to all of the warranties set forth in Section 15.2(c).

 

1.18                        “Consumable” means all bags, liners, filters, membranes and other single use or regularly replaced materials that are required to perform the Manufacturing Process (excluding Raw Materials and Wearables) in accordance with this Agreement.

 

1.19                        “Deliverables” means all or any of the deliverables set out in Exhibit A and “Deliverable” has a cognate meaning.

 

1.20                        “Delivery Dates” means the dates under which the Deliverables have to be transmit to Institut Pasteur according to the Exhibit A.

 

1.21                        “Development Batch” means a Batch produced from a Development Run.

 

1.22                        “Development Run” means a Run performed in accordance with the Master Production Record and any approved validation protocol(s) to confirm and/or to document the operability and reproducibility of the Manufacturing Process at the AMT Facility.

 

1.23                        “EMA” means the European Medicines Agency or any successor agency thereto or replacement thereof, whether in whole or in part.

 

1.24                        “Governmental Authority” means any national, multi-national, regional, state or local regulatory agency, department, bureau, or other governmental entity.

 

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1.25                        “Institut Pasteur Background Information” means all technical know-how and information known to Institut Pasteur and all Institut Pasteur Intellectual Property (including all Institut Pasteur Confidential Information) and in particular any and all scientific, technical or test data including research data, clinical pharmacology data, chemistry, manufacturing and control data (analytical and quality control data, stability data), preclinical data and clinical data relating to the Product.

 

1.26                        “Institut Pasteur Change Request” means a AMT document used to accomplish amendments and modifications to documents which are part of AMT’s cGMP document system, including but not limited to MPRs, standard operating procedures and Materials Specifications.

 

1.27                        “Institut Pasteur Confidential Information” means any clinical data and information, business plans, regulatory and Product strategies and all technical and other information, whether patented or unpatented, relating to Institut Pasteur processes, test methods, operations, technologies, formulations, forecasts and business information, Institut Pasteur Background Information and all other data and information that is disclosed or supplied to AMT by or on behalf of Institut Pasteur pursuant to this Agreement, and/or that is produced by AMT for the Institut Pasteur in the performance of this Agreement.

 

1.28                        “Intellectual Property” means all Patents, copyrights, rights in and to databases, rights in and to trade secrets and know-how and all other intellectual property rights that are owned or controlled by a Party, including all applications and registrations with respect thereto, and all rights to apply for the same, in each case subsisting at any time anywhere in the world.  For purposes of this Section 1.30, “controlled by” means possession of the any and all rights to grant a license or sublicense.

 

1.29                        “Investigative and Corrective Action Reports” or “ICAR” means the document that is used to record the investigation of, as well as the review and disposition of, a failure related to a cGMP manufacturing process or system.

 

1.30                        “Manufacturing Documentation” means all documents and records describing or otherwise related to the Manufacturing Process, other than those embodied in the Master Production Record.

 

1.31                        “Manufacturing Process” means the production process for the manufacture of Product developed by AMT pursuant to this Agreement.

 

1.32                        “Master Production Record” or “MPR” means the document, proposed by AMT and subsequently approved in writing by Institut Pasteur.  The AMT proposed document, or revisions thereto, will be approved by signature and dating by at least one representative of AMT’s quality unit and will be prepared in accordance with Section 6.41 of Volume 4 of the “EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Part II, Basic Requirements for Active Substances used as Starting Materials”, and which specifies:

 

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(a)                                 The name of the Product being manufactured and an identifying document reference code; and

 

(b)                                 A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics; and

 

(c)                                  A complete set of raw material specifications listing specific methods used for confirming compliance with specification; and

 

(d)                                 A complete list of resin, filtration membranes, filter cartridges etc., designated by names or codes sufficiently specific to identify manufacturer, type and/or model, as appropriate; and

 

(e)                                  An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure.  Where the quantity is not fixed, the calculation for each batch size or rate of production should be included.  Variations to quantities will be included where justified; and

 

(f)                                   The production location(s) and production equipment to be used, including the;

 

(i)            The unique identification number of the production location(s) (for example - suite/room numbers, laminar flow cabinets etc.); and

 

(ii)           The unique identification number of each production piece of equipment to be used; and

 

(iii)          Confirmation of the production equipment’s approved calibration status; and

 

(g)                                  Detailed production instructions, including the:

 

(i)            Sequences to be followed; and

 

(ii)           Initial process set-point and acceptable operating ranges of all processing parameters to be used; and

 

(iii)          Sampling instructions for in-process control samples, in-process control methods with their acceptance criteria where appropriate; and

 

(iv)          Time limits for completion of individual processing steps, hold times and/or the total process time limit, where appropriate; and

 

(h)                                 Detailed finished Product Release Specification testing instructions, including the:

 

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(i)            Sampling instructions and Release Testing Specifications indicating the release acceptance criteria; and

 

(ii)           Release Testing methods; and

 

(i)            Where appropriate, special notations and precautions to be followed, or cross references to these; and

 

(j)                                    Instructions for the storage of the Product and isolated intermediate products (for example - Inclusion Bodies) to assure their suitability for use, including the labelling and packaging materials and special storage conditions with time limits and hold times, where appropriate.

 

1.33                        “Material Safety Data Sheet” means a data sheet which contains information on the chemical, physical, and toxicological properties of a potentially hazardous product and recommendations for proper handling, storage, disposal, and emergency response.

 

1.34                        “Materials Specification” or “MS” means a document detailing the specifications for each Raw Material or Consumable, each as mutually approved by the Parties in writing.

 

1.35                        “NDA” means a new drug application for the Product, or any equivalent filing thereto, including, without limitation, a biologies license application filed with the FDA, a marketing authorization application filed with the EMA, or any equivalent application filed with Health Canada, and any supplements or amendments to any of the foregoing.  The NDA shall also include equivalent filings in such other jurisdictions as the parties mutually agree upon in writing pursuant to a Change Order.

 

1.36                        “Non-Conforming Product” means Product that fails to conform to all of the warranties set forth in Section 15.2(c) and “Non-Conformity” shall have a cognate meaning.

 

1.37                        “Patents” shall mean, with respect to an invention, any patent or patent application, and any patent issuing therefrom, together with any extensions, reissues, reexaminations, substitutions, renewals, divisions, continuations and continuations-in-part thereof, and any patent or patent application claiming priority from any application in common with any such patent containing a disclosure substantially similar to that of any such patent, all to the extent the foregoing contain claims covering such invention.

 

1.38                        “Pre-Process Development” shall mean tasks associated with defining ranges, conditions and criteria to be used in Process Development.

 

1.39                        “Process Development” shall mean the demonstration, through Development Runs, that the Manufacturing Process is operable as defined.

 

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1.40                        “Product” means the AAV5 vector-based gene a-N-acetylglucosaminidase (NaGlu) therapy for the treatment of Sanfilippo B disease

 

1.41                        “Project” means the full range of manufacturing and other services to be provided by AMT under this Agreement.

 

1.42                        “Project Plan” means the scope of work for development and manufacturing and overall project scope, together with the allocated costs payable by Institut Pasteur attached as Exhibit A hereto and hereby incorporated into this Agreement, as may be updated from time to time by the Parties mutually agreeing in writing to adopt a revised version.

 

1.43                        “Quality Agreement” means the quality criteria to be agreed between the Parties which, when executed by the Parties, shall be incorporated into this Agreement as an Exhibit C.  The Quality Agreement shall not be an Additional Service.

 

1.44                        “Quality Review and Approval” means AMT’s review and approval in accordance with cGMP, by AMT’s quality assurance department, of a Batch and the associated Batch Disposition Documentation.

 

1.45                        “Raw Material” means all ingredients, solvents and other components of the Product in the amounts required to perform the Manufacturing Process (excluding any Consumables and Wearables) in accordance with this Agreement.

 

1.46                        “Reference Materials” means Product that is generated from a Run that is well characterized, packaged and stored in a controlled manner, and used as a standard or reference for analytical testing purposes.

 

1.47                        “Regulatory Authority” means any or all of the FDA, the EMA and/or Health Canada and any body or bodies which may replace or supersede the same from time to time whether in whole or in part.  “Regulatory Authority” shall also include equivalent bodies in such other jurisdictions as the parties mutually agree upon in writing pursuant to a Change Order.

 

1.48                        “Regulatory Filing” means any or all applications, submitted to Regulatory Authorities for the purpose of registering the Product or the Manufacturing Process as required by statute, and any amendments or supplements thereto, and any other filings required by the Regulatory Authorities relating to the manufacture, testing, sale or distribution of the Product, including, without limitation, an NDA.

 

1.49                        “Release Specification” means in respect of the Product, the document to be agreed by the Parties listing tests to be performed by AMT or approved Subcontractors and the acceptance criteria for these tests such criteria to be based on the “Tentative Acceptance Criteria” set out in Exhibit A.

 

1.50                        “Release Statements” means a document prepared by AMT that provides confirmation that Product has met its assigned Release Specification(s).

 

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1.51                        “Results” means know-how, ideas, results, concepts, materials, works, inventions and discoveries that are made, conceived, reduced to practice or developed in the course of performing under or resulting from this Agreement by AMT or its employees, Sub-contractors or agents, but expressly excluding the Institut Pasteur Background Information, the Institut Pasteur Intellectual Property, the AMT Background Information and the AMT Intellectual Property.

 

1.52                        “Run” means a single complete operation of all, or a discrete portion of, the Manufacturing Process at the AMT Facility.

 

1.53                        “Shipping Guidelines” means AMT’s written procedures, as approved by Institut Pasteur in writing, that describe the methods of packaging, preserving, monitoring and shipping, any and all Institut Pasteur property, including the Product.

 

1.54                        “Storage Guidelines” means AMT’s procedures, as approved by Institut Pasteur in writing, that describe the methods of packaging, preserving, monitoring and storing any and all Institut Pasteur property, including the Product.

 

1.55                        “Subcontractor” means any Third Party that AMT contracts with to perform any services or meet any obligations that are required under the terms and conditions of this Agreement.

 

1.56                        “Third Party” means any person other than Institut Pasteur (and consequently any person other than the membres of the Consortium : INSERM, INSERM-TRANSFERT, ONIRIS, AFM) or AMT.  Genethon is a Third Party.

 

1.57                        “Waste” shall mean any waste material, pollutant and/or contaminant of any kind including, without limitation, any routine process waste or any by-product arising from any activities conducted pursuant to this Agreement.

 

1.58                        “Wearables” means any non-sterile coverings or protective gear used by AMT employees or agents in the course of the performing the development and manufacturing services hereunder, including without limitation gloves, coveralls, booties, eye shields and the like.

 

1.59                        “Working Day” means any day on which clearing banks are open for business in the Netherlands and France provided that any reference to a “day” shall be a calendar day.

 

1.60                        Each of the following definitions are found in the body of this Agreement, or elsewhere, as indicated below:

 

	
Defined Term
    	
 
    	
Section
    
	
Agreement
    	
 
    	
Preamble
    
	
Institut   Pasteur
    	
 
    	
Preamble
    
	
AMT
    	
 
    	
Preamble
    
	
Delivery   Sample
    	
 
    	
15.3(a)
    
	
Development
    	
 
    	
2.1
    

 

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Disputed   Matter
    	
 
    	
21.1
    
	
Effective   Date
    	
 
    	
Preamble
    
	
Executive   Oversight Committee or EOC
    	
 
    	
3.2
    
	
Expert   Determination
    	
 
    	
13.2
    
	
Force   Majeure Event
    	
 
    	
20.1
    
	
Manufacturing   Information
    	
 
    	
11.8
    
	
Notified   Party
    	
 
    	
17.6.1
    
	
Notifying   Party
    	
 
    	
17.6.1
    
	
Parties
    	
 
    	
Preamble
    
	
Party
    	
 
    	
Preamble
    
	
Patent   Claim
    	
 
    	
14.5
    
	
Project   Manager
    	
 
    	
3.2
    
	
Referral   Notice
    	
 
    	
21.2
    
	
Registration
    	
 
    	
11.1
    
	
Replacement   Product
    	
 
    	
13.3
    
	
Term
    	
 
    	
19.1
    

 

2                                         Development and Manufacture; Purchase; Property Decisions

 

2.1                               Process Development and Assay Development.  Subject to the terms and conditions set forth in this Agreement, during the Term, Institut Pasteur hereby retains AMT to, and AMT shall use commercially reasonable efforts, to perform the Process Development and Assay Development (together, the “Development”) of the Manufacturing Process in accordance with this Agreement and Exhibit A, at the AMT Facility, and Institut Pasteur shall pay AMT for such Development work, all in accordance with this Agreement as set out in the Project Plan.  Institut Pasteur shall pay AMT for such Development services in accordance with Exhibit A and Article 8.

 

2.2                               AMT shall carry out the Development as defined in the Project Plan with reasonable skill and care and no less than the level of skill and care to be reasonably expected of a provider of such services, and in compliance with all applicable laws and regulations including cGMP (if applicable).  For the avoidance of doubt, it shall not be considered a breach of this Agreement by AMT if any objective of the Project Plan is not achieved:

 

(a)                                 so long as AMT uses commercially reasonable efforts to perform its obligations; or

 

(b)                                 in relation to all stages of the Project Plan, due to delay caused or contributed to by Institut Pasteur.

 

2.3                               The Parties acknowledge that, having regard to the fact that the work to be performed hereunder is by its nature developmental, AMT does not guarantee to Institut Pasteur the achievement of a successful outcome for the objectives under

 

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the Project Plan, but will use commercially reasonable efforts to carry out such stages of the Project Plan and to ensure timely success.

 

2.4                               Manufacture.  Subject to the terms and conditions, AMT shall use commercially reasonable efforts to meet the agreed estimated timelines and Delivery Dates set forth in the Project Plan and shall manufacture the Clinical Batches within the scope of the Project Plan with reasonable skill and care and no less than the level of skill and care to be reasonably expected of a provider of such services, and in compliance with all applicable laws and regulations including cGMP (if applicable).  Institut Pasteur shall purchase such Clinical Batches from AMT in accordance with Exhibit A and Article 8.

 

2.5                               All right, title and interest on any and all works performed under this Agreement, and in particular the Clinical Batches and Results, to the exclusion of the Manufacturing Process, shall be owned by the Institut Pasteur upon payment for such works under Article 8.

 

2.6                               The steps of the Project Plan which shall be subject to go/no go decisions from Institut Pasteur, and in particular after the completion of each Batch are described in Section 3 and Exhibit A.

 

3                                         Project Plan; Project Management

 

3.1                               Project Plan.  In order to enable the Parties to fulfill their respective obligations under this Agreement, AMT shall implement and perform its obligations as set out in the Project Plan.  The Project Plan may be amended by agreement of the Parties in accordance with Section 3.6.  Adherence to the Delivery Dates set out in the Project Plan is contingent in part on each Party’s reasonably expedient turnaround of document reviews and approvals where such review and approval is necessary.

 

3.2                               Project Management; Appointments.  The day-to-day interactions and management with respect to the Project will be performed by two project managers, one appointed by each Party and each one having the authority to manage the Project in conjunction with the other project manager and to further the aims of the Parties day-to-day (each, a “Project Manager”).  As part of their duties, the Project Managers shall be responsible for monitoring and revising the Project Plan (in accordance with the procedures set forth in Section 3.6), establishing operating guidelines for the Project, defining communication formats, forming and approving Project teams and monitoring the general progress of the Project.  The Project Managers shall be appointed by each respective Party no later than [**] days following the Effective Date.  AMT shall not remove or replace its Project Manager, except where such person has left the employment, where such Person has taken a leave of absence, where such Person is out on disability or sick leave for more than a [**]-week period, or if institut Pasteur agrees in writing to such removal or replacement, without giving not less than [**] days notice in writing to AMT and subject to same skills.

 

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3.3                               Follow up meeting.  The Project Managers shall meet regularly to discuss any issues, problems or other matters, and as much as necessary but at least [**] times per year.

 

3.4                               The Parties shall appoint a committee in charge in particular of any Go/No Go decisions.  The committee shall be composed of members of both Parties, and shall meet regularly, at least [**] a year, and shall draft minutes of its meeting.  This committee shall take the Go/No Go decisions of any [major steps] of the services performed under this Agreement.  The decisions shall be taken by the committee, provided however that the final decision shall be taken by [**].  The committee may assign an expert in order to answer any questions relating to the services performed under this Agreement.

 

3.5                               The Project Managers will prepare minutes of the meeting within [**] Working Days of the meeting and distribute these minutes to the Parties for review and approval.  Either AMT or Institut Pasteur shall be deemed to approve such minutes if it does not object to them within [**] Working Days of submission of the relevant minutes.  In case of any problems, the management of each Party shall be consulted.

 

3.6                               Project Changes.

 

(a)                                 Project Plan Changes.  If at any time either Party is of the reasonable opinion that the Project Plan requires updating (otherwise than as a consequence of any breach of this Agreement by either Party), then such Party shall notify immediately in writing the other Party.  The Parties shall discuss and agree in good faith as soon as practicable, but in any event within [**] Working Days after receipt of such notice a revised Project Plan signed on behalf of each of the Parties.  Upon execution of the new Project Plan described above, the new timelines set forth therein shall govern.

 

(b)                                 AMT Initiated Changes.  Before AMT may amend the Project Plan, AMT shall prepare a Change Order describing in detail the nature of such change(s), and propose such Change Order to Institut Pasteur for Institut Pasteur’s review and written approval.  All approved Change Orders shall be approved by each Party only by signature by the Project Manager of each Party or by such other authorized representatives of AMT and Institut Pasteur that the Project Managers may designate in writing to the other Party.  If any changes contemplated by a Change Order will have a financial or other impact on the Project, AMT shall provide Institut Pasteur with a written description of such impact in the Change Order.  If Institut Pasteur approves the Change Order, Institut Pasteur shall pay AMT any additional charges as detailed in the Change Order.  Any such charge increase shall be priced on a milestone or time and materials basis, as mutually agreed upon by the Parties.  Upon AMT and Institut Pasteur’s approval of the Change Order, this Agreement shall be deemed amended in accordance with such Change Order.

 

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(c)                                  Institut Pasteur Initiated Changes.  Institut Pasteur shall have the right to request relevant modifications to the Project and/or the Project Plan by providing notice thereof to AMT.  Upon receipt of such notice, AMT shall generate a Change Order in accordance with the process described in Section 3.5(b), and submit such Change Order to Institut Pasteur for Institut Pasteur’s review and approval.  If Institut Pasteur approves the Change Order in accordance with Section 3.5(b), Institut Pasteur shall pay AMT any additional charges as detailed in the Change Order.  Upon Institut Pasteur’s approval of such Change Order, this Agreement shall be deemed amended in accordance with such Change Order.

 

4                                         Manufacturing and Processing Activities

 

4.1                               Quality Agreement.  The Quality Agreement shall be agreed and executed within [**] months following the Effective Date and shall specify certain testing, storage, release, cGMP, regulatory and other quality assurance requirements relating to manufacture and shipment of Product by AMT under this Agreement.  AMT shall comply with the Quality Agreement at all times in carrying out its obligations under this Agreement.

 

4.2                               AMT Facility.  All Products to be manufactured for Institut Pasteur hereunder shall be manufactured solely by AMT at the AMT Facility or by an AMT Affiliate if such AMT Affiliate is approved in writing by Institut Pasteur.  Any Affiliate proposed by AMT must be capable of manufacturing Product in accordance with cGMP, the Master Production Record, the Release Specification and the Quality Agreement.  AMT shall be responsible for all scheduling related to the manufacturing at AMT Facility or at AMT Affiliate facilities.  Without prejudice to the foregoing, AMT’s right to contract an Affiliate or a sub-contractor to manufacture Product is subject to AMT remaining, at all times, solely liable to Institut Pasteur for all of the Affiliate or sub-contractor’s activities and for any failure by such an Affiliate to comply with the relevant terms of this Agreement.

 

4.3                               Raw Materials and Consumables.

 

(a)                                 Procurement.  AMT shall be responsible for the procurement of all commercially available Raw Materials, Wearables and Consumables necessary for the manufacture of the Product.  AMT shall not be responsible for delays in the purchase and/or delivery of Raw Materials, Wearables and Consumables that occur despite AMT’s implementation of the foregoing procedures and despite AMT using commercially reasonable efforts to avoid such delays.  The cost of all Raw Materials, Wearables and Consumables that relate to activities included in the Project Plan are included in the sums payable by Institut Pasteur set out in the Project Plan.

 

(b)                                 Compliance with Release Specifications.  All Raw Materials, Wearables and Consumables used in the Manufacturing Process shall comply with the applicable Materials Specifications, or as otherwise agreed in writing by the

 

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Parties.  AMT or a Subcontractor approved in accordance with Section 4.5 shall perform testing and evaluation of the Raw Materials, Wearables and Consumables as required to meet the foregoing obligations.

 

4.4                               Storage and Use of Materials and Product.  All Raw Materials, Wearables and Consumables that are in AMT’s control and are to be used in the manufacture of Product, as well as all product (other than Waste) from the Manufacturing Process and Product in AMT’s control, shall be stored in accordance with the terms and conditions of the Storage Guidelines, the Material Specifications and/or the Master Production Record, or as otherwise mutually agreed in writing by AMT and Institut Pasteur.

 

4.5                               Approval of Subcontracting.  AMT shall not subcontract, sublicense or otherwise delegate all or any portion of its obligations under this Agreement without Institut Pasteur’s prior written approval.  Institut Pasteur may as a condition of giving such consent require that it is directly involved, to a reasonable degree, in monitoring the performance of any Subcontractor appointed by AMT.  Notwithstanding the foregoing, AMT may subcontract certain non-essential or routine tasks without Institut Pasteur’s consent, provided that they are tasks which would normally be sub-contracted by AMT in the normal course of its business and are performed in compliance with Good Industry Practice and, where applicable, cGMP (e.g., cleaning of cGMP suites, and maintenance and service of AMT Facility systems (e.g., Clestra, HEPA certification and electrical upgrades)), on a confidential basis.

 

4.6                               Document Changes.  Any requests by AMT or Institut Pasteur for changes to cGMP documentation, including the Master Production Record and any standard operating procedures, will be handled by the procedure in Section 3.6.

 

5                                         Development Runs.

 

5.1                               AMT shall perform Development Runs and manufacture Development Batches in accordance with the Project Plan, Delivery Dates and the Master Production Record.  AMT shall provide Institut Pasteur with any Development Batches requested by Institut Pasteur that result from any partial or completed Development Runs.  Institut Pasteur shall have the right to make whatever further use of such Development Batches as it shall determine, provided that such use does not violate any applicable laws, rules or regulations.  In the event that AMT becomes aware that it may not be able to achieve any Delivery Dates in respect of Development or the manufacture of Product it shall immediately notify Institut Pasteur and the reasons why, and the Parties will agree in good faith a new Delivery Date under reasonable time limits with regard to the Project Plan.

 

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6                                         Clinical Batches

 

6.1                               An initial Clinical Batch will be manufactured in accordance with the Project Plan for the purposes for a Phase l/ll study (“the First Clinical Batch”) in the quantity described in Exhibit A.

 

6.2                               If the program progresses to a further Phase ll/III study, then as provided in the Project Plan, a second Clinical Batch will be required (“the Second Clinical Batch”), in the quantity to be determined by the Parties.

 

6.3                               Institut Pasteur shall notify AMT in writing that it requires a Second Clinical Batch at least [**] months prior to the proposed Delivery Date of such Second Clinical Batch.  If AMT does not agree to manufacture the Second Clinical Batch, AMT may terminate the Agreement in accordance with Sections 19.2(a) and the licence granted to Institut Pasteur in accordance with Clauses 11.8 to 11.11 shall take effect.  If Institut Pasteur does not request the Second Clinical Batch Institut Pasteur may terminate the Agreement according to the procedure of Section 19.2 (d), but in which case no Manufacturing Information shall be provided to Institut Pasteur under Section 11.8 and no licence shall be granted to Institut Pasteur under Section 14.3 .

 

7                                         Deliveries

 

7.1                               Delivery Date.  For each Clinical Batch, the Delivery Date shall be the date established by the Parties.  If AMT reasonably expects any delay in the Delivery Date agreed for either Batch, it shall promptly inform Institut Pasteur of such expected delay and shall use its commercially reasonable efforts to minimize the delay.  Each Batch will be shipped in accordance with the Shipping Guidelines.

 

7.2                               Delivery Terms.  Within [**] Working Days following Institut Pasteur’s acceptance of a Batch pursuant to Section 13.1, AMT shall make such Batch available to the designated carrier at AMT’s Facility in accordance with the Shipping Guidelines.  Institut Pasteur shall arrange for shipment of each Batch within [**] months after written notice of such availability is provided to Institut Pasteur.  AMT shall provide storage for such Batch in accordance with the Storage Guidelines [**] during such [**] month period; provided, that any additional storage beyond such [**] month period [**] to Institut Pasteur as Additional Services .  The risk of loss for each Batch shall be borne by Institut Pasteur from the date of shipment.  Institut Pasteur shall be responsible for all appropriate approvals and consents of any Governmental Authority necessary for the transportation or shipment of such Batch.

 

7.3                               No Storage of Product.  Notwithstanding anything to the contrary contained in this Agreement, in no event shall AMT be required to store a Batch of Product for more than [**] following the later of (i) Institut Pasteur’s acceptance thereof in accordance with this Agreement; and (ii) the grant of the last of any required

 

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approval(s) and/or consent(s) of any Governmental Authority necessary for the transportation or shipment of such Batch.

 

8                                         Payments

 

8.1                               Payment for Development services.  Institut Pasteur shall pay AMT for all Development services provided hereunder in accordance with Exhibit A.

 

8.2                               Product Pricing.  Institut Pasteur shall pay AMT for all manufacturing services used to produce Product for Institut Pasteur in accordance with Exhibit A.

 

8.3                               Payment Terms.  All invoices for work performed shall, in the case of work carried out pursuant to the Project Plan, be issued when the relevant milestone set out in the Project Plan has been completed and, in the case of Clinical Batches, be issued on the Delivery Date.  All amounts due thereunder shall be due and payable within [**] days after receipt of such invoice which shall be sent from AMT to Institut Pasteur after completion of the relevant milestones or delivery of the Clinical Batches.  Payments shall be made by wire transfer or check in Euros.  Institut Pasteur shall pay interest to AMT on any sums not paid to AMT on the date on which payment should have been made pursuant to the applicable provisions of this Agreement (“Due Date”) over the period from the Due Date until the date of actual payment (both before and after judgment) at the rate of [**] per cent, above the base rate from time to time of Deutsche Bank plc (or, if less, the maximum rate allowed to be charged under applicable laws).  Interest accrues and is payable from day to day.

 

9                                         Documentation

 

9.1                               Regulatory Documentation.  Within [**] days following completion of the Quality Review and Approval for each Clinical Batch, but in any event not later than the Delivery Date, AMT shall provide Institut Pasteur with a copy of all applicable Batch Disposition Documents, which documents shall be in AMT’s standard formats in the form at Exhibit B unless otherwise mutually agreed to by the Parties, provided that such Batch Disposition Documents will not be considered as an Additional Service.  Any Institut Pasteur requests for documents or other work product (other than the MPR, the Manufacturing Documentation and copies of Batch Disposition Documentation and any other documents or work product expressly required to be delivered under this Agreement) that do not exist as of the date of such request or other substantive requests for assistance in compiling any Regulatory Filing shall constitute Additional Services, and AMT shall notify Institut Pasteur of the same, and, if Institut Pasteur authorizes such services, AMT shall prepare a Change Order and invoice Institut Pasteur for such Additional Services.

 

9.2                               Retention and Reserve Samples.  AMT shall identify and retain certain reserve samples of all intermediate production samples generated in the production of a Clinical Batch as applicable, as set forth in the applicable Materials Specifications,

 

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the applicable standard operating procedures, the Master Production Record, Section 15.3 or as otherwise agreed in writing by AMT and Institut Pasteur.  After completion of the applicable Run, AMT shall inform Institut Pasteur of the availability of these samples.  Institut Pasteur shall request these samples on conditions to be determined in good faith between AMT and Institut Pasteur.  AMT shall retain and preserve, at its sole cost and expense, samples and standards of Product in accordance with the requirements of cGMP.

 

9.3                               Analytical Testing.  AMT, or a designated Subcontractor approved in accordance with Section 4.5, shall perform the analytical testing on Batches as set forth in the Master Production Record, or as otherwise agreed in writing by AMT and Institut Pasteur.

 

9.4                               Accurate Documentation.  Each Party shall use its reasonable efforts to provide complete and accurate records and documentation to the other Party in connection with any Deliverable and, to the extent applicable, in accordance with the Quality Agreement, or as otherwise agreed in writing by AMT and Institut Pasteur.

 

10                                  Manufacturing audits

 

10.1                        Institut Pasteur shall have the right to perform, directly or through its representatives, certain manufacturing audits of the AMT Facility or the facilities used by any AMT Affiliate or sub-contractor to manufacture the Product as set forth in the Quality Agreement, or as otherwise agreed in writing by AMT and Institut Pasteur.  All AMT personnel time and resources necessary to complete [**] shall be provided at no cost to Institut Pasteur; however, any AMT personnel time and resources necessary to complete any additional manufacturing audits [**] in that same [**] years shall be invoiced to Institut Pasteur as Additional Services in accordance with the Project Rates.  Institut Pasteur shall be responsible for all third party costs of all manufacturing audits, unless the audit identifies a breach by AMT of its obligations under this Agreement of such significance in which case, the costs of the audit shall be paid by AMT.

 

11                                  Regulatory matters

 

11.1                        Permits.  AMT shall secure and maintain, at its sole cost and expense, current governmental registrations, permits and licenses as are required from time to time by Governmental Authorities in order for AMT to perform all of its obligations under this Agreement (each, a “Registration”), for so long and insofar as is necessary to permit AMT to perform any of its obligations under this Agreement.  AMT shall make copies of such Registrations and all related documents available for viewing by Institut Pasteur and its designees for inspection, upon reasonable request from Institut Pasteur.  All copies will remain in AMT’s control.

 

11.2                        Compliance with cGMPs; Monitoring of Records.  As further described in the Quality Agreement, or as otherwise agreed in writing by AMT and Institut Pasteur, AMT shall monitor and maintain reasonable records respecting its compliance with

 

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cGMPs, including the process of establishing and implementing the operating procedures and the training of personnel as are reasonably necessary to assure such compliance.

 

11.3                        Records.  AMT shall maintain all records required to be maintained by the terms and conditions of the Quality Agreement and by applicable law and regulation, including cGMP.

 

11.4                        Regulatory Communications and Correspondence.  Any and all communications from and to Regulatory Authorities related to the manufacture of the Product at the AMT Facility shall be handled in accordance with the terms and conditions of the Quality Agreement, or as otherwise agreed in writing by AMT and Institut Pasteur.

 

11.5                        Regulatory Filings and Maintenance.  Institut Pasteur shall prepare and maintain all Regulatory Filings.

 

11.6                        Subject to Sections 11.7 to 11.11, because the Manufacturing Process is confidential to AMT, apart from the Batch Disposition Documentation, AMT shall not be obliged to provide any information relating to the Manufacturing Process to Institut Pasteur or any Third Party.

 

11.7                        Whilst AMT is continuing to manufacture Product for Institut Pasteur under this Agreement, AMT shall, upon Institut Pasteur’s request, file information relating to the Manufacturing Process confidentially and directly with Regulatory Authorities or allow it to be cross-referenced in a confidential manner by the Regulatory Authorities for the purposes of supporting any Regulatory Filings made by Institut Pasteur relating to the Product.

 

11.8                        If, pursuant to Section 6.3 and 19.2(a), AMT does not agree to manufacture the Second Clinical Batch then it shall, subject to Sections 11.9 to 11.11 and Section 14.3, provide to Institut Pasteur all the necessary information describing the Manufacturing Process and Manufacturing Documentation to allow a Third Party contracted by Institut Pasteur to manufacture the Product, as well as the Batch Disposition Documentation (the “Manufacturing Information”).

 

11.9                        The appointment of such Third Party manufacturer shall require the consent of AMT, such consent not to be unreasonably withheld, in particular in relation to the treatment of the patients with the Product.  Without limiting the foregoing, it shall be reasonable for AMT to refuse consent if the proposed Third Party manufacturer is Généthon or any of its Affiliates.

 

11.10                 The Manufacturing Information is AMT’s Confidential Information and Institut Pasteur’s obligations in Section 17 shall apply to such Manufacturing Information without limit in time.  Institut Pasteur shall impose on the Third Party manufacturer of the Product equivalent obligations to those set out in Section 17. Without limiting the foregoing, Institut Pasteur and any Third Party contracted by Institut Pasteur to manufacture the Product shall not disclose any Manufacturing Information to Généthon or any of its Affiliates.

 

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11.11                 The Manufacturing Information or any part of it can only be used in relation to the manufacture of Product and for no other purpose whatsoever.

 

11.12                 For the avoidance of doubt, any additional activities which are not included in the Project Plan which are specific to the Institut Pasteur’s Regulatory Filing are subject to a Change Order as described in Section 3.6(c).

 

11.13                 Ownership of Regulatory Filings.  Institut Pasteur shall be the sole owner of all Regulatory Filings (except those filed by AMT in accordance with Section 11.7) and all governmental approvals obtained by Institut Pasteur from any Regulatory Authority with respect to the Product.

 

11.14                 Health and Safety Information.  Each Party shall promptly notify the other of any information or notice of which it becomes aware concerning the safety or efficacy claims of the Product, including, without limitation, any threatened or pending action by any Regulatory Authority.  Institut Pasteur shall be responsible for handling all complaints and communications from Regulatory Authorities with respect to the Product.  AMT shall cooperate in resolving such complaints and responding to such communications to the extent they pertain to the Product and such cooperation is reasonably requested by Institut Pasteur.  Institut Pasteur shall reimburse AMT for all reasonable costs and expenses incurred by AMT in connection with the performance of AMT’s obligations under this Section 11.14 except to the extent that any such complaint or communication arises from any breach of this Agreement by AMT or through the grossly negligent or willful act or omission of AMT, its employees, sub contractor or agents.

 

11.15                 Accident Reports.  Each Party shall report to the other promptly all material accidents related to the manufacture, handling, use or storage of any Raw Materials or Product, which could delay the performance of this Agreement.

 

12                                  Quality Assurance; Quality Control

 

12.1                        Responsibility for Quality Assurance and Quality Control.  Responsibility for quality assurance and quality control of Product shall be allocated as set forth in the Quality Agreement.

 

12.2                        Qualification a Validation of AMT Facility; Utilities.  AMT shall maintain cGMP qualification and validation, as appropriate, of the AMT Facility, as well as the utilities and equipment used in the manufacture of Product at the AMT Facility, and shall make relevant reports applicable thereto (redacted to remove information not related to the manufacture of Product) available to Institut Pasteur for review at AMT’s Facility, at Institut Pasteur’s reasonable request.

 

12.3                        AMT shall be responsible to manufacture the Clinical Batch and the Development Batch, according to the quality requirements decided by both Parties.  AMT shall be the sole responsible for the release of any batches in accordance with the terms of Exhibit A “QP Release”, following the regulations in force.

 

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13                                  Non-conformance

 

13.1                        Notice of Nonconformity.  AMT shall provide Institut Pasteur’s quality assurance department with copies of completed Batch Disposition Documentation, and shall endeavor to do so within [**] Working Days of Quality Review and Approval.  Within [**] Working Days after Institut Pasteur’s receipt of such Batch Disposition Documentation, Institut Pasteur shall determine by review of such Batch Disposition Documentation whether or not, the given Clinical Batch conforms to the warranties set forth in Section 15.2(c) and (d) , provided that AMT provides timely answers to information requests and resolution of issues arising from Institut Pasteur’s review of such Batch Disposition Documentation.  If within the [**] Working Days period, Institut Pasteur’s quality assurance department makes a determination that Institut Pasteur believes such Batch to be nonconforming, Institut Pasteur shall have the right to reject such Batch in its entirety and shall notify AMT in writing within such [**] Working Days period.  Such written notice shall specify the manner in which the Clinical Batch fails to conform to the warranties set forth in Section 15.2(c) and (d).  If Institut Pasteur does not submit written notice of rejection within such [**] Working Days period, such Batch will, subject to the remaining provisions of this Section 13.1, be deemed a Conforming Product and accepted by Institut Pasteur.  In the event that Institut Pasteur desires to accept such Batch prior to the end of the [**] Working Days period, Institut Pasteur will fax written notice of such acceptance to AMT’s Project Manager.

 

13.2                        Within [**] days of receipt of a notice from Institut Pasteur pursuant to Section 13.1, AMT shall notify Institut Pasteur whether or not it accepts or disputes Institut Pasteur’s assertions that the Batch is non-conforming.  In the event of an unresolved dispute the Parties shall appoint an independent testing laboratory or other expert (“Expert”), reasonably acceptable to both Parties, and subject to confidentiality provisions comparable to those set out in Section 17 below, to undertake the relevant analysis, which analysis shall be performed in compliance with the applicable laws of the relevant governmental authority, to determine whether the Batch conformed or did not conform to the warranty in Section 15.2(c) and (d).  Both Parties agree to cooperate with the Expert’s reasonable requests for assistance in connection with its analysis hereunder.  The test results obtained from such Expert shall be conclusive and binding upon the Parties, absent manifest error.

 

13.3                        No AMT Liability.  If it is determined by agreement of the Parties (or in the absence of such agreement, by the Expert in accordance with Section 13.2 that either (i) the Batch is Conforming Product, or (ii) there is a nonconformity with respect to such Batch but the nonconformity was not caused by AMT’s breach of the warranties set forth in Section 15.2(c) and (d), then AMT shall have no liability to Institut Pasteur with respect to such Batch, and Institut Pasteur shall pay for such Batch and for the fees associated with the Expert and the Batch shall be treated in all other respects under this Agreement as in conformance with all of the warranties set forth in Section 15.2(c) and (d) of this Agreement.

 

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13.4                        AMT Liability for Non-Conforming Product; Replacement; Termination.  If following the receipt of a notice from Institut Pasteur pursuant to Section 13.1, it is determined by agreement of the Parties (or in the absence of such agreement, by an Expert appointed in accordance with Section 13.2) that such Batch is Non-Conforming Product and such non-conformance was caused by AMT’s negligence or willful misconduct, or which arises out of or results from any breach of this Agreement by AMT, then (A) (i) AMT shall, promptly, replace such Non-Conforming Product with Conforming Product (the “Replacement Product”) or (ii) if AMT is unable to provide Institut Pasteur with Replacement Product within [**] days after such determination, Institut Pasteur shall be entitled to terminate this agreement on notice in accordance with Section 19.2(d); and (B) if an Expert was retained, AMT shall be responsible for the fees and expenses of the Expert, and (C) AMT shall replace free of charge (or, where appropriate, reimburse Institut Pasteur for the cost of) all Raw Materials and Consumables utilized in the production of the Non-Conforming Product.  Delivery of Replacement Product shall be at no additional cost to Institut Pasteur assuming Institut Pasteur previously paid the purchase price for the Non-Conforming Product, in which case no additional payment for the Replacement Product will be required.  If in accordance with the procedures in Sections 13.1 and the preceding terms of this Section 13.4, the Replacement Product is determined by agreement of the Parties (or in the absence of such agreement, by an Expert appointed in accordance with Section 13.2) that the Replacement Product is Non-Conforming Product and such non-conformance was caused by AMT’s negligence or willful misconduct, or which arises out of or results from any breach of this Agreement by AMT then Institut Pasteur shall be entitled to terminate this agreement on notice in accordance with Section 19.2(d).

 

13.5                        Cooperation in Investigations; Disposition of Non-Conforming Product.  Each Party shall act in good faith and shall cooperate with the other Party and with an Expert appointed pursuant to Section 13.2 or 13.3.  AMT shall dispose of any Non-Conforming Product in accordance with Section 4.4 and all relevant laws, rules and regulations with respect to such disposal, at AMT’s cost if AMT was liable for the nonconformity in accordance with Section 13.3

 

14                                  Ownership and License Grants

 

14.1                        Licenses to AMT.  During this Agreement, Institut Pasteur hereby grants to AMT a royalty-free, non-exclusive, non-transferable, non-sub-licensable, license under any and all Institut Pasteur Intellectual Property and Institut Pasteur Background Information that is necessary for AMT to perform its obligations under this Agreement, including, without limitation, the manufacture of Product for Institut Pasteur but for the sole purposes of implementing the Project under this Agreement.

 

14.2                        No License to Institut Pasteur.  Apart from the right to use the Product delivered to Institut Pasteur under this Agreement, the right to cross reference the documentation filed by AMT with the Regulatory Authorities in accordance with

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Section 11.7 and the right to use the Manufacturing Information in accordance with Sections 11.8 to 11.11 and 14.3, Institut Pasteur has no right or licence to any AMT Background Information or other Intellectual Property of AMT.

 

14.3                        If pursuant to a request of Institut Pasteur according to Sections 6.3, AMT does not agree to manufacture the Second Clinical Batch and consents to the appointment of the Third Party manufacturer for the Product under Section 11.8, then AMT grants Institut Pasteur (and consequently AMT grants to INSERM, INSERM-TRANSFERT, ONIRIS and AFM as members of the Consortium represented herein by Institut Pasteur, expressly acknowledged by the Parties that GENETHON is not a member of the Consortium) a non-exclusive, royalty-free licence to its AMT Background Information on the terms of Sections 11.8 to 11.11 solely to the extent necessary to allow Institut Pasteur and/or a Third Party manufacturer contracted by Institut Pasteur to manufacture Product for Institut Pasteur for the treatment of Sanfilippo B.  AMT may terminate this licence if Institut Pasteur or its Third Party manufacturer breaches the terms of this licence or Sections 11.8 to 11.11 inclusive.  Under the provisions of this Section 14.3, it shall be the responsibility of Institut Pasteur to obtain any Third Party licences that it needs to manufacture Product for the Second Clinical Batch, if any.

 

14.4                        Trademarks.  Notwithstanding anything to the contrary contained in this Agreement, neither Party shall acquire any license to use nor any ownership rights in the trade marks, trading names, trading styles, brands or logos of the other.

 

14.5                        Third Party Intellectual Property.  If after the Effective Date any Third Party files and serves on AMT, or threatens AMT or any Consortium Member to file, pursue or maintain any claim, lawsuit, charge, complaint or other action alleging infringement by AMT of a Third Party Patent based on the manufacture, testing, use, import, offer for sale or sale of the Product (each a “Patent Claim”) then:

 

(a)                                 AMT so notified by the Third Party shall notify Institut Pasteur;

 

(b)                                 AMT shall immediately cease working on the Product under this Agreement and such cessation of work and any consequential delay to the Project Plan shall not amount to any breach of this Agreement;

 

(c)                                  The Parties shall discuss how to deal with such Third Party claim.

 

14.6                        If a solution is not found to resolve this Patent Claim within [**] months of the date a Patent Claim is first received, then each Party shall be entitled to terminate this Agreement in accordance with Section 19.2(b).

 

14.7                        Each Party shall be responsible for their own costs of dealing with and resolving any such Third Party Patent claim.

 

15                                  Representations and Warranties

 

15.1                        Institut Pasteur.  Institut Pasteur hereby represents and warrants to AMT that:

 

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(a)                                 Materials and Information Supplied to AMT.  Institut Pasteur is free to disclose to AMT Institut Pasteur Confidential Information and any other information or materials supplied by Institut Pasteur to AMT in accordance with this Agreement.

 

(b)                                 No Patent Infringement Notice.  At the Effective Date, no Third Party has filed and served on Institut Pasteur or any other Consortium Member, nor threatened in writing to the Institut Pasteur or any other Consortium Member to file, pursue or maintain any claim, lawsuit, charge, complaint or other action alleging infringement by the Institut Pasteur of a Third-Party Patent based on the manufacture, use, import, offer for sale or sale of the Product;

 

(c)                                  No Hazards.  Institut Pasteur has made AMT aware of any hazards reasonably known to it as of the Effective Date involved in handling the Raw Materials, the Product, and any Wastes generated through performance of the validation and manufacturing activities contemplated hereunder;

 

(d)                                 License.  Institut Pasteur has the right, power and authority to grant AMT the license set forth in Section 14.1 and will not during the term of this Agreement enter into any contract, arrangement or commitment in the future which prohibits the grant of such license.

 

(e)                                  Power and Authority.  Institut Pasteur has the corporate power, the authority, and the legal right to enter into this Agreement and to perform its obligations under this Agreement; and

 

(f)                                   Execution, Delivery and Performance of the Agreement.  Institut Pasteur has taken all necessary corporate action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations under this Agreement.  This Agreement has been duly executed and delivered on behalf of Institut Pasteur, and constitutes a legal, valid, binding obligation, enforceable against Institut Pasteur and its successors and assigns in accordance with its terms, except as enforceability may be limited by law.  The execution, delivery and performance of this Agreement does not breach, violate, contravene or constitute a default by the Institut Pasteur under any contracts, arrangements or commitments to which Institut Pasteur is a party or by which it is bound nor does the execution, delivery and performance of this Agreement by Institut Pasteur violate any order, law or regulation of any court, governmental body or administrative or other agency having authority over it.

 

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15.2                        AMT.  AMT hereby represents, undertakes and warrants to Institut Pasteur that:

 

(a)                                 Materials and Information Supplied to Institut Pasteur.  AMT is free to disclose to Institut Pasteur AMT Confidential Information and any other information or materials supplied by AMT to Institut Pasteur in accordance with this Agreement.

 

(b)                                 No Patent Infringement Notice.  At the Effective Date, no Third Party has filed and served on AMT, nor threatened in writing to the AMT to file, pursue or maintain any claim, lawsuit, charge, complaint or other action alleging infringement by AMT or AMT Affiliates of a Third-Party Patent based on the manufacture, use, import, offer for sale or sale of the Product;

 

(c)                                  Product.  AMT warrants the Product manufactured under this Agreement, and in particular that all Clinical Batches of Product manufactured hereunder:  (i) shall be manufactured and analyzed in conformance with the Master Production Record and the Quality Agreement;  (ii) shall be manufactured in compliance with the requirements of cGMP and all other applicable laws and regulations; (iii) shall be packaged in accordance with the Shipping Guidelines; (iv) shall be transferred free and clear of any liens or encumbrances of any kind to the extent arising through or as a result of the acts or omissions of AMT or its suppliers and (iv) shall conform, at the time of delivery, to the Release Specification.

 

(d)                                 Manufacturing.  The Development, the Manufacturing Process and AMT’s Quality Review and Approval shall be conducted in compliance with applicable cGMP and the Quality Agreement and all other applicable laws and regulations;

 

(e)                                  No Hazards.  AMT has made Institut Pasteur aware of any hazards reasonably known to it as of the Effective Date involved in handling the Raw Materials, the Product, and any Wastes generated through performance of the validation and manufacturing activities contemplated hereunder;

 

(f)                                   License.  AMT has the right, power and authority to grant Institut Pasteur the license set forth in Sections 14.2 and 14.3 and will not during the term of this Agreement enter into any contract, arrangement or commitment in the future which prohibits the grant of such license.

 

(g)                                  Power and Authority.  AMT has the corporate power, authority and the legal right to enter into this Agreement and to perform its obligations under this Agreement;

 

(h)                                 Execution, Delivery and Performance of Agreement.  AMT has taken all necessary corporate action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations under this Agreement.  This Agreement has been duly executed and delivered on

 

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behalf of AMT, and constitutes a legal, valid, binding obligation, enforceable against AMT in accordance with its terms except as enforceability may be limited by law.  The execution, delivery and performance of this Agreement does not breach, violate, contravene or constitute a default by AMT under any contracts, arrangements or commitments to which AMT is a party or by which it is bound nor does the execution, delivery and performance of this Agreement by AMT violate any order, law or regulation of any court, governmental body or administrative or other agency having authority over it.

 

15.3                        The Parties agree and acknowledge as follows:

 

(a)                                 that, in accordance with the provisions of this Agreement, AMT shall take a Reference Materials sample of each Clinical Batch manufactured under this Agreement upon completion of its manufacture, which sample shall be a representative sample of the Clinical Batch delivered to the Institut Pasteur (the “Delivery Sample”);

 

(b)                                 that the Delivery Sample shall be retained at its own costs by AMT during the term of this Agreement and for a minimum period of [**] months following its termination; and

 

(c)                                  that, in any circumstance of dispute between the Parties as to the conformance of the relevant Clinical Batch with the requirements of Section 15.2(c)(v) above, such Delivery Sample shall be made available by AMT for the purposes of testing (whether by the Expert in accordance with Section 13.2 or otherwise) without unreasonable delay, and the Parties agree that (save in circumstances where the storage of the Delivery Sample has not been in accordance with the Storage Guidelines) the Conformance or Non-Conformance of such Delivery Sample shall, for the purposes of this Agreement, be deemed to be conclusive as to the Conformance or Non-Conformance of the Conformance or Commercial Batch from which it was taken.

 

15.4                        Disclaimer.  OTHER THAN AS SET FORTH IN SECTION 15, ALL OTHER WARRANTIES, BOTH EXPRESS AND IMPLIED, ARE HEREBY EXPRESSLY DISCLAIMED, INCLUDING, WITHOUT LIMITATION, ANY WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OF THE PRODUCT OR THE SERVICES PROVIDED HEREUNDER.  OTHER THAN THE DEVELOPMENT AND MANUFACTURING SERVICES PROVIDED HEREUNDER, AMT HAS NOT PARTICIPATED IN THE RESEARCH AND DEVELOPMENT OF THE PRODUCT, HAS NOT IN ANY WAY EVALUATED THE PRODUCT’S OR PRODUCT’S SAFETY OR EFFICACY IN HUMANS OR OTHERS, AND SHALL NOT IN ANY WAY BE LIABLE FOR INSTITUT PASTEUR’S USE OF A CLINICAL BATCH WHICH HAS BEEN PRODUCED BY AMT IN ACCORDANCE WITH THE TERMS OF THIS AGREEMENT.

 

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16                                  Indemnification

 

16.1                        AMT shall indemnify and hold harmless Institut Pasteur from and against any claims, losses, liabilities, costs (including, without limitation, reasonable attorneys’ fees and expenses), damages and expenses arising out of or in connection with any claim by a Third Party arising out of:

 

(a)                                 any material breach by AMT of this Agreement;

 

(b)                                 AMT’s grossly negligent acts or omissions or willful misconduct; and/or

 

provided that:

 

(a)                                 Institut Pasteur gives notice to AMT of such claim as soon as reasonably possible upon becoming aware of the same; and

 

(b)                                 Institut Pasteur gives AMT the sole conduct of the defence and settlement of such claim and does not at any time admit liability or otherwise attempt to settle the claim subject to AMT providing reasonable assurances, to Institut Pasteur’s reasonable satisfaction, with respect to AMT’s ability to pay for any costs or liabilities which Institut Pasteur may incur by reason of AMT’s conduct of such defence or settlement of such claims; provided, however, that (i) any such settlement by AMT shall not adversely affect Institut Pasteur’s rights under this Agreement or impose any obligations on Institut Pasteur in addition to those set forth herein, and (ii) Institut Pasteur shall have the right, but not the obligation, to be represented by counsel of its own selection and expense.

 

16.2                        Subject to the provisions of the article 16.1 of this Agreement, Institut Pasteur shall indemnify and hold harmless AMT from and against any claims, losses, liabilities, costs (including, without limitation, reasonable attorneys’ fees and expenses), damages and expenses arising out of or in connection with any claim by a Third Party arising out of:

 

(a)                                 any material breach by Institut Pasteur of this Agreement;

 

(b)                                 the packaging, testing, labelling, handling, distribution, use, import or sale of the Product in any form;

 

(c)                                  Institut Pasteur’s grossly negligent acts or omissions or willful misconduct; and/or

 

provided that

 

(a)                                 AMT gives notice to Institut Pasteur of such claim as soon as reasonably possible upon becoming aware of the same; and

 

27

 

(b)                                 AMT gives Institut Pasteur the sole conduct of the defence and settlement of such claim and does not at any time admit liability or otherwise attempt to settle the claim subject to Institut Pasteur providing reasonable assurances, to AMT’s reasonable satisfaction, with respect to Institut Pasteur’s ability to pay for any costs or liabilities which AMT may incur by reason of Institut Pasteur’s conduct of such defence or settlement of such claims; provided, however, that (i) any such settlement by Institut Pasteur shall not adversely affect AMT’s rights under this Agreement or impose any obligations on AMT in addition to those set forth herein, and (ii) AMT shall have the right, but not the obligation, to be represented by counsel of its own selection and expense.

 

16.3                        Insurance.  AMT shall maintain public liability insurance with an indemnity limit of [**] Euros (€[**]) for any one occurrence.  AMT shall maintain appropriate commercial general liability insurance including, without limitation, product liability and contractual liability coverage with respect to the development, manufacture, import, sale, offer for sale and use of the Manufacturing Process, Deliverables and Product in an amount equal to [**] Euros (€[**]).  AMT shall maintain such insurance for so long as it continues to manufacture or sell Product or services and for a period of [**] years after the end of this Agreement.

 

16.4                        Disclaimer of Consequential Damages.  IN NO EVENT SHALL EITHER PARTY BE LIABLE TO THE OTHER OR ANY OF ITS AFFILIATES FOR ANY CONSEQUENTIAL, INCIDENTAL, INDIRECT, SPECIAL, PUNITIVE OR EXEMPLARY DAMAGES (INCLUDING, WITHOUT LIMITATION, LOST PROFITS, BUSINESS OR GOODWILL) SUFFERED OR INCURRED BY SUCH OTHER PARTY OR ITS AFFILIATES IN CONNECTION WITH THIS AGREEMENT, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGES.

 

16.5                        Limitation of Liability.  BOTH PARTIES HEREBY AGREE THAT TO THE FULLEST EXTENT PERMITTED BY LAW, AMT’S LIABILITY TO INSTITUT PASTEUR, FOR ANY AND ALL INJURIES, CLAIMS, LOSSES, EXPENSES, OR DAMAGES, WHATSOEVER, ARISING OUT OF OR IN ANY WAY RELATED TO THIS AGREEMENT FROM ANY CAUSE, INCLUDING, BUT NOT LIMITED TO, NEGLIGENCE, ERRORS, OMISSIONS OR STRICT LIABILITY, SHALL NOT EXCEED THE AMOUNT PAID TO AMT UNDER THIS AGREEMENT.  TO THE EXTENT THAT THIS CLAUSE CONFLICTS WITH ANY OTHER CLAUSE, THIS CLAUSE SHALL TAKE PRECEDENCE OVER SUCH CONFLICTING CLAUSE.  IF APPLICABLE LAW PREVENTS ENFORCEMENT OF THIS CLAUSE, THEN THIS CLAUSE SHALL BE DEEMED MODIFIED TO PROVIDE THE MAXIMUM PROTECTION FOR AMT AS IS ALLOWABLE UNDER APPLICABLE LAW.  THE FOREGOING LIMITATION SHALL NOT APPLY TO LIABILITY ARISING FROM DEATH OR PERSONAL INJURY DIRECTLY CAUSED BY AMT’S NEGLIGENCE OR FROM FRAUDULENT ACTS OR WILFUL MISCONDUCT.

 

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17                                  Confidentiality

 

17.1                        AMT Confidentiality Obligations.  AMT shall not use Institut Pasteur Confidential Information except as authorized under this Agreement and shall not disclose Institut Pasteur Confidential Information to any Third Party other than: (i) employees, consultants, agents or Subcontractors of AMT or AMT’s Affiliates who are bound by similar obligations of confidentiality and nonuse and who have a need to know such information in order to perform their duties or services in connection with AMT’s obligations under this Agreement; (ii) any Regulatory Authority to the extent that it requires such information in connection with making Regulatory Filings and maintaining Regulatory Authority approvals for the Product under the provisions of this Agreement and on Institut Pasteur’s request; or (iii) any Governmental Authority in connection with securing and/or maintaining registrations under the provisions of this Agreement and on Institut Pasteur’s request.

 

17.2                        Institut Pasteur Confidentiality Obligations.  Institut Pasteur shall not use AMT Confidential Information except as authorized under this Agreement and shall not disclose any AMT Confidential Information to any Third Party other than as authorized under this Agreement and other than : (i) employees, consultants, or agents of Institut Pasteur who are bound by similar obligations of confidentiality and nonuse and who have a need to know such information in order to perform their duties or services in connection with Institut Pasteur’s obligations under this Agreement or the development or commercialization of the Product; (ii) any Regulatory Authority to the extent that it requires such information in connection with making Regulatory Filings and maintaining Regulatory Authority approvals for the Product or (iii) any Governmental Authority in connection with securing and/or maintaining registrations.

 

17.3                        Responsibility for Compliance with Confidentiality and Nonuse Obligations.  Each Party shall be responsible for any intentional misuse or misappropriation, by such Party, its Affiliates, or the employees, consultants, agents, Subcontractors or sublicensees of such Party or such Party’s Affiliates, of the other Party’s Confidential Information.  Each Party shall use its reasonable endeavours to enforce the obligations of confidence imposed upon such persons by it in accordance with Section 17.8.

 

17.4                        Terms of Agreement.  Except for any disclosure that is necessary to comply with national rules or regulations (including the rules and regulations of any national stock exchange on which such Party’s securities are traded) or disclosure to a Party’s employees, Affiliates, consultants, agents, professional advisers, Subcontractors, sublicensees, potential acquirors, investors or potential investors under similar conditions of confidentiality, or to the extent necessary in order to enforce its rights in any court of competent jurisdiction or in any arbitration proceedings or in order to participate in any such proceedings neither Party shall, without the prior written consent of the other Party which consent may be dependant on the disclosure being under similar conditions of confidentiality to this 

 

29

 

Agreement, disclose in any manner to any Third Party the terms and conditions of this Agreement.

 

17.5                        Exclusions.  The obligations of confidentiality and nonuse set forth in Section 17.1 and Section 17.2 shall not apply to any information for which it is evidenced that: (i) at the time of disclosure, is known publicly or thereafter becomes known publicly through no fault of the recipient, its Affiliates, their employees, consultants, agents, Subcontractors or sublicensees; (ii) becomes available to the recipient from a Third Party which is not legally prohibited from disclosing such information; (iii) was developed by the recipient independently of Confidential Information obtained from the disclosing Party as evidenced by written records; (iv) was already known to the recipient before receipt from the disclosing Party, as shown by its prior written records; or (v) is released with the prior written consent of the disclosing Party.  In determining whether or not the disclosing Party’s Confidential Information has entered the public domain, the obligations of confidentiality shall no longer apply to only that portion of said Confidential Information that has become public, and portions remaining confidential shall retain their status as Confidential Information.

 

17.6                        Notification of Mandatory Disclosure.

 

(a)                                 Notification and Consultation.  In the event that a Party (in such case, the “Notifying Party”) believes it is required by applicable statute or regulation (including the rules and regulations of any national stock exchange on which such Party’s securities are traded), or by judicial or administrative process to disclose any part of the other Party’s (in such case, the “Notified Party”) Confidential Information, the Notifying Party shall (1) promptly notify the Notified Party of each such requirement and identify the documents so required to be disclosed thereby, so that the Notified Party may seek an appropriate protective order or other remedy and/or waive compliance by the Notifying Party with the provisions of this Agreement, and (2) consult with the Notified Party on the advisability of taking legally available steps to resist or narrow the scope of such disclosure.

 

(b)                                 Limited Disclosure.  If, in the absence of such a protective order or such a waiver by the Notified Party of the provisions of this Agreement, the Notifying Party is nonetheless required by applicable law to disclose any part of the Notified Party’s Confidential Information, the Notifying Party may disclose such Confidential Information without liability under this Agreement, except that the Notifying Party shall furnish only that portion of the Confidential Information which is legally required to be disclosed.

 

17.7                        No Licenses.  Except as expressly provided in Section 14 hereof, no right or license, either express or implied, is granted under any Intellectual Property right or by virtue of the disclosure of Confidential Information under this Agreement, or otherwise.

 

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17.8                        Maintenance of Confidentiality.  Each Party shall apply at least the same level of security to the other Party’s Confidential Information as it would to its own most confidential information and shall use all reasonable and customary precautions to safeguard the confidentiality of the other Party’s Confidential Information, including ensuring that all employees, consultants, agents, Subcontractors or sublicensees who are provided access to such Confidential Information are informed of the confidential and proprietary nature of such Confidential Information and are subject to enforceable contractual confidentiality and nonuse obligations that are at least as restrictive as those contained in this Agreement.

 

17.9                        Equitable Relief.  Each Party agrees that (i) the other Party and its Affiliates would be irreparably injured by a material breach of the confidentiality and nonuse provisions of this Agreement by the employees, consultants, agents, Subcontractors or sublicensees of the breaching Party or its Affiliates, (ii) that monetary remedies would be inadequate to protect the other Party against any actual or threatened material breach of the provisions of this Section 17 by the employees, consultants, agents, Subcontractors or sublicensees of the breaching Party or its Affiliates, and, (iii) without prejudice to any other rights and remedies otherwise available to the other Party, the breaching Party agrees, upon proof of any such actual or threatened material breach, to the granting of equitable relief, including injunctive relief and specific performance, in the other Party’s favor.

 

17.10                 Duration.  The obligation of confidentiality and non use of this Section 17 shall be effective during this Agreement and for [**] years after the expiration or termination of this Agreement save in respect of any Manufacturing Documentation, the Master Production Record or any other information relating to the Manufacturing Process for which the obligations of confidentiality and non use under this Section 17 shall continue without limit in time.

 

18                                  Use of Names

 

Neither Party shall make use of the name of the other Party in any advertising or promotional material, or otherwise, in connection with this Agreement or any related agreements, without the prior written consent of such other Party.

 

To the extent useful or required for disclosure purposes AMT will make a public announcement about the relationship with Institut Pasteur.  The language will be subject to the prior written approval of Institut Pasteur.

 

19                                  Term; Termination

 

19.1                        Term: Option to Extend.  Unless sooner terminated pursuant to the terms of this Agreement, the term of this Agreement shall commence on the Effective Date and shall continue until the completion of the Parties’ obligations under this Agreement, provided however that the delivery of the Clinical Batch shall be effective twelve (12) months after the Effective Date.  However, in case of delay due to scientific, technologic or regulatory problems, the Parties will meet to

 

31

 

analyse them and determine together an additional reasonable extension period necessary to solve the problem concerned.

 

19.2                        Termination.  This Agreement may be terminated as follows:

 

(a)                                 AMT may immediately terminate this Agreement after provision of the First Clinical Batch, by notifying thirty (30) days in advance Institut Pasteur in writing that it will not manufacture the Second Clinical Batch.

 

(b)                                 If a solution is not found to resolve a Patent Claim within [**] months of the date a Patent Claim is first received in accordance with Section 14.6, then each Party shall be entitled to terminate this Agreement immediately by providing notice to the other Party.

 

(c)                                  Termination on Notice.  Each Party may terminate this Agreement, without liability to the other Party, by giving thirty (30) days notice to the other Party if it reasonably believes that there are serious issues with respect to the Product or to the Second Batch, such that the continuation of the Agreement is not possible for technical feasibility reasons (including vector specifications).

 

(d)                                 Termination by Institut Pasteur.  Institut Pasteur may terminate this Agreement by giving thirty (30) days notice to AMT in the circumstances set out in Sections 6.3 and 13.4 or in case of refusal by the regulatory authority to perform the clinical trial, subject in this last case to the payment of the services performed by AMT.

 

(e)                                  Material Breach.  Either Party may terminate this Agreement, by written notice to the other Party, for any material breach of this Agreement by the other Party, if such breach is not cured within [**] days after the breaching Party receives written notice of such breach from the nonbreaching Party; provided, however, if such breach is not capable of being cured within such [**] day period, the cure period shall be extended on a mutual reasonable consent for such amount of time as may be reasonably necessary to cure such breach, so long as the breaching Party is making diligent efforts to do so.  Such termination shall be effective upon expiration of such cure period.

 

(f)                                   Force Majeure; No-Fault Termination.  Either Party shall have the right to terminate this Agreement, without liability to the other Party, upon providing written notice thereof to the other Party, such termination to be effective thirty (30) days from the date of such notice if, as a result of a Force Majeure Event, a Party is unable fully to perform its obligations under this Agreement for any continuous period of one hundred and eighty (180) days.

 

(g)                                  Insolvency.  Either Party may terminate this Agreement upon notice to the other Party, upon (a) the dissolution, termination of existence, liquidation or business failure of the other Party; (b) the appointment of a custodian or

 

32

 

receiver for the other Party who has not been terminated or dismissed within ninety (90) days of such appointment; (c) the institution by the other Party of any proceeding under national bankruptcy, reorganization, receivership or other similar laws affecting the rights of creditors generally or the making by such Party of a composition or any assignment for the benefit of creditors under any national bankruptcy, reorganization, receivership or other similar law affecting the rights of creditors generally, which proceeding is not dismissed within ninety (90) days of filing.

 

(h)                                 Cumulative Remedies.  Any right to terminate this Agreement shall be in addition to and not in lieu of all other rights or remedies that the Party giving notice of termination may have at law or in equity or otherwise.

 

19.3                        Consequences of Termination.

 

(a)                                 Payment of Amounts Due.  Expiration or termination of this Agreement for any reason shall not exempt, unless otherwise agreed between the Parties in this Agreement, any Party from paying to the other Party any amounts properly due but unpaid to such Party at the time of such expiration or termination, including, without limitation, payments due under Section 8 hereof, on a prorata basis according to the work carried out up to that date, except in case of termination for AMT’s breach.

 

(b)                                 Termination of Development Activities.  The Parties shall mutually agree in good faith and as soon as reasonably possible upon which Development milestone activities that are in progress as of the effective date of any termination hereunder shall be completed and which shall be terminated effective immediately.  The Agreement shall continue to survive with respect to those in progress milestone activities which the Parties agree to continue in good faith.

 

(c)                                  Termination of Runs.  Runs that are in process as of the effective date of any termination hereunder shall not be cancelled unless otherwise agreed by the Parties in writing and the Agreement shall continue to survive with respect to those in process Runs.  Product that has been fully manufactured as of the date of such termination, but for which Quality Review and Approval has not been completed, shall remain subject to the terms of this Agreement, and the Agreement shall continue to survive with respect to such Product, unless otherwise agreed by the Parties.

 

(d)                                 Raw Materials, Consumables and Resins.  Upon expiration or termination of this Agreement Institut Pasteur shall purchase from AMT (to the extent not previously paid for by Institut Pasteur), at AMT’s Acquisition Cost, all remaining usable Raw Materials and Consumables acquired and paid for by AMT for the manufacture of Product under this Agreement, provided however, that as of the date of receipt of the termination notice, AMT shall place no further orders for Raw Materials and Consumables except as may

 

33

 

be necessary for completion of any portion of AMT’s services hereunder that are not immediately terminated, according to Sections 19.3 (b) and (c).

 

(e)                                  Return of Materials, of Institut Pasteur Confidential Information and Institut Pasteur Background Information.  Upon expiration or termination of this Agreement, unless otherwise directed by Institut Pasteur, AMT shall promptly and at Institut Pasteur’s sole cost and expense (except in case of termination for AMT’s breach) deliver to Institut Pasteur or, at Institut Pasteur’s election, destroy, (i) all Institut Pasteur Confidential Information and Institut Pasteur Background Information, except for a single copy and/or sample which may be retained to record its obligations under this Agreement only and which shall remain subject to the obligations of nonuse and confidentiality set forth in this Agreement, (ii) all Reference Materials being held by AMT (except that AMT shall have the right to keep a retained sample of each Reference Material according to the provisions of this Agreement), and (iv) all remaining Raw Materials, Consumables purchased pursuant to Section 19.3(d), (iii) all work in progress, (iv) all completed and in-progress Batches, (v) all Batch Disposition Documentation to the extent not previously provided and (vi) all other items in the possession, power or control of AMT, title to which is (or is to be, upon due delivery and payment therefor under this Agreement) held by Institut Pasteur.  AMT shall in no way be responsible for any claims, demands, losses, liabilities, expenses or damages, whatsoever, arising out of or in anyway related to Institut Pasteur’s use of any such “work in progress” or “in progress Batches” delivered up.  If any Institut Pasteur owned property (Raw Materials, Product etc.) remains at the AMT Facility for a period longer than six (6)months after expiration or termination of this Agreement, Institut Pasteur shall pay for such storage as Additional Services.

 

(f)                                   Return of AMT Confidential Information.  Upon expiration or termination of this Agreement, Institut Pasteur shall promptly return all AMT Confidential Information to AMT, except for a single copy which may be retained for documentation purposes only and which shall remain subject to the obligations of nonuse and confidentiality set forth in this Agreement.

 

(g)                                  Grant of Licence to Institut Pasteur.  In the event of termination by AMT in accordance with Clause 19.2(a) AMT shall grant Institut Pasteur the licence set out in, and in accordance with, Sections 11.8 to 11.11 and 14.3.

 

(h)                                 Accrued Rights.  Except as otherwise expressly set forth herein, any termination or expiration of this Agreement shall be without prejudice to any right which shall have accrued to the benefit of either Party and shall not relieve either Party of any obligation which has accrued prior to the effective date of such termination or expiration, which obligations shall remain in full force and effect for the period provided therein or, if no period is provided therein, then such obligations shall remain in full force and effect indefinitely.

 

34

 

19.4                        Surviving Rights.  Sections 1, 2.5, 9, 10, 11, 14 to 19, 21 and any other terms of this Agreement (to the extent they are intended to survive the termination or expiration of this Agreement), together with the rights and obligations contained therein, shall survive the termination or expiration of this Agreement.

 

20                                  Force Majeure

 

20.1                        Effects of Force Majeure.  No Party shall be in breach of this Agreement if there is any failure of performance under this Agreement (except for payment of any amounts due under this Agreement) occasioned by any reason beyond the control and without the fault or negligence of the Party affected thereby, including, without limitation, an act of God, fire, flood, act of government or state, war, civil commotion, insurrection, acts of terrorism, embargo, sabotage, or any other reason beyond the control and without the fault or negligence of the Party affected thereby (a “Force Majeure Event”).  Such excuse shall continue as long as the Force Majeure Event continues.  Upon cessation of such Force Majeure Event, the affected Party shall promptly resume performance under this Agreement as soon as it is commercially reasonable for the Party to do so.

 

20.2                        Notice of Force Majeure.  Each Party agrees to give the other Party prompt written notice of the occurrence of any Force Majeure Event, the nature thereof, and the extent to which the affected Party will be unable to fully perform its obligations under this Agreement.  Each Party further agrees to use commercially reasonable efforts to correct the Force Majeure Event as quickly as practicable (provided that in no event shall a Party be required to settle any Labor dispute) and to give the other Party prompt written notice when it is again fully able to perform such obligations.

 

20.3                        Termination.  This Agreement may be terminated as a result of a Force Majeure Event only in accordance with Section 19.2(e) hereof.

 

35

 

21                                  Miscellaneous

 

21.1                        Notices.  Any notice required or permitted to be given under this Agreement by any Party shall be in writing and shall be (a) delivered personally, (b) sent by registered mail, return receipt requested, postage prepaid, (c) sent by a nationally-recognized courier service guaranteeing next-Working Day or second Working Day delivery, charges prepaid, or (d) delivered by facsimile (with documented evidence of transmission), to the addresses or facsimile numbers of the other Party set forth below, or at such other addresses as may from time to time be furnished by similar notice by any Party.  The effective date of any notice under this Agreement shall be the date of receipt by the receiving Party.

 

If to AMT:
 For the Attention of the Chief Executive Officer 
 Amsterdam Molecular Therapeutics (AMT) B.V.  
 Meibergdreef 61 
 1105BA Amsterdam 
 The Netherlands

 

If to Institut Pasteur:
 For the attention of the Legal Director
 25-28, rue du Docteur Roux 75724 Paris Cedex 15, France

 

And

 

For the attention of the Medical Director
 25-28, rue du Docteur Roux 75724 Paris Cedex 15, France

 

21.2                        Applicable Law.  This Agreement shall be construed, interpreted and enforced in accordance with the internal substantive laws of the Netherlands, without reference to the choice of law doctrine of such state.

 

21.3                        Headings.  All headings in this Agreement are for convenience of reference only and shall not affect the interpretation of this Agreement.

 

21.4                        Exhibits.  All exhibits or appendices referred to herein form an integral part of this Agreement and are incorporated into this Agreement by such reference.

 

21.5                        Security Procedures.  All Institut Pasteur personnel visiting or having access to the AMT Facility agree to abide by AMT standard policies, operating procedures and security procedures as established by AMT and communicated to Institut Pasteur.

 

21.6                        Assignment.  This Agreement shall be binding upon the successors and assigns of the Parties and the name of a Party appearing herein shall be deemed to include the names of its successors and assigns.  Neither Party may assign its interest under this Agreement without the prior written consent of the other Party, such consent not to be unreasonably withheld; provided, however, either Party may assign its interest under this Agreement, without the prior written consent of the other Party to an

 

36

 

Affiliate but only for as long as such Affiliate remains an Affiliate of the relevant Party.  Any permitted assignment of this Agreement by either Party will be conditioned upon that Party’s permitted assignee agreeing in writing to comply with all the terms and conditions contained in this Agreement.  Any purported assignment without a required consent shall be void.  No assignment shall relieve any Party of responsibility for the performance of any obligation that accrued prior to the effective date of such assignment.

 

21.7                        Severability.  If any part of this Agreement shall be found to be invalid or unenforceable under applicable law in any jurisdiction, such part shall be ineffective only to the extent of such invalidity or unenforceability in such jurisdiction, without in any way affecting the remaining parts of this Agreement in that jurisdiction or the validity or enforceability of the Agreement as a whole in any other jurisdiction.  In addition, the part that is ineffective shall be reformed in a mutually agreeable manner so as to as nearly approximate the intent of the Parties as possible.

 

21.8                        Independent Contractors.  Each of the Parties is an independent contractor and nothing herein contained shall be deemed to constitute the relationship of partners, joint venturers, nor of principal and agent between the Parties.  Neither Party shall at any time enter into, incur, or hold itself out to Third Parties as having authority to enter into or incur, on behalf of the other Party, any commitment, expense, or liability whatsoever.

 

21.9                        Waiver.  No waiver of any term, provision or condition of this Agreement whether by conduct or otherwise in any one or more instances shall be deemed to be or construed as a further or continuing waiver of any such term, provision or condition or of any other term, provision or condition of this Agreement.

 

21.10                 Counterparts.  This Agreement and any amendment hereto may be executed in any number of counterparts, each of which shall for all purposes be deemed an original and all of which shall constitute the same instrument.  This Agreement shall be effective upon full execution by facsimile or original, and a facsimile signature shall be deemed to be and shall be as effective as an original signature.

 

21.11                 No Solicitation of Employees.  During the Term and for one (1) years thereafter, each of the Parties agrees not to seek to induce or solicit any employee of the other Party or its Affiliates to discontinue his or her employment with the other Party or such Affiliate in order to become an employee or an independent contractor of the soliciting Party or its Affiliates; provided, however, that neither Party shall be in violation of this Section 21.11 as a result of making a general solicitation for employees or independent contractors.  For the avoidance of doubt the publication of an advertisement shall not constitute solicitation or inducement.

 

21.12                 Entirety; Amendments.  This Agreement, including any exhibits attached hereto and referenced herein, constitutes the full understanding of the Parties and a complete and exclusive statement of the terms of their agreement with respect to

 

37

 

the specific subject matter hereof, and no terms, conditions, understandings or agreements purporting to modify or vary the terms thereof shall be binding unless hereafter made in a written instrument referencing this Agreement and signed by each of the Parties.

 

21.13                 Preamble.  The Preamble and the Background referred to herein form an integral part of this Agreement.

 

21.14                 Preference.  The terms of this Agreement shall prevail in the event of a conflict between this Agreement and any exhibits or appendices.

 

[the remainder of this page intentionally blank]

 

38

 

IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed as of the Effective Date.

 

 

	
 
    	
INSTITUT   PASTEUR
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
By:
    	
/s/   A. Douly
    
	
 
    	
Name:
    	
 
    
	
 
    	
Title:
    	
 
    
	
 
    	
Date:
    	
January 7th, 2011
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
AMSTERDAM   MOLECULAR THERAPEUTICS (AMT) BV
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
By:
    	
/s/   J. Alday
    
	
 
    	
Name:
    	
 
    
	
 
    	
Title:
    	
 
    
	
 
    	
Date:
    	
11   01 2011
    

 

39

 

Exhibit A 
 Project Plan

 

Sanfilippo B or mucoplysaccharidosis type IIIB (MPSIIIB) is a lysosomal storage disease for which currently no treatment is available.  The rationale for the present approach is the observation that the phenotype of MPSs can be reversed by enzyme replacement therapy.  In case of Sanfilippo B the disease is caused by an autosomal recessive genetic defect of the lysosomal enzyme -N-acetylglucosaminidase (NaGlu).  It was shown recently in different preclinical models that gene delivery of NaGlu has the potential to cure Sanfilippo B.  The goal of the present project is to produce GMP grade AAV-NaGlu vector in sufficient amounts for clinical trials.  The efficacy and safety of this vector will be tested in different animal models (for efficacy by measuring enzyme activity in MPSIIIB mice, for safety by performing toxicology and biodistribution studies in normal rats and dogs) before it will be applied in a phase I clinical trial.

 

Responsibilities

 

The table below outlines the main tasks and the parties responsibility for the delivery of the task.

 

	
 
    	
 
    	
Task
    	
 
    	
AMT responsibility
    	
 
    	
Institut Pasteur
   responsibility
    
	
1
    	
 
    	
Process   Development
    	
 
    	
[**]
    	
 
    	
[**]
    
	
2
    	
 
    	
Assay   Development
    	
 
    	
[**]
    	
 
    	
[**]
    
	
3
    	
 
    	
In   vivo tests in mice
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
Tox   in rats and dogs
    	
 
    	
 
    	
 
    	
[**]
    
	
4
    	
 
    	
MSV/WSV   for cGMP batches
    	
 
    	
[**]
    	
 
    	
[**]
    
	
5
    	
 
    	
cGMP   batch production
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Assay to de developed

 

AAV5-specific assays will be developed by AMT; these will include:

 

[**]

 

In addition, AMT will develop a transgene specific Q-PCR.  A basic protocol has been already established at AMT, however, this process needs to be qualified prior to the initiation of the clinical phase I study.

 

A second Q-PCR will be established in collaboration with a service provider.  This Q.-PCR method will be used by Institut Pasteur in biodistribution studies in rats.

 

Develop production platform

 

AMT will develop a robust upstream and downstream process suitable for the production of GMP material.  The progress of the development process will be monitored by Q-PCR (and in vivo studies in mice).  The in vivo studies will measure the transduction efficiency of AAV5-NaGlu, and will be used as potency assay.  Institut Pasteur will be responsible for the in vivo potency assays that will accompany the process development work.  MPSIIIB mice will be used for the

 

40

 

study.  The mice will be diagnosed at birth by PCR, they will be used for the study when aged between week [**].  The material from the [**] development batches will be used to perform these studies.  The NaGlu catalytic activity resulting from gene transfer by the AAV5-NaGlu vector will be measured in brain extracts approximately [**] weeks post injection.

 

AMT has planned to deliver a maximum of [**] development batches during this phase.  The production of the [**] development batch will be done adapting the AAV5-NaGlu production process previously developed at AMT.

 

The current AAV5 process is based on AMT’s proprietary baculovirus / insect cell platform which will be used to produce the AAV5-NaGlu vector.  The vector will be purified by DNA-ase incubation followed by a chemical lysis step after which cell debris is removed by depth filtration.  The clarified harvest is incubated overnight as a viral inactivation step.  The inactivated material is purified by affinity chromatography and ion-exchange chromatography after which buffer exchange is performed using ultrafiltration/diafiltration (UF/DF).  The intended formulation buffer consists of phosphate buffered saline (PBS) supplemented with [**].  After UF/DF the product is frozen at [**] and samples are analyzed according to a predetermined list of analyses and specification.  The result of the Q-PCR analysis will be used to dilute the product to the target concentration of the finished product.  The product will be filled into [**] vials with a chorobutyl stopper and aluminum cap filled with [**] of finished product.  The closed vials will be stored at [**] for storage until release and use.

 

Following the delivery of the batch, Institut Pasteur will test the batch in vivo in a mouse model (in vivo potency study).  If needed, further process optimization will be employed for the production of the [**] development batch, which will be again tested as above.  Final process optimization work will result in the production of the [**] development batch, which will be again tested as above.  The process used for the most successful in vivo study (highest NaGlu activity per mg of protein in extracts prepared from the entire injected brain hemisphere) will be employed for the production of the Tox and clinical material.  Purchasing new equipment for optimization of the manufacturing process is not included in the scope of this project.

 

Project phases

 

1.                                      Development batches

 

AMT will deliver maximally [**] development batches which will be performed on a maximum of [**] scale.  The purified product will be tested with a Q-PCR by AMT to determine the strength.  A sample will be shipped to Institut Pasteur for an in vivo test in the mouse model to test its in vivo activity and whether it meets the criteria (to be established) for further product development.  After completion of each batches there will be a formal Go/No Go based on the outcome of the in-vivo test results obtained by Institut Pasteur.  The in vivo tests determine whether the product produced by AMT would be meeting the requirements for a clinical study.  AMT and Institut Pasteur have to define the requirements for successful in vivo activity.

 

2.                                      Analytical development

 

AMT will develop some assays for the AAV5-NaGlu vector characterization.  These will include:

 

41

 

[**]

 

For other assays such as general test for contaminations, sucrose content, bioburden, sterility, infectious particles assay, rcAAV, residual host cell DNA and protein, residual Triton, residual Benzonase it is assumed that no development is needed and this is therefore not included in the scope of this project.

 

A typical bill of testing for the finished product is listed in the Table below.  Some process related impurities such as residual Benzonase, Triton, infectious baculovirus are tested on the active substance level and safety assays such as adventitious virus agents are tested during the manufacturing process on the bulk harvest prior to addition of Triton.  AMT and Institut Pasteur have to agree on the number of (critical) in process controls for which AMT will make a proposal for discussion.

 

42

 

Tentative Acceptance Criteria - Batch 1

 

	
Test parameter
    	
 
    	
Tentative Acceptance Criteria
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    

 

43

 

	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    

 

Please note that the above table provides estimate acceptance criteria.  Exact acceptance criteria will need to be discussed and agreed in the project team but with no substantial changes.

 

3.                                      MSV/WSV production

 

AMT will produce a GMP compliant Master Seed Virus and Working Seed Virus Bank of at least [**] vials of the baculovirus containing the NaGlu gene cassette.  The MSV and WSV will be tested according to EP requirements and similar to previous virus banks which were qualified by AMT.  The GMP compliant AAV5 and Rep containing MSV and WSV baculoviruses are already available for the production of the NaGlu vector.

 

4.                                      GMP batch

 

Because of the small amounts of product that are expected for a clinical phase I study and because it is expected that the AAV5-NaGlu product is stable for a long period of time at conditions of [**] or lower, one [**] cGMP batch will be produced for supply of both the Tox material as well as the clinical material.  In additional to the batch production, the appropriate testing will be done as required.  AMT and Institut Pasteur will have to agree on the final bill of testing for the clinical drug product.  AMT will release the product to Institut Pasteur based on meeting the specifications on the bill of testing.  Acceptance of the batch by Institut Pasteur is done based on AMT release statement.

 

5.                                      Stability study

 

AMT will conduct a short stability study on the material used in the Tox study to prove that the product was still stable upon the start of the study.  The clinical batch will also be put on stability for a period of a maximum [**] months and will be periodically tested for stability.  Based on the outcome, the finished product can be given a shelf life of [**] months.

 

6.                                      Reference standard

 

AMT will use some material of the GMP batch for the initial reference standard and will qualify the reference standard based on a protocol which will have to be agreed between Institut Pasteur and AMT.

 

44

 

7.                                      Tox and safety studies

 

Not included in AMT’s project scope.  Tox study will be performed under responsibility of Institut Pasteur.  AMT can contribute advice upon request based on its experience in conducting gene therapy Tox and safety studies

 

8.                                      Phase l/II clinical study

 

Not included in AMT’s project scope.  Clinical study and all its related activities (analysis of clinical samples etc.) will be performed under responsibility of Institut Pasteur.  AMT can contribute advice upon request based on its experience in conducting gene therapy clinical trial, for up to [**] hours without charge.

 

9.                                      Viral clearance / inactivation study

 

AMT will produce [**] using an identical recipe to the cGMP clinical batch to generate materials for an adventitious viral agents removal study and for a baculovirus removal study.  The [**] study will be outsourced to a qualified contract  laboratory.  In the [**] study one enveloped and one unenveloped model virus will be tested for inactivation and clearance by the process (singular experiment).  AMT will report the first study and will make the reports available for submission of the IMPD or equivalent application for the clinical study by Institut Pasteur.

 

Regulatory Affairs Strategy

 

Contacts to AFSSAPS have already been established by Institut Pasteur.  Institut Pasteur will be responsible for the interaction with AFSSAPS.  Institut Pasteur will keep AMT informed about any advice received that relates to manufacturing.

 

Institut Pasteur is responsible for the orphan drug application.  AMT will contribute information related to product development and manufacturing as part of this project, if any.

 

QP Release

 

AMT, as contract manufacturer, will release the manufacturing data as well as the quality control data generated by AMT or AMT’s vendors.  The QP of AMT will provide Institut Pasteur with a certificate stating that production has taken place according to GMP and test results (excluding the potency assay carried out by Institut Pasteur below) comply with the specification.

 

Institut Pasteur is responsible for the evaluation of the potency assay.  The QP of Institut Pasteur will release the product for clinical use, taking into account the QP release of AMT and the result of the potency assay.

 

45

 

Project Plan - Delivery Dates

 

[**]

 

Milestones based on start of practical activities on [**]:

 

	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    

 

Stability study: proposal for criteria for [**] month study at timepoints [**]

 

Stability acceptance criteria for alipogene tiparvovec

 

	
Test parameter
    	
 
    	
Acceptance Criteria
    	
 
    	
Method
    
	
 
    	
 
    	
General tests
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    

 

46

 

	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    

 

47

 

Development costs

 

The estimate costs for development and production of the clinical batch(es) and licensing costs are in euros and are:

 

	
 
    	
 
    	
Batch [**]
    	
 
    	
Batch [**]
    
	
Development   (including Quality Agreement):
    	
 
    	
 
    	
 
    	
 
    
	
Process   development
    	
 
    	
[**]
    	
 
    	
 
    
	
Assay   development
    	
 
    	
[**]
    	
 
    	
 
    
	
Virus   removal study
    	
 
    	
[**]
    	
 
    	
 
    
	
Stability   study
    	
 
    	
[**]
    	
 
    	
[**]
    
	
Preliminary   ref. standard qualification 
    	
 
    	
 
    	
 
    	
 
    
	
[**]   GMP batch
    	
 
    	
[**]
    	
 
    	
 
    
	
Manufacture:
    	
 
    	
 
    	
 
    	
 
    
	
[**]   GMP batch
    	
 
    	
[**]
    	
 
    	
[**]
    
	
IMPD   / IB
    	
 
    	
[**]
    	
 
    	
 
    
	
Qualification   of analytics
    	
 
    	
[**]
    	
 
    	
[**]
    
	
Overheads   on FTE
    	
 
    	
[**]
    	
 
    	
 
    
	
Total   Cost estimate
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Discount

 

AMT recognise the substantial time committed to this project to date by all parties.  In the interests of trying to support this project going forward, AMT is prepared to offer [**] against the costs of each of Batch [**] and Batch [**] above.

 

Payment Plan

 

	
Signature   fee
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    

 

48

 

Additional Services

 

Additional storage of Batches, or any other Institut Pasteur owned property (Raw Materials, Product, etc) beyond the first [**] month period : €[**] per month per [**] volume (or part thereof)

 

Provision of documents or other work product (other than the MPR, the Manufacturing Documentation and copies of Batch Disposition Documentation and any other documents or work product expressly required to be delivered under this Agreement) that do not exist as of the date of request or other substantive requests for assistance in compiling any Regulatory Filing : €[**]/hour for AMT staff together with reimbursement of third party expenses as invoiced to AMT.

 

Additional manufacturing audits : €[**]/hour for AMT staff together with reimbursement of third party expenses as invoiced to AMT.

 

49

 

Exhibit B

 

AMT’s Standard Formats for its Batch Disposition Documents

 

The Certificate of Analysis (CoA) shall be substantially in the form set out below:

 

[the remainder of this page intentionally blank]

 

50

	
  

  	
  controlled
  document - confidential Certificate of Analysis SMS number: Product: Part
  number: Batch number: Production stage: Expiry date: Test, Method                                                Specification
  Result pH, (QC-AIM-0013) Genome copies, (QC-AIM-0009) Endotoxin Osmolality,
  (QC-AIM-0017) Extractable Volume, (QC-AIM-0037) Color, (QC-AIM-0006) Clarity,
  (QC-AIM-0042) Sub-visible Particles, (Ph.Eur.2.9.19) Sub-visible Particles,
  (Ph.Eur.2.9.19) Residual Baculovirus DNA, (QC-AIM-0024) Residual SF+ DNA
  Residual SF+ Protein Sterility, (SB281) Physical State, (QC-AIM-0006) Capsid
  Protein composition by microfluidic electrophoresls, (QC-AIM-0031) Protein
  Purity by micro fluidic electrophoresis, (QC-AIM-0031) Protein impunities by
  microfluidic electrophoresis, (QC-AIM-0031) Total Proteins, (QC-AIM-0022)
  Potency, Sucrose by refraction index, (QC-AIM-0008) Ratio full: infectious
  particles (gc/lp), (calculation) Ratio total: full particies (tp/gc),
  (QC-AIM-0025) Monomer AAV Particles by DLS, (QC-AIM-0028) Particle aggregate
  by DLS, (QC-AIM-0028) Remarks : N/a Conclusion : The results comply with the
  specifications. Authorized signature : Name: AMT BV Visiting address
  Meibergdreef 61 1105 BA Amsterdam The Netherlands Postal address P.O.Box
  22506 1100 DA Amsterdam The Netherlands tel +31 (0)20 566 7394 fax +31 (0)20
  566 9272 info@amibiopharma.com www.amibiopharma.com

  

 

 

51

 

 

The Certificate of Release (CoR) shall be substantially in the form set out below:

 

[the remainder of this page intentionally blank]

 

52

	
  

  	
  Certificate of
  Release For product for clinical use Product name: Date manufactured: Proper
  name: Expiry/retest date: Quantity: Storage conditions: Batch number:
  Manufacturer: AMT Production Site: Meibergdreef 61, 1105 BA Amsterdam, The
  Netherlands Sponsor: Sponsor Address: Clinical Investigation Site (s):
  Address: Release tests: : All test results are within approved
  specifications. : Not all testing specifications have been met. The rationale
  for use is appended. Certificaron statement: I hereby certify that the above
  information is authentic and accurate. This batch has been manufactured at
  the above-mentioned site in full compliance with the EU GMP requirements and
  the specifications described in module 3 of the Investigational Medicinal
  Product Dossier (IMPD), date xxx, version x. The batch manufacturing and
  analytical records were reviewed and found to be in compliance with GMP. AMT
  is certified by the Dutch Health Authorities (ministerie van VWS),
  manufacture licence no. 108990F, to manufacture biological products (gene
  therapeutics) for clinical trial use. Name: A. Vroege Position: Qualified
  Person Signature: Date: Release statement by Sponsor:

  

 

53
 

 

	
  

  	
  Considering
  that all requirements of article 9 of EU Directive 2001/20/EC have been
  fulfilled, I, as representative of the Sponsor, authorize the shipment of
  this batch of XXXX to the clinical investigation site(s) mentioned above.
  Name: Position: Signature: Date:

  

 

54

 

 

Exhibit C
  Quality agreement

 

To be completed within [**] months after the Effective Date

 

55

 

 

	
 
    	
INSTITUT PASTEUR
    	
(1)
    
	
 
    	
 
    	
 
    
	
 
    	
and
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
AMSTERDAM MOLECULAR THERAPEUTICS (AMT) BV
    	
(2)
    

 

 

AMENDMENT N°1 TO THE DEVELOPMENT 
 and MANUFACTURING AGREEMENT

 

 

 

THIS AMENDMENT N°1 TO THE DEVELOPMENT AND MANUFACTURING AGREEMENT (this “Amendment”) is effective as of January 7th, 2011 (“Effective Date”).

 

BY AND BETWEEN

 

ON THE ONE HAND

 

(1)           INSTITUT PASTEUR a non profit private foundation organized under the laws of France with offices at 25-28 rue du Docteur Roux, 75 724 Paris Cedex 15, France, VAT FR 65 775 684 897 (“Institut Pasteur”), acting herein in the name and behalf of the Consortium (“Consortium” and each designated individually as “Consortium Member”) which has been organized under an agreement by and between the following members:

 

L’INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE, Etablissement Public á caractére Scientifique et Technologique, organized under the laws of France, having its principal offices at 101 rue de Tolbiac, 75013 Paris, (“INSERM”),

 

INSERM TRANSFERT, Société Anonyme, organized under the laws of France, registered under RCS Paris n° 434 033 619 having its principal offices at 7, rue Watt - 75013 Paris, (“INSERM-TRANSFERT”),

 

L’ECOLE NATIONALE VETERINAIRE ET DE L’AGROALIMENTAIRE ET DE L’ALIMENTATION DE NANTES ATLANTIQUE, centre d’expérimentation sur l’animal en thérapie génique et cellulaire, organized under the laws of France, having its principal offices at Atlanpole - La Chantrerie - 44 307 NANTES, (“ONIRIS”),

 

INSTITUT PASTEUR a non profit private foundation organized under the laws of France with offices at 25-28 rue du Docteur Roux, 75 724 Paris Cedex 15, France, VAT FR 65 775 684 897 (“INSTITUT PASTEUR”),

 

L’ASSOCIATION FRANCAISE CONTRE LES MYOPATHIES, L’Association Francaise contre les Myopathies, an association governed by the law of July 1, 1907, reconnue d’utilite pubtique de droit prive, organized and existing under the laws of France, having its principal office at L’lnstitut de Myologie, 47-83 boulevard de L’Hopitat, 75651 Paris Cedex 13, (AFM)

 

(“the Consortium represented herein by “Institut Pasteur”)]

 

And

 

1

 

ON THE OTHER HAND

 

(2)           AMSTERDAM MOLECULAR THERAPEUTICS (AMT) BV a company incorporated under the laws of the Netherlands, with offices at P.O.Box 22506 - 1100 DA Amsterdam, The Netherlands, (“AMT”).

 

(each, a “Party” and together the “Parties”)

 

BACKGROUND:

 

(A)          The Parties have signed a Development and Manufacturing Agreement dated January 7th, 2011 (hereinafter the “Agreement”).

 

(B)          The Parties have identified some points to be clarified in the Agreement.

 

IT IS NOW AGREED AS FOLLOWS:

 

1              Modifications

 

1.1.         The provisions of the Article 4.1 of the Agreement is cancelled and replaced by the following :

 

“4.1.Quality Agreement. The Quality Agreement shall be agreed and executed within [**] months following the Effective Date and shall specify certain testing, storage, release, cGMP, regulatory and other quality assurance requirements relating to manufacture and shipment of Product by AMT under this Agreement. AMT shall comply with the Quality Agreement at all times in carrying out its obligations under this Agreement. “

 

1.2.         The Exhibit A of the Agreement is cancelled and replaced by the Exhibit A of this Amendment.

 

2              Miscellaneous

 

2.1.         All the other provisions of the Agreement remain unchanged and fully applicable between the Parties.

 

2.2.         This Amendment is effective retroactively from January 7th, 2011.

 

2.3.         This Amendment makes integral part of the Agreement.

 

IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed as of the Effective Date.

 

2

 

	
 
    	
INSTITUT PASTEUR
    
	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
By:
    	
/s/ Christophe Mauriet
    
	
 
    	
Name:
    	
Christophe Mauriet
    
	
 
    	
Title:
    	
Senior Executive Vice-President
    
	
 
    	
Date:
    	
04 ADUT 2011
    
	
 
    	
 
    	
 
    
	
 
    	
 
    
	
 
    	
AMSTERDAM MOLECULAR THERAPEUTICS (AMT) BV
    
	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
By:
    	
/s/ J. Preusling (M. Mare)
    
	
 
    	
Name:
    	
J. Preusling 
    	
M Mareli
    
	
 
    	
Title:
    	
Dir. PMI OPS 
    	
Dir. HR
    
	
 
    	
Date:
    	
12 Aug 11 
    	
12 Aug 11
    

 

3

 

Exhibit A
 Project Plan

 

Sanfilippo B or mucoplysaccharidosis type IIIB (MPSIIIB) is a lysosomal storage disease for which currently no treatment is available. The rationale for the present approach is the observation that the phenotype of MPSs can be reversed by enzyme replacement therapy. In case of Sanfilippo B the disease is caused by an autosomal recessive genetic defect of the lysosomal enzyme -N-acetylglucosaminidase (NaGlu). It was shown recently in different preclinical models that gene delivery of NaGlu has the potential to cure Sanfilippo B. The goal of the present project is to produce GMP grade AAV-NaGlu vector in sufficient amounts for clinical trials. The efficacy and safety of this vector will be tested in different animal models (for efficacy by measuring enzyme activity in MPSIIIB mice, for safety by performing toxicology and biodistribution studies in normal rats and dogs) before it will be applied in a phase I clinical trial.

 

Responsibilities

 

The table below outlines the main tasks and the parties responsibility for the delivery of the task.

 

	
 
    	
 
    	
Task
    	
 
    	
AMT responsibility
    	
 
    	
Institut Pasteur
   responsibility
    
	
1
    	
 
    	
Process   Development
    	
 
    	
[**]
    	
 
    	
[**]
    
	
2
    	
 
    	
Assay   Development
    	
 
    	
[**]
    	
 
    	
[**]
    
	
3
    	
 
    	
In   vivo tests in mice
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
Tox   in rats and dogs
    	
 
    	
 
    	
 
    	
[**]
    
	
4
    	
 
    	
MSV/WSV   for cGMP batches
    	
 
    	
[**]
    	
 
    	
[**]
    
	
5
    	
 
    	
cGMP   batch production
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Assay to de developed

 

AAV5-specific assays will be developed by AMT; these will include:

 

[**]

 

In addition, AMT will develop a transgene specific Q-PCR. A basic protocol has been already established at AMT, however, this process needs to be qualified prior to the initiation of the clinical phase I study.

 

A second Q-PCR will be established in collaboration with a service provider. This Q.-PCR method will be used by Institut Pasteur in biodistribution studies in rats.

 

Develop production platform

 

AMT will develop a robust upstream and downstream process suitable for the production of GMP material. The progress of the development process will be monitored by Q-PCR (and in vivo studies in mice). The in vivo studies will measure the transduction efficiency of AAV5-NaGlu, 

 

4

 

and will be used as potency assay. Institut Pasteur will be responsible for the in vivo potency assays that will accompany the process development work. MPSIIIB mice will be used for the study. The mice will be diagnosed at birth by PCR, they will be used for the study when aged between week [**]. The material from the [**] development batches will be used to perform these studies. The NaGlu catalytic activity resulting from gene transfer by the AAV5-NaGlu vector will be measured in brain extracts approximately [**] weeks post injection.

 

AMT has planned to deliver a maximum of [**] development batches during this phase. The production of the [**] development batch will be done adapting the AAV5-NaGlu production process previously developed at AMT.

 

The current AAV5 process is based on AMT’s proprietary baculovirus / insect cell platform which will be used to produce the AAV5-NaGlu vector. The vector will be purified by DNA-ase incubation followed by a chemical lysis step after which cell debris is removed by depth filtration. The clarified harvest is incubated overnight as a viral inactivation step. The inactivated material is purified by affinity chromatography and ion-exchange chromatography after which buffer exchange is performed using ultrafiltration/diafiltration (UF/DF). The intended formulation buffer consists of phosphate buffered saline (PBS) and [**]. After UF/DF the product is frozen at [**] and samples are analyzed according to a pre-determined list of analyses and specification. The result of the Q-PCR analysis will be used to dilute the product to the target concentration of the finished product. The product will be filled into [**] vials with a chorobutyl stopper and aluminum cap filled with 1.2 mL of finished product. The closed vials will be stored at [**] for storage until release and use.

 

Following the delivery of the batch, Institut Pasteur will test the batch in vivo in a mouse model (in vivo potency study). If needed, further process optimization will be employed for the production of the [**] development batch, which will be again tested as above. Final process optimization work will result in the production of the [**] development batch, which will be again tested as above. The process used for the most successful in vivo study (highest NaGlu activity per mg of protein in extracts prepared from the entire injected brain hemisphere) will be employed for the Tox studies. The same process will be taken into a GMP environment for the production of clinical material. Purchasing new equipment for optimization of the manufacturing process is not included in the scope of this project.

 

Project phases

 

1.               Development batches

 

AMT will deliver maximally [**] development batches which will be performed on [**] scale. The purified product will be tested with a Q-PCR by AMT to determine the strength. A sample will be shipped to Institut Pasteur for an in vivo test in the mouse model to test its in vivo activity and whether it meets the criteria (to be established) for further product development. After completion of each batches there will be a formal Go/No Go based on the outcome of the in-vivo test results obtained by Institut Pasteur. The in vivo tests determine whether the product produced by AMT would be meeting the requirements for a clinical study. AMT and Institut Pasteur have to define the requirements for successful in 

 

5

 

vivo activity. Documentation of the development batches is such that they can be used for a tox study by Institut Pasteur. For this tox batch extra release assays are needed.

 

2.               Analytical development

 

AMT will develop some assays for the AAV5-NaGlu vector characterization. These will include:

 

[**]

 

For other assays such as general test for contaminations, sucrose content, bioburden, sterility, infectious particles assay, rcAAV, residual host cell DNA and protein, residual Triton, residual Benzonase it is assumed that no development is needed and this is therefore not included in the scope of this project.

 

A typical bill of testing for the finished product is listed in the Table below. Some process related impurities such as residual Benzonase, Triton, infectious baculovirus are tested on the active substance level and safety assays such as adventitious virus agents are tested during the manufacturing process on the bulk harvest prior to addition of Triton. AMT and Institut Pasteur have to agree on the number of (critical) in process controls for which AMT will make a proposal for discussion.

 

6

 

Tentative Acceptance Criteria - Batch 1

 

	
Test parameter
    	
 
    	
Tentative Acceptance Criteria
    
	
General tests and tests   for contamination
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    
	
[**]
    	
 
    	
[**]
    

 

7

 

	
 
    	
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[**]
    	
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[**]
    	
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[**]
    	
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[**]
    	
[**]
    

 

Please note that the above table provides estimate acceptance criteria. Exact acceptance criteria will need to be discussed and agreed in the project team but with no substantial changes.

 

3.              MSV / WSV production

 

AMT will produce a GMP compliant Master Seed Virus and Working Seed Virus Bank of at least [**] vials of the baculovirus containing the NaGlu gene cassette. The MSV and WSV will be tested according to EP requirements and similar to previous virus banks which were qualified by AMT. The GMP compliant AAV5 and Rep containing MSV and WSV baculoviruses are already available for the production of the NaGlu vector.

 

4.              GMP batch

 

Because of the small amounts of product that are expected for a clinical phase I study and because it is expected that the AAV5-NaGlu product is stable for a long period of time at conditions of [**] or lower, [**] cGMP batch will be produced for supply the clinical material. In additional to the batch production, the appropriate testing will be done as required. AMT and Institut Pasteur will have to agree on the final bill of testing for the clinical drug product. AMT will release the product to Institut Pasteur based on meeting the specifications on the bill of testing. Acceptance of the batch by Institut Pasteur is done based on AMT release statement.

 

5.              Stability study

 

AMT will conduct a stability study on the material used in the Tox study to prove that the product was still stable upon the start of the study, and to determine a preliminary shelf life. The clinical batch will also be put on stability for a period of a maximum [**] months and will be periodically tested for stability. Based on the outcome, the finished product can be given a shelf life of [**] months.

 

8

 

6.              Reference standard

 

AMT will use some material of the GMP batch for the initial reference standard and will qualify the reference standard based on a protocol which will have to be agreed between Institut Pasteur and AMT.

 

7.              Tox and safety studies

 

Not included in AMT’s project scope. Tox study will be performed under responsibility of Institut Pasteur. AMT can contribute advice upon request based on its experience in conducting gene therapy Tox and safety studies.

 

8.              Phase I/II clinical study

 

Not included in AMT’s project scope. Clinical study and all its related activities (analysis of clinical samples etc.) will be performed under responsibility of Institut Pasteur. AMT can contribute advice upon request based on its experience in conducting gene therapy clinical trial, for up to [**] hours without charge.

 

9.              Viral clearance / inactivation study

 

AMT will produce [**] using an identical recipe to the cGMP clinical batch to generate materials for an adventitious viral agents removal study and for a baculovirus removal study. The [**] study will be outsourced to a qualified contract laboratory. In the [**] study one enveloped and one unenveloped model virus will be tested for inactivation and clearance by the process (singular experiment). AMT will report the first study and will make the reports available for submission of the IMPD or equivalent application for the clinical study by Institut Pasteur.

 

Regulatory Affairs Strategy

 

Contacts to AFSSAPS have already been established by Institut Pasteur. Institut Pasteur will be responsible for the interaction with AFSSAPS. institut Pasteur will keep AMT informed about any advice received that relates to manufacturing.

 

Institut Pasteur is responsible for the orphan drug application. AMT will contribute information related to product development and manufacturing as part of this project, if any.

 

QP Release

 

AMT, as contract manufacturer, will release the manufacturing data as well as the quality control data generated by AMT or AMT’s vendors. The QP of AMT will provide Institut Pasteur with a certificate stating that production has taken place according to GMP and test results comply with the specification.

 

9

 

Project Plan - Delivery Dates

 

[**]

 

Milestones based on start of practical activities on [**]:

 

	
[**]
    	
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[**]
    	
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Stability study: proposal for criteria for [**] month study at timepoints [**]

 

Stability acceptance criteria

 

	
Test parameter
    	
 
    	
Acceptance Criteria
    	
 
    	
Method
    
	
General tests
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
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10

 

	
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11

 

Development costs

 

The estimate costs for development and production of the clinical batch(es) and licensing costs are in euros and are:

 

	
 
    	
 
    	
Batch
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Batch
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Development   (including Quality Agreement):
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Process   development
    	
 
    	
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Assay   development
    	
 
    	
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Virus   removal study
    	
 
    	
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Stability   study
    	
 
    	
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Preliminary   ref. standard qualification [**] GMP batch
    	
 
    	
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Release   assays [**]
    	
 
    	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Manufacture:
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]   GMP batch
    	
 
    	
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IMPD   / IB
    	
 
    	
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Qualification   of analytics
    	
 
    	
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Overheads   on FTE
    	
 
    	
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QP   costs
    	
 
    	
 
    	
 
    	
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Total   Cost estimate
    	
 
    	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Discount

 

AMT recognise the substantial time committed to this project to date by all parties. In the interests of trying to support this project going forward, AT is prepared to offer [**] against the costs of each of Batch [**] and Batch [**] above.

 

Payment Plan

 

	
Signature fee
    	
 
    	
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Additional Services

 

Additional storage of Batches, or any other Institut Pasteur owned property (Raw Materials, Product, etc) beyond the first [**] month period : €[**] per month per [**] volume (or part thereof)

 

Provision of documents or other work product (other than the MPR, the Manufacturing Documentation and copies of Batch Disposition Documentation and any other documents or work product expressly required to be delivered under this Agreement) that do not exist as of the date of

 

12

 

request or other substantive requests for assistance in compiling any Regulatory Filing : €[**]/hour for AMT staff together with reimbursement of third party expenses as invoiced to AMT.

 

Additional manufacturing audits : €[**]/hour for AMT staff together with reimbursement of third party expenses as invoiced to AMT.

 

13Exhibit 10.15

 

Confidential Materials omitted and filed separately with the

Securities and Exchange Commission.  Double asterisks denote omissions.

 

LICENSE AGREEMENT

 

Preamble

 

This License Agreement (this “Agreement”) effective as of November 30, 2010 (the “Effective Date”), is made by and between Amsterdam Molecular Therapeutics (AMT) B.V., a closed limited liability company with registered offices at Meibergdreef 61, 1100 DA Amsterdam, the Netherlands (“AMT’), and Amgen Inc., a Delaware corporation whose address is One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA (“Amgen”).  AMT and Amgen are sometimes referred to herein individually as a “Party” and collectively as the “Parties”.

 

Recitals

 

WHEREAS, AMT is a company engaged in the research, development, manufacturing and commercialization of gene therapy products, including research and development of therapeutics for the treatment of neurological diseases and other diseases; and

 

WHEREAS, Amgen is a company engaged in the research, development, manufacturing and commercialization of pharmaceutical and biotechnology products, including research and development of therapeutics for the treatment of neurological diseases and other diseases; and

 

WHEREAS, Amgen has developed glial-cell derived neurotrophic factor (“GDNF”) for the treatment of neurological diseases and has certain rights to Licensed Patent Rights and Licensed Know-How (each as defined below), but Amgen is not currently engaged in the Exploitation (as defined below) of any gene therapy treatment with respect to GDNF; and

 

WHEREAS, Amgen and AMT previously entered into that certain License and Collaboration Agreement dated as of September 11, 2008 (the “Original Agreement”) pursuant to which the Parties agreed to participate in a collaboration relating to the development and production of a recombinant adeno-associated virus (“AAV”) that delivers GDNF; and

 

WHEREAS, the Parties wish to terminate the Original Agreement and by this Agreement to provide for a license by Amgen to AMT under the Licensed Patent Rights and the Licensed Know-How for the Exploitation of GDNF Products (as defined below).

 

NOW, THEREFORE, the Parties in consideration of the mutual representations, warranties and covenants contained herein and for other good and valuable consideration, hereby agree as follows:

 

ARTICLE 1.                                    DEFINITIONS

 

The following terms shall have the meanings set forth below:

 

SECTION 1.1                                             “AAV” has the meaning set forth in the Recitals.

 

Amgen Contract No.: 2010549620

 

1

 

SECTION 1.2                                             “Affiliate” means any Person which controls, is controlled by or is under common control with a Party.  For purposes of this Section 1.2 (“Affiliate”), “control” shall mean (i) in the case of corporate entities, direct or indirect ownership of fifty percent (50%) or more of the stock or shares entitled to vote for the election of directors and (ii) in the case of non-corporate entities, direct or indirect ownership of fifty percent (50%) or more of the equity or income interest therein.  Notwithstanding the preceding provisions, with respect to an Affiliate of a Party to this Agreement, once such entity ceases to be an Affiliate of such Party, then, without any further action, such entity shall cease to have any rights, including license and sublicense rights, under this Agreement by reason of being an Affiliate.

 

SECTION 1.3                                             “Agreement” has the meaning set forth in the Preamble.

 

SECTION 1.4                                             “Amgen” has the meaning set forth in the Preamble.

 

SECTION 1.5                                             “Amgen Indemnified Parties” has the meaning set forth in Section 9.9.2 (By AMT).

 

SECTION 1.6                                             “AMT” has the meaning set forth in the Preamble.

 

SECTION 1.7                                             “AMT Improvements” means all Know-How and Materials comprising or relating to any results generated solely by or on behalf of AMT in its Exploitation of GDNF Products up to the date of any termination of this Agreement comprising (i) construction of the baculoviruses required for manufacturing of a GDNF Product in insect cells and any other process development or optimization of AMT’s baculovirus-based vector production system in insect suspension culture (upstream) or affinity chromatography-based purification system (downstream); or (ii) improvements and characterization of AMT’s AAV5 platform, particularly for CNS applications; in each case including but not limited to all improvements, modifications and developments generated solely by or on behalf of AMT in its Exploitation of GDNF Products up to the date of any termination of this Agreement to the AMT Licensed Know-How (including AMT Manufacturing Technology) and Materials comprising AMT Licensed Know-How as of the Original Agreement Effective Date relating to the subject matter described in clauses (i) and (ii) above.

 

SECTION 1.8                                             “AMT Indemnified Parties” has the meaning set forth in Section 9.9.1 (By Amgen).

 

SECTION 1.9                                             “AMT Licensed Know-How” means all Know-How including AMT Manufacturing Technology and Materials that is Controlled by AMT and/or its Affiliates during the term of this Agreement including AMT Improvements.

 

SECTION 1.10                                      “AMT Licensed Patent Rights” means (i) (a) the patents and patent applications listed on Schedule 1.10 and any patent applications from which any such patents or patent applications claim priority and any patent applications filed by AMT claiming or otherwise in relation to AMT Improvements; (b) all patent applications filed in any jurisdiction corresponding to or claiming priority directly or indirectly from any patent and/or patent 

 

2

 

application referred to in the foregoing clause (a); (c) all divisionals, continuations and continuations-in-part of the patent applications referred to in the foregoing clauses (a) and (b); (d) all patents issuing from the patent applications referred to in the foregoing clauses (a), (b) and (c); and (e) all reissues, re-filings, re-examination certificates, registrations, confirmations, extensions, substitutions, renewals, foreign counterparts, and supplementary protection certificates of the patents and/or patent applications referred to in the foregoing clauses (a), (b), (c) and (d), and (ii) any and all patents and/or patent applications Controlled during the term of this Agreement by AMT and/or its Affiliates that would (absent the licenses granted herein) be infringed by the Exploitation of a GDNF Product or the infringement of which would (absent the licenses granted herein) be induced or contributed to by the Exploitation of a GDNF Product.  For purposes of determining whether a patent application falls within this definition, a patent application shall be considered “infringed” if its pending claims would be infringed if issued as then currently set forth in the patent application.

 

SECTION 1.11                                      “AMT Manufacturing Technology” means any of the following that are reasonably necessary for manufacturing of GDNF Products: (i) AAVs, virions, plasmids, host cells, packaging cells, or components of any of the foregoing, reagents, assays, processes, and protocols; (ii) data, including in vivo and in vitro data produced by or on behalf of AMT or its Affiliates; and (iii) any other documentation (including any CMC sections of regulatory filings) or materials in each case (i), (ii) and (iii) Controlled by AMT or its Affiliates.

 

SECTION 1.12                                      “Bankruptcy Code” has the meaning set forth in Section 9.21 (License to Intellectual Property).

 

SECTION 1.13                                      “Bundle” means a GDNF Product (a) sold together with another pharmaceutical product for a single price including fixed combinations or (b) sold as part of a delivery agent (such as a viral vector) which contains two or more different therapeutic genes or therapeutic fragments of genes and not all of the therapeutic genes or fragments of genes encode GDNF or a fragment of GDNF that has Functional Activity.

 

SECTION 1.14                                      “Business Day” means a calendar day that is neither (a) a public holiday in New York, New York, (b) a recognized Federal holiday in the U.S. (b) a government-recognized holiday in the Netherlands, nor (d) a formal company-specific holiday of a Party, including Amgen’s voluntary holiday shut downs.

 

SECTION 1.15                                      “Calendar Quarter” means each respective period of 3 consecutive months ending on March 31, June 30, September 30 and December 31 of each Calendar Year.

 

SECTION 1.16                                      “Calendar Year” means each respective period of 12 months commencing on January 1 and ending on December 31.

 

SECTION 1.17                                      “CMO” has the meaning set forth in Section 3.1 (Manufacturing).

 

SECTION 1.18                                      “COGS” means all direct costs actually incurred by AMT and/or its Affiliates (and for the purposes of Section 4.2(iii), and/or its Sublicensees) in (i) the manufacture (or 

 

3

 

procurement from Third Parties) of GDNF Products, including purchase of raw materials used to manufacture GDNF Products, payments to Third Party subcontractors for the manufacture of GDNF Products and (ii) the provision of services using GDNF Products, but in each case excluding Third Party License Payments; provided, however, that (A) “COGS” shall not include any amounts attributable to (i) idle or underutilized facilities, (ii) general corporate overhead, or (iii) equity-based compensation provided to any employee, officer or director of AMT and/or its Affiliate (and for the purposes of Section 4.2(iii), and/or its Sublicensees), and (B) in determining “COGS,” amounts related to or attributable to employees of AMT and/or its Affiliates (and for the purposes of Section 4.2(iii), and/or its Sublicensees) shall only be included to the extent they are Employment Costs allocable to personnel directly involved in the manufacture of GDNF Products such as equipment operators, line mechanics, set up mechanics and material handlers to supply the line, and amounts allocable to time during which such Product-Related Personnel conduct other activities (including without limitation manufacture of other products), as well as Employee Costs for any other personnel, shall be excluded.

 

SECTION 1.19                                      “Collaboration Option” has the meaning set forth in Section 2.6 (Collaboration Option).

 

SECTION 1.20                                      “Collaboration Territory” means the U.S., Mexico and Canada.

 

SECTION 1.21                                      “Completion of the first Phase 2 Clinical Trial” means completion and approval of the Clinical Study Report as defined in ICH E6 or its equivalent in any jurisdiction where such Phase 2 Clinical Trial is carried out.

 

SECTION 1.22                                      “Confidential Information” means all proprietary information (whether or not patentable) communicated to either Party by or on the behalf of the other Party and indicated in writing as “Confidential” (or, if disclosed orally or visually, indicated in a written summary as confidential within [**] days of the initial disclosure thereof), including:  formulations, techniques, methodology, equipment, instrumentation, data, reports, know-how, sources of supply, patent positioning, business plans and projections, Sublicense terms, Payment Reports, and strategy and other information about prosecution of the Licensed Patent Rights, including the content of any communications under Section 7.1 (Patent Prosecution).

 

SECTION 1.23                                      “Control” means with respect to any Know-How (including any Licensed Know-How), Material or intellectual property rights (including Licensed Patent Rights) to which either Party has rights as of the Original Agreement Effective Date or obtains rights after the Original Agreement Effective Date but before termination of this Agreement, possession by a Party or its Affiliate of the ability (whether by ownership, license or otherwise) to grant access, a license or a sublicense to such Know-How, Material or intellectual property right as provided for in this Agreement (i) without violating the terms of any agreement with any Third Party in existence as of the Original Agreement Effective Date and (ii) without requiring any further payment (whether or not then due and payable) under any agreement with any Third Party (unless Amgen has, in accordance with Section 8.5.1.1 (Grant of License), elected to pay AMT any

 

4

 

amounts owed to such Third Party under the Third Party Agreements by reason of Amgen’s Exploitation of GDNF Products).

 

SECTION 1.24                                      “Cover” means that the Exploitation of a GDNF Product within the Licensed Field would infringe or induce or contribute to the infringement of a Patent Right absent a license thereof.

 

SECTION 1.25                                      “Data Package” has the meaning set forth in Section 2.6 (Collaboration Option).

 

SECTION 1.26                                      “Defending Party” has the meaning set forth in Section 7.2 (Defense of Third Party Infringement Claims).

 

SECTION 1.27                                      “Diligence Notice” has the meaning set forth in Section 5.5 (Diligence Schedule).

 

SECTION 1.28                                      “Divest” means, with respect to any Subsequent Distracting Program, the sale, exclusive license or other transfer of all of the right, title and interest in and to such Subsequent Distracting Program, as applicable, including technology, know-how, patent(s), trademark(s), and other assets solely relating thereto, (except to the extent that such other assets have uses other than for the Subsequent Distracting Program) to an independent Third Party by AMT or its Affiliates without the retention or reservation of any rights or interest, including not exercising nor having the ability to materially participate in or advise with respect to the research, development, manufacture or commercialization of any product in the Subsequent Distracting Program (other than solely an economic interest, the right to enforce customary terms and conditions contained in the relevant agreements effectuating such Divestiture (such as obligations to use diligent efforts to develop and/or commercialize the Subsequent Distracting Program) and customary reversionary rights in the event of certain terminations).  For avoidance of doubt, co-development and co-marketing arrangements are not considered transactions that Divest a Subsequent Distracting Program.

 

SECTION 1.29                                      “Effective Date” has the meaning set forth in the Preamble.

 

SECTION 1.30                                      “EMA” means the European Medicines Agency and any successor agency.

 

SECTION 1.31                                      “Employment Costs” means actual costs incurred by AMT and/or its Affiliates with respect to any employee, but excluding any allocable overhead.

 

SECTION 1.32                                      “Enforcement Action” has the meaning set forth in Section 7.3 (Enforcement).

 

SECTION 1.33                                      “Enforcing Party” has the meaning set forth in Section 7.3 (Enforcement).

 

SECTION 1.34                                      “Exploit” means to research, have researched, develop, have developed, make, have made, use, have used, offer for sale, have offered for sale, sell, have sold, import, have

 

5

 

imported, export have exported or otherwise exploit, or transfer possession of or title in, a product.  Cognates of the word “Exploit” shall have correlative meanings.

 

SECTION 1.35                                      “FDA” means the United States Food and Drug Administration and any successor agency.

 

SECTION 1.36                                      “Foreign Currency Amount” has the meaning set forth in Section 6.3 (Exchange Rate; Manner and Place of Payment).

 

SECTION 1.37                                      “Functional Activity” means neurotrophic activity with respect to dopaminergic neurons with an ability to (i) signal through the GDNF receptor complex and (ii) (a) increase tyrosine hydroxylase immunoreactivity or (b) protect against neurotoxin-mediated cell death.

 

SECTION 1.38                                      “IFRS” means International Financial Reporting Standards, consistently applied, as used by AMT to record the relevant transaction.

 

SECTION 1.39                                      “Infringing Product” has the meaning set forth in Section 7.3 (Enforcement).

 

SECTION 1.40                                      “GDNF” has the meaning set forth in the Recitals.

 

SECTION 1.41                                      “GDNF Product” means any Gene Therapy product capable of delivering GDNF or the gene encoding GDNF, or in either case any fragment of GDNF that has Functional Activity.

 

SECTION 1.42                                      “Gene Therapy” means therapy conducted by means of delivery (by any means, including ex vivo, in vivo or otherwise) of one or more nucleic acid sequences (including, DNA, RNA or any hybrids thereof and combinations with other chemical entities or macromolecules, whether coding or noncoding).

 

SECTION 1.43                                      “Governmental Authority” means any government or supranational administrative agency, commission or other governmental or supranational authority, body or instrumentality, or any federal, state, local, domestic or foreign governmental or supranational regulatory body.

 

SECTION 1.44                                      “IND” means an Investigational New Drug Application (including any amendments thereto) submitted to the FDA or any comparable filings with a Governmental Authority in any country outside the U.S. for a drug or other therapy, before the commencement of clinical trials involving a GDNF Product.

 

SECTION 1.45                                      “Know-How” means data, inventions, know-how, trade secrets, methods, knowledge and information (including chemical manufacturing data, toxicological data, pharmacological data, preclinical data, assays, platforms, formulations, specifications, and quality control testing data), in each case reasonably necessary for the Exploitation of GDNF Products.

 

6

 

SECTION 1.46                                      “Launch” means the date of the first commercial sale by AMT, its Affiliate or its Sublicensee of a GDNF Product.

 

SECTION 1.47                                      “Law” means, individually and collectively, any and all laws, ordinances, rules, directives, administrative circulars and regulations of any kind whatsoever of any Governmental Authority within the applicable jurisdiction together with the rules and regulations of any securities exchange.

 

SECTION 1.48                                      “Licensed Field” means all uses in Gene Therapy.

 

SECTION 1.49                                      “Licensed Know-How” means any Know-How that (i) is Controlled by Amgen and/or its Affiliates and (ii) was provided by Amgen to AMT under the Original Agreement (but only to the extent expressly designated in writing by Amgen as “Amgen Licensed Know-How”).  For the avoidance of doubt, the cell lines 32D and NGR-38 and the protocols outlining the methodology for the purposes of assessing the biological activity of the GDNF construct are Licensed Know-How.

 

SECTION 1.50                                      “Licensed Patent Rights” means (i) the patents and patent applications listed on Schedule 1.50 and any patent applications from which any such patents or patent applications claim priority; (ii) all patent applications filed in any jurisdiction corresponding to or claiming priority directly or indirectly from any patent and/or patent application referred to in the foregoing clause (i); (iii) all divisionals, continuations and continuations-in-part of the patent applications referred to in the foregoing clauses (i) and (ii); (iv) all patents issuing from the patent applications referred to in the foregoing clauses (i), (ii) and (iii); (v) all reissues, re-filings, re-examination certificates, registrations, confirmations, extensions, substitutions, renewals, foreign counterparts, and supplementary protection certificates of the patents and/or patent applications referred to in the foregoing clauses (i), (ii), (iii) and (iv); (vi) any other Patent Rights Controlled by Amgen and/or its Affiliates as of the Effective Date necessary for the Exploitation of a GDNF Product (but only to the extent such Patent Rights Cover any GDNF Product as developed by AMT as of the Effective Date); and (vii) any other Patent Rights Controlled by Amgen and/or its Affiliates during the Payment Term that have been conceived, generated or reduced to practice in the course of any research conducted in accordance with Section 2.2 and that are necessary or useful for the Exploitation of a GDNF Product.

 

SECTION 1.51                                      “Losses” has the meaning set forth in Section 9.9.1 (By Amgen).

 

SECTION 1.52                                      “Materials” means biological materials or chemical compounds including GDNF AAVs, virions, plasmids, host cells, packaging cells, or components of any of the foregoing, assays, screens, data, protocols, knock-out mice and other animal models, cell lines, cells, nucleic acids, receptors and reagents.

 

SECTION 1.53                                      “NDA” means a New Drug Application, Biological License Application or other applicable regulatory filing submitted to the FDA, the EMA or any equivalent entity outside the U.S. and the European Union for a drug or other therapy, which if granted, would be sufficient to permit under applicable Law the promotion and/or sale of such drug or other therapy.

 

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SECTION 1.54                                      “Net Revenues” means Net Sales and Net Service Revenues.  Notwithstanding the foregoing, in the event that Amgen exercises the Collaboration Option, Net Revenues shall exclude any Net Revenues achieved by Amgen, its Affiliates and/or their respective sublicensees in the Collaboration Territory.

 

SECTION 1.55                                      “Net Sales” means the gross invoiced sales prices charged for GDNF Products sold by or for AMT and/or its Affiliates (and for the purposes of Section 4.2(iii), and its Sublicensees) in arms length transactions to Third Parties (but not including sales relating to transactions between AMT, its Affiliates (and for the purposes of Section 4.2(iii), its Sublicensees), and/or their respective agents, unless for end use consumption), less the total of the following charges or expenses as determined in accordance with IFRS: (i) trade, cash, prompt payment and/or quantity discounts including promotional or service discounts; (ii) returns, allowances, rebates, chargebacks, or payments to government agencies; (iii) retroactive price reductions applicable to sales of such product; (iv) fees paid to distributors, selling agents (excluding any sales representatives of AMT or any of its Affiliates (or for the purposes of Section 4.2(iii), its Sublicensees)), group purchasing organizations and managed care entities or similar types of organizations; (v) credits or allowances for product replacement, whether cash or trade; (vi) non-recoverable sales taxes, excise taxes, tariffs and duties (excluding taxes when assessed on income derived from sales); and (vii) bad debt, freight or other transportation charges, insurance charges, additional special packaging, and other governmental charges.  Notwithstanding the foregoing, the Parties intend that Net Sales exclude amounts invoiced for or revenues attributable to services ancillary to the delivery or use of GDNF Products including surgical procedures, hospital stays or the like, as well as amounts invoiced for devices sold in connection with any GDNF Product.  If AMT (or its Affiliates (or for the purposes of Section 4.2(iii), its Sublicensees)) sells a GDNF Product to a Third Party to whom it also provides other products or services (including any device used or sold in connection with such GDNF Product), AMT (and its Affiliates (and for the purposes of Section 4.2(iii), its Sublicensees)) shall not price, discount or otherwise offer (including bundling) the GDNF Product in any way that benefits such other products or services at the expense of such GDNF Product or otherwise disadvantages Amgen with respect to royalties that would be paid to Amgen hereunder.  In all events, AMT (and its Affiliates (and for the purposes of Section 4.2(iii), its Sublicensees)) shall price and offer GDNF Products sold by it hereunder in a manner consistent with standard practices in the pharmaceutical industry and applicable Law.

 

Any disposal of GDNF Products at no charge for, or use of GDNF Products at no charge in clinical or pre-clinical trials, and GDNF Products given as free samples, or distributed at no charge to patients unable to purchase GDNF Product shall not be included in Net Sales.

 

Upon any sale or other disposal of any GDNF Product for any consideration other than an exclusively monetary consideration on bona fide arm’s length terms, then for purposes of calculating the Net Sales under this Agreement, such GDNF Product shall be deemed to be sold at the average sales price for such GDNF Product having the same dosage form and strength during the applicable reporting period in the country where such sale or other disposal occurred when such GDNF Product is sold alone and not with other products, and if such GDNF Product is not

 

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sold alone in such country during the applicable reporting period, then such GDNF Product shall be deemed to be sold at the average sales price during the applicable reporting period generally achieved for such GDNF Product having the same dosage form and strength in the rest of the world.

 

Where a GDNF Product is sold in a Bundle, then for the purposes of calculating the Net Sales under this Agreement, such GDNF Product shall be deemed to be sold for an amount equal to (X/(X+Y)) * Z, where: X is the average sales price during the applicable reporting period for such GDNF Product being sold alone (in the same dosage form) (or, should more than one GDNF Product be included in a Bundle with a product other than a GDNF Product, the sum of such average sales prices for the included GDNF Products) in the particular country of sale; Y is the sum of the average sales price during the applicable reporting period in the particular country of sale, when sold alone, of each pharmaceutical (other than the included GDNF Product(s)) included in the Bundle (in the same dosage form); and Z equals the Net Sales of such Bundle. In the event that a GDNF Product or one or more of the other pharmaceuticals in the Bundle are not sold separately (in the same dosage form), the Parties will discuss in good faith to determine an equitable fair market price to apply to such GDNF Product or other pharmaceutical in the Bundle.

 

SECTION 1.56                                      “Net Service Revenues” shall mean the revenues from any use of a GDNF Product in the provision of a service performed by or for AMT and its Affiliates and Sublicensees, to the extent not taken into account as Net Sales, less the total of the following charges or expenses as determined in accordance with IFRS, in each case as they relate to the provision of such service using a GDNF Product during such time period: (i) trade, cash, prompt payment and/or quantity discounts including promotional or service discounts; (ii) allowances, rebates, chargebacks, or payments to government agencies; and (iii) fees paid to selling agents (excluding any representatives of AMT or any of its Affiliates or Sublicensees), group purchasing organizations and managed care entities or similar types of organizations.  Notwithstanding the foregoing, the Parties intend that Net Service Revenues exclude amounts invoiced for or revenues attributable to services ancillary to the delivery or use of GDNF Products including surgical procedures, hospital stays or the like, as well as amounts invoiced for devices sold in connection with any GDNF Product.  If AMT (or its Affiliates or Sublicensees) uses a GDNF Product in connection with the provision of a service to a Third Party to whom it also provides other products or services (including any device used or sold in connection with such GDNF Product), AMT (and its Affiliates and Sublicensees) shall not price, discount or otherwise offer (including bundling) the GDNF Product in any way that benefits such other products or services at the expense of such GDNF Product or otherwise disadvantages Amgen with respect to royalties that would be paid to Amgen hereunder.  In all events, AMT (and its Affiliates and Sublicensees) shall price and offer services using GDNF Products hereunder in a manner consistent with standard practices in the pharmaceutical industry and applicable Law.

 

Where AMT (or its Affiliates or Sublicensees) uses a GDNF Product in a Bundle in connection with the provision of a service to a Third Party, then for the purposes of calculating the Net Service Revenues under this Agreement, such service shall be deemed to be provided for an amount equal to (X/(X+Y)) * Z, where: X is the average sales price during the applicable reporting period for the

 

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services in relation to such GDNF Product being provided alone (or, should more than one GDNF Product be included in a Bundle with a pharmaceutical product other than a GDNF Product, the sum of such average sales prices for the included GDNF Product) in the particular country of the provision of the service; Y is the sum of the average sales price during the applicable reporting period in the particular country of the provision of the service, when sold alone, of each pharmaceutical product (other than the included GDNF Product(s)) included in the Bundle; and Z equals the Net Service Revenues of such Bundle.  In the event that a service in connection with a GDNF Product or one or more of the other pharmaceutical products in the Bundle are not sold separately, the Parties will discuss in good faith to determine an equitable fair market price to apply to such GDNF Product services or other pharmaceutical products in the Bundle.  For the purposes of this definition, a GDNF Product service upon which Net Service Revenues are payable is that service directly related to the use of the GDNF Product and not any ancillary services.  For example, but not by way of limitation, a GDNF Product service would be the injection of a GDNF Product into a patient but would not cover any fees payable for the patient’s hospital stay or for other procedures carried out on the patient, for example to check that they are suitable for treatment.

 

SECTION 1.57                                      “Original Agreement” has the meaning set forth in the Recitals.

 

SECTION 1.58                                      “Original Agreement Effective Date” means September 11, 2008.

 

SECTION 1.59                                      “Partnered Net Revenues” means any Net Revenue attributable to the sale of a GDNF Product that is the subject of a profit and loss allocation between AMT and any Sublicensee.  For the avoidance of doubt, Partnered Net Revenues does not include any Sublicensing Revenue, in particular royalties or milestones paid by a Sublicensee to AMT.

 

SECTION 1.60                                      “Party” has the meaning set forth in the Preamble.

 

SECTION 1.61                                      “Patent Rights” means any patent applications and any patents issuing from such patent applications, author certificates, inventor certificates, utility certificates, improvement patents and models, and certificates of addition and all counterparts of them throughout the world, including any divisional applications and patents, filings, renewals, continuations, continuations-in-part, patents of addition, extensions, reissues, substitutions, confirmations, registrations, revalidation and additions of or to any of them, as well as any supplementary protection certificates and equivalent protection rights in respect of any of them.

 

SECTION 1.62                                      “Payment Report” has the meaning set forth in Section 6.1 (Payment; Reports).

 

SECTION 1.63                                      “Payment Term” means, with respect to a Licensed Product in a given country, the period of time commencing on Launch of such Licensed Product in such country and continuing until the later of (a) expiration of the last to expire Licensed Patent Right issued in such country containing at least one Valid Claim Covering the GDNF Product and (b) the tenth (10th) anniversary of Launch of such GDNF Product in such country.

 

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SECTION 1.64                                      “Person” means an individual, corporation, partnership, limited liability company, trust, business trust, association, joint stock company, joint venture, pool, syndicate, sole proprietorship, unincorporated organization, governmental authority or any other form of entity not specifically listed herein.

 

SECTION 1.65                                      “Phase 2 Clinical Trial” means, with respect to the United States, any human clinical trial conducted in the specific patient population with the disease or condition of interest intended to be studied in a Phase 3 Clinical Trial for the purposes of preliminary assessment of efficacy in the indication being studied, as described under 21 C.F.R. §312.21(b) (or its successor regulation), and that, if the defined end-points are met, is sufficient to allow the initiation of a Phase 3 Clinical Trial in the indication being studied, or, with respect to a jurisdiction other than the United States, an equivalent clinical study.

 

SECTION 1.66                                      “Phase 3 Clinical Trial” means, with respect to the United States, any human clinical trial, that, if the defined end-points are met, is designed and intended to be a pivotal trial to support the filing of an application to obtain Regulatory Approval with the FDA (or its successor) as required under 21 C.F.R. §312.21 (c) (or its successor regulation), or, with respect to a jurisdiction other than the United States, an equivalent clinical study.

 

SECTION 1.67                                      “Reasonably Diligent Efforts” means, with respect to a particular GDNF Product and those activities hereunder with respect to such GDNF Product including development and commercialization, those efforts and resources that AMT would normally use with respect to a pharmaceutical product, which product is owned by AMT or to which AMT has similar rights with a similar market potential at a similar stage in development or product life as the GDNF Product, taking into account all relevant factors, based on the facts and circumstances at the time, including without limitation safety and efficacy issues, other medical and clinical considerations, product labeling or anticipated labeling, product profile, present and future market potential, past performance of similar products (including both GDNF Products and AMT’s own pharmaceutical products that are of similar market potential), competitive market conditions, the likely timing of the product’s entry into the market, financial considerations, intellectual property considerations and the likelihood of regulatory approval.

 

SECTION 1.68                                      “Regulatory Approval” means, in the applicable country, any approvals (including pricing and reimbursement approvals, where necessary to initiate marketing activities), licenses, registrations or authorizations of any national or international or local regulatory agency, department, bureau or other governmental entity, necessary and sufficient for the marketing and sale of a GDNF Product by AMT, its Affiliate or Sublicensee.

 

SECTION 1.69                                      “Regulatory Filings” means all applications, filings, dossiers and the like (excluding routine adverse event expedited or periodic reporting), submitted to a Governmental Authority for the purpose of obtaining Regulatory Approval from that Governmental Authority in the Licensed Field.

 

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SECTION 1.70                                      “Revenue Sharing Payments” has the meaning set forth in Section 4.2 (Revenue Sharing).

 

SECTION 1.71                                      “Sublicense” means a grant of any right or license to Exploit GDNF Products under the Licensed Patent Rights and/or the Licensed Know-How and/or a grant of any right or license to Exploit GDNF Products under the AMT Licensed Patent Rights and/or AMT Licensed Know-How.  Likewise, “Sublicensee” means the Person to whom rights are granted under a Sublicense.  For the avoidance of doubt, the grant of a right or license with respect to any one or more activities identified within the definition of “Exploit” shall be a “Sublicense” for purposes of this Agreement, regardless of whether such Sublicense conveys to the applicable Sublicensee a right or license with respect to all activities within the definition of “Exploit.” By way of illustration and not limitation, the granting to a Third Party of a license to sell, but not manufacture, GDNF Products shall be a “Sublicense.” For the sake of clarity, unless the Parties agree otherwise, Amgen’s election to exercise the Collaboration Option shall not result in Amgen being a Sublicensee for the purposes of this Agreement.

 

SECTION 1.72                                      “Sublicensing Revenue” means in respect of any GDNF Products, all cash payments received, and the fair market value of all non-cash consideration (excluding the fair market value of any monies paid to AMT in subscription for new AMT equity or other instruments capable of conversion into AMT equity) received, by AMT and/or any of its Affiliates from any Third Party in consideration for a transaction, series of transactions or other arrangement in which such Third Party obtains (i) a Sublicense of the Licensed Patent Rights and/or Licensed Know-How (or any option or other right to obtain a Sublicense of the Licensed Patent Rights and/or Licensed Know-How) and/or (ii) a license of the AMT Licensed Patent Rights and/or AMT Licensed Know-How (or any option or other right to obtain a license of the AMT Licensed Patent Rights and/or AMT Licensed Know-How), including, without limitation, up-front payments, milestones, royalties, research funding (provided that with respect to research funding payments, only the amounts in excess of AMT’s external costs and internal costs directly related to such research activities shall be included), and any monies paid to AMT in subscription for new AMT equity or other instruments capable of conversion into AMT equity in excess of the fair market value thereof (provided, however, that Sublicensing Revenue shall exclude Partnered Net Revenues).  Notwithstanding the foregoing, in the event that Amgen exercises the Collaboration Option, Sublicensing Revenues shall exclude any payments made by Amgen, its Affiliates and/or their respective sublicensees to AMT in respect of the Collaboration Territory.

 

SECTION 1.73                                      “Subsequent Distracting Product” means a Gene Therapy product that delivers GDNF or the gene encoding GDNF, or in either case any fragment of GDNF that has Functional Activity that is the subject of a Subsequent Distracting Program.

 

SECTION 1.74                                      “Subsequent Distracting Program” means, during the applicable period specified in Article 8 (Termination), the Exploitation of any Gene Therapy product that delivers GDNF or the gene encoding GDNF, or in either case any fragment of GDNF that has Functional Activity.

 

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SECTION 1.75                                      “Subsequent Distracting Transaction” means, during the applicable period specified in Section 8.5.1.3, any transaction whereby a Third Party that is engaged in a Subsequent Distracting Program becomes an Affiliate or is merged with AMT during the applicable period.

 

SECTION 1.76                                      “Taxes” has the meaning set forth in Section 6.4.1 (Payment of Taxes).

 

SECTION 1.77                                      “Third Party” means a Person other than (i) AMT or any of its Affiliates, and (ii) Amgen or any of its Affiliates.

 

SECTION 1.78                                      “Third Party License Payments” means (i), with respect to any agreement that relates to intellectual property rights that solely Cover a GDNF Product, any payments made by AMT and/or its Affiliates (whether up-front payments, milestones, royalties or research funding (provided that with respect to research funding payments, only the amounts in excess of AMT’s external costs and internal costs directly related to such research activities shall be included) during the term of this Agreement to any Third Party for intellectual property rights that are necessary in the Exploitation of GDNF Products (but solely with respect to intellectual property rights that would be infringed by the Exploitation of GDNF Products absent a license therefore) including but not limited to payments to the National Institutes of Health and/or the Food and Drug Administration, and (ii), with respect to any agreement that relates to intellectual property rights that Cover more than solely a GDNF Product, any royalty payments made by AMT and/or its Affiliates during the Payment Term to any Third Party for intellectual property rights that are necessary in the Exploitation of GDNF Products.  For the sake of clarity, Third Party License Payments specifically excludes any payments that are related to any device used in connection with the delivery of a GDNF Product.

 

SECTION 1.79                                      “Unpartnered Net Revenues” means any Net Revenue other than Partnered Net Revenues.

 

SECTION 1.80                                      “U.S.” or “United States” means the several States of the United States of America, the District of Columbia, and the commonwealths, territories, and possessions of the United States of America.

 

SECTION 1.81                                      “VAT” has the meaning set forth in Section 6.4.3 (VAT).

 

ARTICLE 2.                                    LICENSES

 

SECTION 2.1                                             License to AMT.  Subject to Section 2.2, Amgen hereby grants to AMT and its Affiliates, during the Payment Term, (i) a worldwide, exclusive (even as to Amgen) license, with the right to grant Sublicenses, under the Licensed Patent Rights to Exploit GDNF Products in the Licensed Field, and (ii) a worldwide, exclusive (even as to Amgen) license, with the right to grant Sublicenses, under the Licensed Know-How to Exploit GDNF Products in the Licensed Field.  Upon expiration of the Payment Term in a giving country, Amgen hereby grants to AMT and its Affiliates (i) a worldwide, non-exclusive license, with the right to grant Sublicenses, under the Licensed Patent Rights to Exploit GDNF Products in the Licensed Field, and (ii) a worldwide,

 

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non-exclusive license, with the right to grant Sublicenses, under the Licensed Know-How to Exploit GDNF Products in the Licensed Field.

 

SECTION 2.2                                             Retention of Rights.  Notwithstanding anything herein to the contrary, Amgen retains (on behalf of itself and its Affiliates) a non-exclusive license under the Licensed Know-How and Licensed Patent Rights to: (i) conduct research (including preclinical and non-clinical activities and including academic collaborations, but excluding in vivo and clinical activities) with respect to, but not to develop or commercialize, GDNF Products in the Licensed Field; and (ii) use, make and have made GDNF Products for the purposes of such research.  Additionally, notwithstanding anything herein to the contrary, Amgen retains (on behalf of itself and its Affiliates) the right to Exploit, and authorize (by license or otherwise) Third Parties to Exploit, GDNF outside the Licensed Field.  No more than [**] during the Term, AMT may ask Amgen in writing whether, during the period from the last request (or if there has not been such a request, from the Effective Date) Amgen is or has been a party to an academic collaboration with respect to GDNF Products in the Licensed Field.  Amgen shall reply to AMT within [**] days of any such request by AMT and if in such reply Amgen notifies AMT that Amgen is or has been a party to such a collaboration, Amgen shall also inform AMT whether any inventions have been created, developed or reduced to practice in the course of such collaboration, the identity and nature of such inventions and whether Amgen owns or has taken an exclusive license to such inventions.  If Amgen does not own or has not taken an exclusive license to such inventions then AMT may request Amgen to use good faith efforts to obtain an exclusive license to such inventions (to the extent Amgen has the contractual right to do so) for the benefit of AMT (provided that AMT shall be solely and directly liable for any amounts payable to the academic collaborator in relation to such license).  Amgen represents and warrants that, as of the Effective Date, it owns or has been granted a license to all inventions with respect to GDNF Products in the Licensed Field that have been created, developed or reduced to practice in the course of any academic collaboration to which Amgen is or has been a party.

 

SECTION 2.3                                             Transfer of Licensed Know-How.  AMT hereby acknowledges that Amgen has completed its obligation to transfer Know-How and Materials to AMT under the Original Agreement and Amgen has no unfulfilled obligations to transfer any Know-How or Materials to AMT.  AMT acknowledges that the Materials transferred by Amgen to AMT under the Original Agreement are experimental in nature and may have unknown characteristics and therefore agrees to use prudence and reasonable care in the use, handling, storage, transportation and disposition and containment of any such Materials.  Accordingly, no such Materials (unless expressly provided by Amgen otherwise in writing) shall be used in any human application, including any clinical trial.

 

SECTION 2.4                                             No Other Rights.  AMT acknowledges that the rights and licenses granted under this Article 2 (Licenses) and elsewhere in this Agreement are limited to the scope expressly granted.  Accordingly, except for the rights expressly granted under this Agreement, no right, title, or interest of any nature whatsoever is granted whether by implication, estoppel, reliance, or otherwise, by Amgen to AMT.  All rights that are not specifically granted herein are reserved to Amgen.  Without limiting the foregoing, AMT hereby acknowledges that Amgen retains the right

 

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to Exploit, and authorize (by license or otherwise) Third Parties to Exploit, any product other than a GDNF Product even if such product is covered by a claim within the Licensed Patent Rights.  For the sake of clarity, Amgen has granted certain rights under the Licensed Know-How and Licensed Patent Rights to MedGenesis Therapeutix Inc. and Biovail Laboratories International SRL outside of the Licensed Field.

 

SECTION 2.5                                             Limited Exploitation Rights.  Without limiting the provisions of Section 2.4 (No Other Rights), AMT agrees (on behalf of itself and its Affiliates), and shall cause each of its Sublicensees to agree as a condition to the grant of a Sublicense, not to Exploit any Licensed Know-How or Licensed Patent Rights in any use outside the Licensed Field or for any products other than GDNF Products.

 

SECTION 2.6                                             Collaboration Option.  AMT shall notify Amgen in writing within [**] Business Days after Completion of the first Phase 2 Clinical Trial (whether a stand-alone clinical trial or in combination with another clinical trial, i.e., a phase 1/2 clinical trial or phase 2/3 clinical trial) for the first GDNF Product.  Amgen shall have [**] Business Days from receipt of such notice to request from AMT a data package containing such information as Amgen may reasonably request and as may be available regarding such GDNF Product (the “Data Package”).  In the event that Amgen requests such Data Package, then Amgen shall have the right, by giving notice in writing to AMT, to exercise an option to obtain an exclusive license from AMT to Exploit GDNF Products in the Collaboration Territory (the “Collaboration Option”) (such option to expire [**] Business Days after the later of (i) receipt of the complete Data Package and (ii) a face-to-face meeting between the Parties to discuss any data contained in the Data Package (provided that such meeting is held within [**] Business Days after receipt of the complete Data Package).  In the event Amgen exercises the Collaboration Option, then the Parties shall enter exclusive good faith negotiations for a period of [**] Business Days (from the date of Amgen’s notice exercising the Collaboration Option) with respect to a definitive agreement governing the respective rights and obligations of the Parties with respect thereto.  In the event that the Parties are unable to enter into a definitive agreement within such [**] Business Day period, then AMT shall have the right to retain its development and commercialization rights in the Collaboration Territory; provided, however, that AMT would not be entitled to subsequently grant development or commercialization rights in the Collaboration Territory to a Third Party on financial terms less favorable to AMT than those last offered by Amgen.

 

ARTICLE 3.                                    MANUFACTURING, REGULATORY AND COMMERCIAL ACTIVITIES

 

SECTION 3.1                                             Manufacturing.  AMT, itself or through one or more Third Party contract manufacturers designated by it that have appropriate expertise and are suitably qualified, including holding the requisite permits and having been subject to or available for appropriate audits and inspections by the relevant regulatory bodiesis solely responsible for the manufacture and supply of requirements of GDNF Products (including any GDNF used in a GDNF Product).  In addition to the CMOs listed on Schedule 3.1, AMT may, with the prior written consent of Amgen, such consent not to be unreasonably withheld or delayed, transfer the Licensed Know-How related to

 

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the manufacture of GDNF to one or more other Third Party contract manufacturers at AMT’s own expense, under obligations of confidentiality and limitations on use consistent with those set out in this Agreement.  From time to time upon the written request of Amgen (but not more than [**]), AMT shall deliver to Amgen a written summary of manufacturing activities conducted hereunder by it since the last such report.  In the event that Amgen exercises the Collaboration Option and all other terms of a collaboration agreement are agreed by the Parties within the time period specified in Section 2.6 (Collaboration Option), AMT would agree, upon Amgen’s request, to supply Amgen with clinical and commercial GDNF Product for use in the Collaboration Territory at AMT’s cost as determined on an IFRS basis.

 

SECTION 3.2                                             Regulatory Process.  Subject to the terms of any collaboration agreement entered into by the Parties in accordance with Section 2.6 (Collaboration Option), AMT shall have sole and full control, authority, discretion and right to conduct (by itself, through its Affiliates or via a Third Party) and make all decisions regarding all development and regulatory matters (including interaction with all Governmental Authorities and preparation of any Regulatory Filings) with respect to GDNF Products.  From time to time upon the written request of Amgen (but not more than [**] in any Calendar Year), AMT shall deliver to Amgen a written summary of development and regulatory activities conducted hereunder by it since the last such report.  Amgen shall grant a right of reference to AMT to all Regulatory Approvals and Regulatory Filings owned by Amgen as of the Effective Date, if any, relating to GDNF Products in the Licensed Field.  All Regulatory Approvals and Regulatory Filings obtained by AMT relating to GDNF Products in the Licensed Field shall be solely owned by AMT and held in the name of AMT or its respective designated Affiliates or Sublicensee(s).

 

SECTION 3.3                                             Commercial Activities.  Subject to the terms of any collaboration agreement entered into by the Parties in accordance with Section 2.6 (Collaboration Option), AMT shall have sole responsibility for commercialization of GDNF Products.  AMT shall be solely responsible for all costs incurred in its commercialization of GDNF Products.  From time to time upon the written request of Amgen (but not more than [**] in any Calendar Year), AMT shall deliver to Amgen a written summary of commercialization activities conducted hereunder by it since the last such report; provided that nothing in this Section 3.3 (Commercial Activities) shall require AMT to disclose the identity of any current or prospective customer.  AMT shall have sole discretion with respect to the pricing of GDNF Products.

 

ARTICLE 4.                                    FEES AND REVENUE SHARING PAYMENTS

 

SECTION 4.1                                             Milestone Fee.  Upon the first approval of an NDA with respect to a GDNF Product achieved by AMT and/or its Affiliates (the “Approval Milestone”), AMT shall promptly (and, in any event, no later than [**] days) notify Amgen in writing of such occurrence and the amount received, and Amgen will invoice AMT for a one-time payment in the amount of the greater of (a) ten million US Dollars (US$10,000,000) and (b) [**]% of any milestone payments received by AMT from Third Parties in respect of the Approval Milestone.  Such payment shall be due and payable by AMT within [**] days after receipt of the invoice from Amgen.  The milestone

 

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fee is payable only once and shall not be payable for subsequent or repeated achievements of such milestone event with one or more of the same or different GDNF Products.

 

SECTION 4.2                                             Revenue Sharing Payments.

 

During the Payment Term, AMT shall make payments (“Revenue Sharing Payments”) to Amgen equal to:

 

(i)                                     [**] percent ([**]%) of any and all Unpartnered Net Revenues received by AMT and/or its Affiliates (but not by its Sublicensees) in any Calendar Quarter, less:

 

(a)                                 COGS attributable to the GDNF Product sold or used in connection with the applicable service performed in such Calendar Quarter;

 

(b)                                 any patent prosecution and maintenance costs incurred by AMT in the event that it has assumed responsibility to prosecute and maintain any of the Licensed Patent Rights in accordance with Section 7.1 (Patent Prosecution); and

 

(c)                                  any and all Third Party License Payments that are payable by AMT and/or any of its Affiliates in such Calendar Quarter ((a), (b), and (c) together being “Allowable Offsets”).

 

For the purpose of calculating Unpartnered Net Revenues for any given Calendar Quarter the maximum deduction for all Allowable Offsets taken together in a Calendar Quarter shall be [**] percent ([**]%) (the “Floor”) of the total applicable Unpartnered Net Revenues for that Calendar Quarter.  If the existence of the Floor results in AMT not being able to deduct the full amount of any Allowable Offsets in the Calendar Quarter when such deduction first becomes applicable then AMT can roll forward the outstanding amount to the next Calendar Quarter;

 

(ii)                                  [**] percent ([**]%) of any and all Sublicensing Revenues received by AMT and/or its Affiliates in any Calendar Quarter; and

 

(iii)                               [**] percent ([**]%) of any and all Partnered Net Revenues received by AMT and/or its Sublicensee (and/or their respective Affiliates) in any Calendar Quarter, less:

 

(a)                                 COGS attributable to the GDNF Product sold or used in connection with the applicable service performed in such Calendar Quarter;

 

(b)                                 any patent prosecution and maintenance costs incurred by AMT in the event that it has assumed responsibility to prosecute and maintain any of the Licensed Patent Rights in accordance with Section 7.1 (Patent Prosecution); and

 

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(c)                                  any and all Third Party License Payments that are payable by AMT and/or any of its Affiliates in such Calendar Quarter ((a), (b), and (c) together being “Allowable Offsets”).

 

For the purpose of calculating Partnered Net Revenues for any given Calendar Quarter the maximum deduction for all Allowable Offsets taken together in a Calendar Quarter shall be [**] percent ([**]%) (the “Floor”) of the total applicable Partnered Net Revenues for that Calendar Quarter.  If the existence of the Floor results in AMT not being able to deduct the full amount of any Allowable Offsets in the Calendar Quarter when such deduction first becomes applicable then AMT can roll forward the outstanding amount to the next Calendar Quarter.

 

ARTICLE 5.                                    DILIGENCE

 

SECTION 5.1                                             Use of Reasonably Diligent Efforts.  AMT shall use Reasonably Diligent Efforts to develop at least one GDNF Product, and seek to obtain Regulatory Approvals for such GDNF Product in the U.S. and the European Union, and commercialize such GDNF Product.

 

SECTION 5.2                                             Sequential Implementation.  The Parties acknowledge that developing and seeking Regulatory Approvals for a GDNF Product may include sequential implementation of clinical trials and intervals between clinical trials for data interpretation and clinical program planning and approval.

 

SECTION 5.3                                             Holistically Determined.  Amgen acknowledges that in determining whether AMT has met its requirement to use Reasonably Diligent Efforts in accordance with Section 5.1 (Use of Reasonably Diligent Efforts) reference will be made to the totality of AMT’s activities with respect to all GDNF Product(s) (if, in AMT’s sole discretion, it decides to develop more than one GDNF Product) in all countries, not on a country-by-country basis.

 

SECTION 5.4                                             Excluded from Consideration.  Notwithstanding Section 5.3 (Holistically Determined), in determining whether AMT has used Reasonably Diligent Efforts, Reasonably Diligent Efforts shall be determined as if no payments were required to be made by AMT pursuant to Article 4 (Fees and Revenue Sharing Payments) of this Agreement.

 

SECTION 5.5                                             Diligence Schedule.  In addition to the obligations of AMT to use Reasonably Diligent Efforts set forth above, AMT shall commence a proof of concept study in non-human primates (“POC Study”) within [**] months from the Effective Date (“Diligence Period”), provided however that, where there is a study plan, budget and agreement in place for the POC Study but such POC Study has not commenced within the Diligence Period because there are insufficient animals available that are suitable for use in such study, for example due to elevated anti-AAV antibody titre levels, the Diligence Period shall be extended until such animals are available.  During this extension period, AMT shall use Reasonably Diligent Efforts to ensure the availability of such animals as soon as practicably possible.  If the POC Study has not commenced within the initial [**] month Diligence Period, AMT shall promptly (but in no event later than [**] days after the end of such initial Diligence Period) notify Amgen in writing of such failure to

 

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achieve such event within the Diligence Period (the “Diligence Notice”) and if such failure is due to the lack of animals then AMT shall provide details thereof and the Diligence Period shall be extended.  If the failure of AMT to commence the POC Study within [**] months from the Effective Date is due to factors other than lack of animals, Amgen shall have the right to terminate the Agreement by providing written notice to AMT no later than twenty (20) Business Days after receipt of the Diligence Notice.

 

ARTICLE 6.                                    REPORTS, PAYMENTS AND RECORDS

 

SECTION 6.1                                             Payment; Reports.  During the Payment Term, AMT will prepare and deliver to Amgen Revenue Sharing Payments and reports supporting such Revenue Sharing Payments (as described below) for each Calendar Quarter within [**] days of the end of each such Calendar Quarter.  Each Revenue Sharing Payment will be made from a single account in the country in which AMT is headquartered accompanied by a report of (i) Net Revenues of GDNF Products stating:  (a) the aggregate gross invoiced sales prices charged for GDNF Products and the aggregate revenues from any use of a GDNF Product in the provision of a service performed; (b) Net Sales and Net Service Revenues of GDNF Products during the applicable Calendar Quarter; (c) COGS related to units sold and services provided in such Calendar Quarter; and (ii) the amount and type of payment received from each Sublicensee during the applicable Calendar Quarter and (iii) any and all Third Party License Payments that are payable by AMT and/or any of its Affiliates in such Calendar Quarter (a “Payment Report”).  From time to time, Amgen may change its accounting and financial reporting practices from Calendar Quarters and Calendar Years to fiscal quarters and fiscal years or vice versa.  If Amgen notifies AMT of a change in Amgen’s accounting and financial reporting practices from Calendar Quarters and Calendar Years to fiscal quarters and fiscal years or vice versa, then thereafter, beginning with the period specified in the notice, the payment, reporting and other obligations of AMT hereunder related to Calendar Quarters and Calendar Years shall be deemed satisfied by compliance therewith in accordance with the new reporting periods (fiscal reporting periods or calendar reporting periods, as the case may be) instead of the previously utilized reporting periods.

 

SECTION 6.2                                             Invoices.  To the extent an invoice is required to be submitted by Amgen to AMT, such invoice shall be addressed to:

 

AMT
 FAO Finance Department 
 P.O. Box 22506 
 1100 DA Amsterdam 
 The Netherlands

 

Invoices not submitted to the foregoing address may be subject to delay or return.

 

SECTION 6.3                                             Exchange Rate; Manner and Place of Payment.  With respect to Net Revenues invoiced or expenses incurred in a currency other than U.S. dollars or Sublicensing Revenue received in a currency other than U.S. dollars (each a “Foreign Currency Amount”), the Foreign

 

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Currency Amount shall be converted into the U.S. dollar equivalent using a rate of exchange which corresponds to the rate used by AMT, for the respective reporting period, related to recording such Foreign Currency Amount in its books and records that are maintained in accordance with IFRS (provided, however, that if, at such time, AMT does not use a rate for converting into a U.S. dollar equivalent that is maintained in accordance with IFRS, then AMT will use a rate of exchange which corresponds to the rate of exchange for such currency reported in The Wall Street Journal, Internet U.S. Edition, as of the last day of the applicable reporting period (or, if unavailable on such date, the first date thereafter on which such rate is available)).  Any payment of royalties or Revenue Sharing Payment shall be calculated based upon the U.S. dollar equivalent calculated in accordance with the foregoing.  Any Payment Report required under Section 6.1 (Payment; Reports) shall provide the details and background information used to calculate such currency conversion.  All payments shall be made in U.S. dollars.

 

Payment of all sums due hereunder shall be made by check, wire transfer, or electronic funds transfer (EFT), at Amgen’s choice, to the following:

 

[**]

 

SECTION 6.4                                             Taxes.

 

6.4.1                     Payment of Taxes.  All excises, taxes, and duties, excluding any value-added tax (collectively “Taxes”) levied on account of a payment made by AMT to Amgen pursuant to this Agreement will be the responsibility of and paid by Amgen or shall be subject to the withholding, remittance, and offset provisions of this Section 6.4 (Taxes).

 

6.4.2                     Withholding by AMT.  In the event that Law requires AMT to withhold Taxes with respect to any payment to be made by AMT pursuant to this Agreement, AMT will withhold such Taxes from the amount due and furnish, within [**] days of the date of such withholding, Amgen with proof of payment of such Taxes.  AMT will provide reasonable assistance to Amgen in its efforts to claim an exemption of Taxes, obtain a refund of Taxes withheld, or obtain a credit with respect to such Taxes paid.  In order for Amgen to secure an exemption from, or a reduction in, any withholding of Taxes, Amgen shall provide to AMT such forms as reasonably required for each type of payment to be made pursuant to the Agreement for which an exemption from, or a reduction in, any withholding of Taxes is claimed.  In the event that a form previously furnished to AMT expires, is incorrect, or is inapplicable to the type of payment to be made, due to a change in circumstances or otherwise, Amgen shall furnish a new form to AMT prior to the payment of any such amount in order to secure an exemption from, or a reduction in, any withholding of Taxes with respect to such payment.

 

6.4.3                     VAT.  All payments due to Amgen from AMT pursuant to this Agreement shall be paid exclusive of any value-added tax (“VAT”) (which, if applicable, shall be payable by AMT upon receipt of a valid VAT invoice).

 

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SECTION 6.5               Audits.  AMT shall keep (and cause its Affiliates and Sublicensees to keep) true and fair records of the underlying revenue and expense data relating to the calculations of Net Revenues and Revenue Sharing Payments, as well as any other payments required under this Agreement.  Amgen shall have the right, at its own expense and not more than [**] during the term of this Agreement, to have an independent, certified public accountant, selected by Amgen, audit the records of AMT, its Affiliates and Sublicensees in the location(s) where such records are maintained by the applicable entity upon reasonable notice (which shall be no less than [**] days prior written notice) and during regular business hours, and for the sole purpose of verifying the basis and accuracy of payments required and made under this Agreement.  To the extent that AMT does not have the right to grant Amgen the right to audit its Sublicensees’ books and records hereunder, AMT shall obtain for itself such right and, at the request of Amgen, AMT shall exercise such audit right with respect to Sublicensees and provide the results of such audit for inspection by Amgen pursuant to this Section 6.5 (Audits).  The books and records for any particular Calendar Year shall only be subject to [**].  The report and communication of such accountant with respect to such an audit shall be limited to a certificate stating whether any report made or payment submitted by AMT during such audited period is accurate or inaccurate and the amount of any payment discrepancy.  Such accountant shall provide Amgen and AMT with a copy of each such report simultaneously.  Should the audit lead to the discovery of a discrepancy to Amgen’s detriment, AMT shall pay the amount of the discrepancy within [**] days of AMT’s receipt of the report.  Additionally, in the event that the discrepancy is to Amgen’s detriment and is greater than [**] percent ([**]%) of all payments due in such audited period, then AMT shall pay interest on such amount at an annual rate of the [**].  Should the audit lead to the discovery of a discrepancy to AMT’s detriment, AMT will have the right to deduct such amount from any future payment obligations.  Amgen shall pay the full cost of the audit unless the discrepancy is to Amgen’s detriment and is greater than [**] percent ([**]%) of all payments due in such audited period, in which case AMT shall pay or reimburse the reasonable cost charged by such accountant for such audit.  Upon the expiration of [**] years following the end of any Calendar Year, the right to audit the books and records for such Calendar Year shall expire and the calculation of payments payable with respect to each such Calendar Year shall be binding and conclusive upon Amgen and AMT, its Affiliates and Sublicensees shall be released from any liability or accountability with respect to payments for such Calendar Year.  AMT shall no longer be required to retain such records for such Calendar Year after the expiration of such [**] year period.

 

SECTION 6.6               Confidentiality.  Amgen shall treat all financial information subject to review under this Article 6 (Reports, Payments and Records), or under any related Sublicense, as AMT’s Confidential Information.

 

ARTICLE 7.            PATENT PROSECUTION

 

SECTION 7.1               Patent Prosecution.  As between the Parties, Amgen shall have the sole right, at Amgen’s sole expense, to control the Prosecution and Maintenance of the Licensed Patent Rights, including, if Amgen so elects, through the use of outside counsel.  Solely with respect to Licensed Patent Rights covering the GDNF Products in whole or in part in the Licensed Field, Amgen agrees to: (i) keep AMT reasonably informed with respect to such activities; and (ii) provide AMT 

 

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with all material documentation and correspondence from, sent to or filed with patent offices regarding the Licensed Patent Rights.  If Amgen (or its designee) determines to abandon any claims within the Licensed Patent Rights that have application solely in the Licensed Field, then Amgen shall provide AMT with notice at least [**] days prior to the date such abandonment would become effective.  In such event, subject to any right of a Third Party as of the Effective Date to control Prosecution and Maintenance of the Licensed Patent Rights, AMT shall have the right, at its option, to control the Prosecution and Maintenance of such claims, at its own expense (subject to Section 4.2(i) and 4.2(iii)), in Amgen’s name.  For purposes of the foregoing, “Prosecution and Maintenance” means, with respect to a patent or patent application, the preparing, filing, prosecuting and maintenance of such patent or application, as well as re examinations, reissues, requests for patent term extensions and the like with respect thereto, together with the conduct of interferences, the defense of oppositions and other similar proceedings with respect to the particular patent or patent application.

 

SECTION 7.2               Defense of Third Party Infringement Claims.  If any GDNF Product Exploited by or under the authority of AMT becomes the subject of a Third Party’s claim or assertion of infringement of a patent relating to the manufacture, use, sale, offer for sale or importation of such GDNF Product, the Party first having notice of the claim or assertion shall promptly notify the other Party, and the Parties shall promptly confer to consider the claim or assertion and the appropriate course of action.  Unless the Parties otherwise agree in writing, each Party shall have the right to defend itself against a suit that names it as a defendant (the “Defending Party”).  Neither Party shall enter into any settlement of any claim described in this Section 7.2 (Defense of Third Party Infringement Claims) that admits to the invalidity or unenforceability of the Licensed Patent Rights, incurs any financial liability on the part of the other Party or requires an admission of liability, wrongdoing or fault on the part of the other Party without such other Party’s written consent, which consent shall not be unreasonably withheld or delayed.  In any event, the other Party shall reasonably assist the Defending Party and cooperate in any such litigation at the Defending Party’s request and expense.

 

SECTION 7.3               Enforcement.

 

7.3.1                     Subject to the provisions of this Section 7.3 (Enforcement), in the event that a Party reasonably believes that any Licensed Patent Right is being infringed by a Third Party or is subject to a declaratory judgment action or impeachment action (or any other similar judicial court proceeding) arising from such infringement, in each case with respect to the manufacture, use, sale, offer for sale or importation of a GDNF Product in the Licensed Field (an “Infringing Product”), such Party shall promptly notify the other Party.  In such event, AMT shall have the initial right (but not the obligation) to enforce such Licensed Patent Rights in the Licensed Field with respect to infringement by an Infringing Product, or to defend any declaratory judgment action or impeachment action (or defend any other similar judicial court proceeding) with respect thereto (an “Enforcement Action”), at AMT’s expense.  Amgen shall join, at AMT’s expense, as a party plaintiff if required by applicable Law to maintain the action and, in any event, shall, at AMT’s expense, give AMT reasonable assistance and authority to file and 

 

22

 

prosecute such Enforcement Action.  If, in an Enforcement Action initiated by AMT, Amgen is involuntarily joined other than by AMT, then AMT shall bear Amgen’s expenses for the prosecution of the Enforcement Action.  In the event that any Licensed Patent Right covering both the Licensed Field and activity outside the Licensed Field is being infringed by a Third Party or is subject to a declaratory judgment action, impeachment action or any other challenge to the Licensed Patent Rights, then, subject to Section 7.3.4, upon AMT’s written request, Amgen shall use good faith reasonable efforts to gain the cooperation of any licensee of the Licensed Patent Rights for use outside of the Licensed Field in connection with the enforcement with respect to such infringement or with respect to the defense of any such declaratory judgment action, impeachment action or other challenge.

 

7.3.2                     In the event that AMT fails to initiate an Enforcement Action to enforce such Licensed Patent Rights against such an Infringing Product in the Licensed Field, within [**] days of a request by Amgen to do so (or such shorter period of time as necessary to prevent the loss of Amgen’s (or its designee’s) ability to subsequently initiate an Enforcement Action or diminution of rights or remedies thereunder (whether due to an expiration of the statute of limitations, estoppel by laches or similar doctrine)), Amgen (or its designee) may initiate an Enforcement Action against such infringement at its own expense.  The Party initiating or defending any such Enforcement Action (the “Enforcing Party”) shall keep the other Party reasonably informed of the progress of any such Enforcement Action, and such other Party shall have the right to participate with counsel of its own choice at its own expense.  In any event, the other Party shall reasonably cooperate with the Enforcing Party, including providing information and materials, at the Enforcing Party’s request and expense.

 

7.3.3                     Any recovery received as a result of any Enforcement Action to enforce Licensed Patent Rights in the Licensed Field pursuant to this Section 7.3 (Enforcement) shall be used first to reimburse the Parties for the costs and expenses (including attorneys’ and professional fees) incurred in connection with such Enforcement Action (and not previously reimbursed), and the remainder of the recovery shall be shared as follows:

 

7.3.3.1           If AMT is the Enforcing Party: (i) with respect to such portion of the recovery that is characterized as lost profits in the Licensed Field, [**] percent ([**]%) to AMT (provided, however, that such portion of the recovery will be used to calculate Net Revenues attributable to such lost profits (and AMT shall pay Amgen Revenue Sharing Payments on such (hypothetical) Net Revenues in accordance with Section 4.2(i)); and (ii) with respect to such portion of the recovery that is not characterized as lost profits, [**] percent ([**]%) to AMT;

 

7.3.3.2           If Amgen or its designee is the Enforcing Party, [**] to Amgen and [**] to AMT; and

 

7.3.3.3           In all cases, any such remainder which is a recovery from such an Enforcement Action which represents damages from sales of products other than Infringing Products or 

 

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outside the Licensed Field (e.g. sales of a product outside the Licensed Field) shall inure solely and be paid over to Amgen.

 

7.3.4                     For clarity, except as may be otherwise agreed between the Parties in writing, as between the Parties, Amgen shall have the exclusive right, at its expense, to control the enforcement of or defend any declaratory judgment action with respect to the Licensed Patent Rights outside the Licensed Field and shall retain all recoveries arising therefrom.  Amgen shall notify AMT of any such action, and, if Amgen (rather than a licensee of Amgen) is directly handling such action, then Amgen shall keep AMT reasonably informed of the progress of any such action and reasonably consider any comments AMT may have with respect to such action.

 

7.3.5                     Neither Party shall enter into any settlement of any claim described in this Section 7.3 (Enforcement) that admits to the invalidity or unenforceability of the Licensed Patent Rights, incurs any financial liability on the part of the other Party or requires an admission of liability, wrongdoing or fault on the part of the other Party without such other Party’s written consent, which consent shall not be unreasonably withheld or delayed.  In any event, the other Party shall reasonably assist the Enforcing Party and cooperate in any such litigation at such Enforcing Party’s request and expense.

 

SECTION 7.4               Patent Term Extensions/Supplementary Protection Certificates.  Subject to any rights of a licensee of Amgen existing as of the Effective Date under any Licensed Patent Rights (a “Pre-Existing Licensee”), Amgen hereby authorizes AMT, its Affiliates and Sublicensees to seek patent term extensions and supplementary protection certificates (collectively, “PTEs”) of any or all Licensed Patent Rights in all countries throughout the world where such rights are obtainable.  Prior to seeking any such PTEs, AMT shall notify Amgen in writing of its intent to seek a PTE (a “PTE Notice”).  Amgen shall notify AMT in writing within [**] days of receipt of a PTE Notice of whether AMT is permitted to seek such a PTE or whether such PTE would be reasonably likely to conflict with a Pre-Existing Licensee’s right to seek any similar patent term extensions and supplementary protection certificates.  Amgen shall reasonably cooperate with AMT’s efforts to file applications for such patent term extensions and supplementary protection certificates; provided, however, that AMT shall reimburse Amgen for its reasonable out-of-pocket expenses with respect to such cooperation.

 

SECTION 7.5               Patent Marking.  AMT shall mark (or caused to be marked) all GDNF Products marketed and sold hereunder with appropriate Licensed Patent Rights numbers or indicia at Amgen’s request to the extent permitted by Law, in those countries in which such notices impact recoveries of damages or remedies available with respect to infringements of patents.

 

ARTICLE 8.            TERMINATION

 

SECTION 8.1               Term.  The term of this Agreement shall commence on the Effective Date, and, unless sooner terminated, continue in perpetuity.

 

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SECTION 8.2               Termination by AMT.

 

8.2.1                     Termination At Will.  AMT shall have the right to terminate this Agreement at any time by giving Amgen ninety (90) days’ written notice of AMT’s election to terminate this Agreement.

 

8.2.2                     Default.  Upon any material breach of this Agreement by Amgen, AMT, in addition to any other remedy available at law or equity, shall have the right to provide notice to Amgen of such material breach.  In the event such material breach has not been cured by Amgen within [**] days after receipt of such notice, then, AMT shall have the right to terminate this Agreement by providing Amgen with [**] days written notice provided, however, that if such breach is not susceptible of cure within the stated [**] day period and Amgen uses diligent, good faith efforts to cure such breach, the stated period will be extended by an additional [**] days.

 

SECTION 8.3               Termination by Amgen.

 

8.3.1                     Monetary Default.  Upon any failure by AMT to timely pay undisputed amounts due to Amgen required to be paid under this Agreement, Amgen, in addition to any other remedy available at law or equity, shall have the right to terminate this Agreement by giving AMT thirty (30) days’ prior written notice.  This Agreement shall terminate upon the expiration of such thirty (30) day period, unless on or before such date AMT has paid such amounts (including the payment of interest on such amounts at an annual rate of the [**], in which case the Agreement shall continue unaffected.

 

8.3.2                     Diligence Default.  Amgen shall have the right to terminate the Agreement in accordance with Section 5.5 (Diligence Schedule).

 

8.3.3                     Nonmonetary Default.  Upon any material non-monetary breach of this Agreement by AMT (i.e., not involving the payment by AMT of any amounts required to be paid under this Agreement), Amgen, in addition to any other remedy available at law or equity, shall have the right to provide notice to AMT of such material non-monetary breach.  In the event such material non-monetary breach has not been cured by AMT within [**] days after receipt of such notice, then, Amgen shall have the right to terminate this Agreement by providing AMT with [**] days written notice provided, however, that if such breach is not susceptible of cure within the stated [**] day period and AMT uses diligent, good faith efforts to cure such breach, the stated period will be extended by an additional [**] days.

 

SECTION 8.4               Effects of Termination of this Agreement.

 

8.4.1                     Sublicenses.  Save as expressly provided in Section 8.4.3 and Section 8.5 (Reversion Rights), termination of this Agreement for any reason shall effect the immediate and simultaneous termination of all Sublicenses and of all rights extended to the Affiliates of AMT subject to the provisions of Section 8.4.2 (GDNF Product in Stock).

 

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8.4.2                     GDNF Product in Stock.  For a period of [**] days after the termination of this Agreement under either Section 8.2 (Termination by AMT) or 8.3 (Termination by Amgen), AMT, its Affiliates and Sublicensees shall have the right to sell off any stock of GDNF Product on hand or in-process and provide services relating to GDNF Products, and the provisions of Section 4.2 (Revenue Sharing) and the payment provisions of this Agreement shall apply to such sales.

 

8.4.3                     Sublicensees.  In the event of the termination of this Agreement under Section 8.3 (Termination by Amgen), Amgen will, if required by AMT (and provided that the applicable Sublicensee is not in breach of any Sublicense granted to it under this Agreement), enter into direct licenses with up to no more than [**] Sublicensees of AMT on terms which are the same as or substantially similar to those set out in this Agreement; provided, however, that the request shall be made once and all Sublicensed territories throughout the world must be covered by the aggregate direct license agreements.

 

SECTION 8.5               Reversion Rights.

 

8.5.1                     At Will or For AMT’s Breach.  In the event that AMT terminates the Agreement under Section 8.2.1 (Termination At Will) or Amgen terminates the Agreement under Section 8.3.1 or 8.3.3 (but not under Section 8.3.2), then, the following provisions shall apply:

 

8.5.1.1           Grant of License.  Upon Amgen’s written request, AMT grants Amgen and its Affiliates a worldwide, royalty-bearing, exclusive license, with the right to grant Sublicenses, under the AMT Licensed Patent Rights and AMT Licensed Know-How to Exploit GDNF Products in the Licensed Field on the terms of Articles 4,6, 8.2.1, 8.3.1 and 8.3.3 of this Agreement such that the term “AMT” shall be replaced by the term “Amgen” and the term “Amgen” by the term “AMT” save that the Revenue Sharing Payments due to AMT shall be [**] percent ([**]%) for payments under Section 4.2(i), [**] percent ([**]%) for payments under Section 4.2(iii), and [**] percent ([**]%) for payments under Section 4.2(iii).  In addition, the provisions of Section 9.5 shall apply to the AMT Licensed Know-How save that Amgen’s obligations in respect of the AMT Licensed Know-How shall apply for [**] years post termination (rather than [**] years post termination).  In the event that any intellectual property rights that are useful or necessary to Exploit GDNF Products are not included in the foregoing license grant by reason of a requirement on the part of AMT under a written agreement, including any patents licensed to AMT by the National Institutes of Health and/or the FDA, (a “Third Party Agreement”) to pay a Third Party any amounts with respect to Amgen’s Exploitation of a GDNF Product, Amgen shall have the right, but not the obligation, to elect to obtain a license under such Third Party intellectual property rights.  In the event Amgen elects to obtain such a license, Amgen shall provide written notice thereof to AMT.  If Amgen so elects, then each Party shall use Reasonably Diligent Efforts to obtain such a direct license to Amgen from such Third Party provided that such license is on substantially similar terms to the Third Party Agreement and in any event on 

 

26

 

financial terms that are no less favourable to Amgen than under the Third Party Agreement.  If it is not possible to obtain such a direct license to Amgen then AMT shall use Reasonably Diligent Efforts to grant a sublicense under the Third Party Agreement to Amgen, to the extent that such sublicensing is allowed by the Third Party Agreement.  If sublicensing under any Third Party Agreements is allowed but limited or restricted, AMT shall, upon request by Amgen, seek consent or take such other actions as are reasonably necessary to seek to enable AMT to sublicense under such Third Party Agreements.  In the event that Amgen elects to obtain a sublicense, then Amgen shall pay AMT any amounts owed to such Third Party under the Third Party Agreements by reason of Amgen’s Exploitation of GDNF Products.  Amgen shall indemnify AMT on the terms of Section 8.9.1 in respect of any Third Party (including any licensor) claims relating to Amgen’s performance under the sublicense.  Amgen shall have the right, in its sole discretion, to terminate the sublicense upon [**] days written notice to AMT.  For any sublicenses granted by AMT to Amgen under this Section 8.5.1.1 (Grant of License), AMT shall maintain the underlying Third Party Agreement in full force and effect and shall promptly notify Amgen of any notice of default or other circumstances related to the underlying Third Party Agreement that may reasonably affect the sublicense granted to Amgen.

 

8.5.1.2           No Other Rights.  Amgen acknowledges that the rights and licenses granted under Section 8.5.1.1 are limited to the scope expressly granted.  Accordingly, except for the rights expressly granted under Section 8.5.1.1, no right, title, or interest of any nature whatsoever is granted whether by implication, estoppel, reliance, or otherwise, by AMT to Amgen.  All rights that are not specifically granted herein are reserved to AMT.  Without limiting the foregoing, Amgen hereby acknowledges that AMTretains the right to Exploit, and authorize (by license or otherwise) Third Parties to Exploit, any product other than a GDNF Product even if such product is covered by a claim within the AMT Licensed Patent Rights.

 

8.5.1.3           Limited Exploitation Rights.  In the event that Amgen requests a license from AMT in accordance with Section 8.5.1.1 (Grant of License), without limiting the provisions of Section 8.5.1.2 (No Other Rights), Amgen agrees (on behalf of itself and its Affiliates), and shall cause each of its Sublicensees to agree as a condition to the grant of a Sublicense, not to Exploit any AMT Licensed Know-How or AMT Licensed Patent Rights in any use outside the Licensed Field or for any products other than GDNF Products.

 

8.5.1.4           Cooperation.  The Parties shall work together in good faith for a period of [**] days to transfer to Amgen any GDNF Product developed by AMT prior to the date of such termination, including by transferring Regulatory Filings related to the program and manufacturing of GDNF Products.

 

8.5.1.5           Exclusivity.  AMT hereby agrees that for a period of three (3) years thereafter (i) neither it nor any of its Affiliates shall itself Exploit any Gene Therapy product that delivers 

 

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GDNF or the gene that encodes GDNF, or in either case any fragment of GDNF that has Functional Activity and (ii) neither it nor any of its Affiliates shall grant to any Third Party a license under the AMT Licensed Patent Rights or the AMT Licensed Know-How to Exploit any Gene Therapy product that delivers GDNF or the gene that encodes GDNF, or in either case any fragment of GDNF that has Functional Activity.  Notwithstanding the foregoing, in the event that AMT or its Affiliate enters into a Subsequent Distracting Transaction during such three (3) year period, AMT shall either (x) Divest the Subsequent Distracting Program, (y) terminate the Subsequent Distracting Program, or (z) pay Amgen (a) milestones with respect to such Subsequent Distracting Product(s) pursuant to Article 4 (Fees and Revenue Sharing Payments) hereunder on a retroactive basis; and (b) Revenue Sharing Payments with respect to such Subsequent Distracting Product(s) pursuant to Article 4 (Fees and Revenue Sharing Payments) hereunder on a going forward basis from the date of the closing of the Subsequent Distracting Transaction (in each case treating such Subsequent Distracting Product as a GDNF Product) until the end of the Payment Term.  If AMT elects to Divest the Subsequent Distracting Program, then it will use its reasonable efforts to Divest such Subsequent Distracting Program.  In the event AMT elects to Divest the Subsequent Distracting Program and fails to complete such Divestiture within [**] of the closing of the Subsequent Distracting Transaction, then AMT will be deemed to have elected to pay Amgen milestones and royalties as set forth in the preceding sentence.  If AMT elects to terminate the Subsequent Distracting Program then it will terminate all activities of such program (other than as required by Law) within [**] days after the closing of the Subsequent Distracting Transaction.

 

SECTION 8.6               For Amgen’s Breach or for AMT’s breach under Section 8.3.2.  In the event that AMT terminates the Agreement under Section 8.2.2 or Amgen terminates the Agreement under Section 8.3.2 then Amgen and its Affiliates shall have no right to any license under the AMT Licensed Patent Rights and AMT Licensed Know-How or any right or license to any Regulatory Filings related to the program and manufacturing of GDNF Products.

 

SECTION 8.7               Surviving Obligations and Provisions.  In addition to any provision of this Agreement that expressly survives the termination of this Agreement, the provisions of Sections 4.1 (Milestone Fees) (with respect to milestones reached prior to such termination), 4.2 (Revenue Sharing Payments) (with respect to sales made before such termination, or pursuant to Section 8.4.2 (GDNF Product in Stock and payments received by AMT from Sublicensees before such termination), 7.1 (Patent Prosecution), 8.4 (Effects of Termination of this Agreement), 8.5 (Reversion Rights), 8.6 (For Amgen’s Breach or for AMT’s breach under Section 8.3.2) and 8.7 (Surviving Obligations and Provisions) and Articles 1 (Definitions), 6 (Reports, Payments and Records) (with respect to periods with sales of GDNF Products made before such termination or payments received before such termination, or pursuant to Section 8.4.2 (GDNF Product in Stock)), and 9 (General) (excluding Section 9.7.1 (Representations, Warranties and Covenants)) shall survive the termination of this Agreement.  Except those provisions of this Agreement that expressly survive the termination of this Agreement, all other provisions of this Agreement shall terminate and be of no further effect upon the termination of this Agreement for any reason.

 

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ARTICLE 9.            GENERAL

 

SECTION 9.1               Termination of Original Agreement.  Effective as of the Effective Date, Amgen and AMT hereby expressly terminate the Original Agreement including, except to the extent set forth in this Agreement, any terms which expressly or impliedly survive the termination of the Original.  Each of Amgen and AMT on behalf of itself and its Affiliates and successors releases and discharges the other and its Affiliates and successors from all duties and obligations whatsoever in respect of the Original Agreement, provided that each of Amgen and AMT and their successors do not waive any rights, action, proceedings, claims, costs, awards and damages which it may have against the other or any of its Affiliates or successors and which have arisen or which may arise in relation to the Original Agreement.  This Agreement and all Schedules attached to this Agreement constitute the entire agreement between the Parties as to the subject matter of such documents.  All prior and contemporaneous negotiations, representations, warranties, agreements, statements, promises and understandings are superseded and merged into, extinguished by and completely expressed by such documents.  No Party shall be bound by or charged with any written or oral agreements, representations, warranties, statements, promises or understandings not specifically set forth in such documents.

 

SECTION 9.2               Addresses and Notices.  All notices, requests, reports and other communications provided in this Agreement shall be in writing and shall be deemed to have been made or given when received, if delivered by hand or sent by e-mail, facsimile or overnight courier:

 

If to Amgen:

 

Amgen Inc.
 One Amgen Center Drive 
 Thousand Oaks, CA 91320-1799 
 Fax: 805-499-6751 
 Attention: Corporate Secretary

 

If to AMT:

 

Amsterdam Molecular Therapeutics 
 PO Box 22506 
 1100 DA
 Amsterdam, Netherlands 
 Fax: 31 20 566 9272

Attention:    For billing: Finance (Financef@amtbiopharma.com)
 For all other issues: The Chief Executive Officer

 

Such addresses may be altered by written notice so given.

 

29

 

SECTION 9.3               Applicable Law.  This Agreement and its effect are subject to and shall be construed and enforced in accordance with the law of the State of New York, without regard to its conflicts of laws, except as to any issue which depends upon the validity, scope or enforceability of any Licensed Patent Right, which issue shall be determined in accordance with the laws of the country in which such patent was issued.  Each of the Parties hereby irrevocably and unconditionally consents to submit to the exclusive jurisdiction of the courts of the State of New York for any matter arising out of or relating to this Agreement and the transactions contemplated hereby, and agrees not to commence any litigation relating thereto except in such courts.  Each of the Parties hereby irrevocably and unconditionally waives any objection to the laying of venue of any matter arising out of this Agreement or the transactions contemplated hereby in the courts of the State of New York and hereby further irrevocably and unconditionally waives and agrees not to plead or claim in any such court that any such matter brought in any such court has been brought in an inconvenient forum.  The Parties agree that a final judgment in any such matter shall be conclusive and may be enforced in other jurisdictions by suits on the judgment or in any other manner provided by law.  Any proceeding brought by either Party under this Agreement shall be exclusively conducted in the English language.

 

SECTION 9.4               Performance by Affiliates.  Either Party shall have the right to exercise its rights and perform its obligations hereunder through its Affiliates, provided it shall remain responsible for such performance.

 

SECTION 9.5               Confidential Information.

 

9.5.1                     Obligations and Restrictions.  A Party receiving Confidential Information under this Agreement or the Original Agreement shall, subject to Section 8.5.1.1, until [**] years following the termination of this Agreement, maintain such Confidential Information in confidence, and shall not disclose, divulge or otherwise communicate such Confidential Information to others, except to directors, officers, employees, consultants, subcontractors, Sublicensees and/or agents who are bound by like terms of confidentiality, nor use it for any purpose, except pursuant to, and in order to carry out, the terms and objectives of this Agreement.  The receiving Party further agrees to exercise reasonable precautions to prevent and restrain the unauthorized disclosure of such Confidential Information by any of its directors, officers, employees, consultants, subcontractors, Sublicensees and agents.  Additionally, the terms of this Agreement and the Original Agreement will be held in confidence by the Parties until [**] years following the termination of this Agreement or the Original Agreement, except to the extent necessary in order to enforce its rights under this Agreement or as required by the rules of any securities exchange or automated quotation system or to the extent such terms are required to be disclosed to a governmental agency, or in response to involuntary compulsory process issued by a court, administrative agency or any governmental body having apparent jurisdiction provided the Party subject to such process first provides notice to the other Party hereto (to the extent practicable) and reasonably cooperates with efforts by the notified Party to secure confidential

 

30

 

protection of such terms.  The obligations of the Parties under this Section 9.5.1 are subject to the provisions of Section 9.5.2 and 9.5.3.

 

9.5.2                     Release from Restrictions.  The provisions of Section 9.5.1 (Obligations and Restrictions) shall not apply to any Confidential Information that:

 

(i)                                     was generally available to the public or otherwise part of the public domain at the time of its disclosure to the receiving Party through no fault of the receiving Party;

 

(ii)                                  became generally available to the public or otherwise part of the public domain after its disclosure through no fault of the receiving Party;

 

(iii)                               at the time of receipt by a Party was independently known to such Party without obligation of confidentiality from a source other than the other Party to this Agreement or anyone acting on behalf of any of them;

 

(iv)                              has been made available to such Party without obligation of confidentiality by a Third Party having the lawful right to do so without breaching any such obligation of nonuse or confidentiality to any Party to this Agreement; or

 

(v)                                 was independently developed by the receiving Party (without reference to or use of Confidential Information of the disclosing Party).

 

9.5.3                     Activities Related to GDNF Products.  The restrictions set forth in this Section 9.5 (Confidential Information) shall not prevent (i) a Party from preparing, filing, prosecuting or maintaining a patent application or its resulting patents related to a GDNF Product in accordance with the terms of this Agreement, or (ii) AMT from disclosing Confidential Information to governmental agencies to the extent required or desirable to secure government approval for the development, manufacture or marketing of a GDNF Product, or (iii) AMT from conducting Exploitation with respect to GDNF Products as permitted by this Agreement (including the disclosure of Confidential Information to Sublicensees), or (iv) a Party from disclosing Confidential Information of the other Party or the terms of this Agreement to: (a) its actual or potential investments bankers and other advisers (including financial, accounting and legal); (b) actual and prospective lenders or funders for the purpose of obtaining financing for its business; and (c) to a bona fide potential acquirer or merger partner for the purposes of evaluating entering into a merger or acquisition, provided, however, any such disclosure shall be subject to the Third Party receiving such Confidential Information or the terms of this Agreement being obligated to substantially the same extent as set forth in this Section 9.5 (Confidential Information) to hold in confidence and not make use thereof for any purpose other than those permitted by this Agreement.

 

SECTION 9.6                                             Compliance With Law; Severability.  Nothing in this Agreement shall be construed to require the commission of any act contrary to Law.  If this Agreement conflicts with 

 

31

 

any statute, law, ordinance or treaty concerning the legal right of the parties to contract, the latter shall prevail.  In such event, the affected provisions of this Agreement shall be curtailed and limited only to the extent necessary to bring it within the applicable legal requirements and the validity, legality and enforceability of the remaining provisions of this Agreement shall not in any way be affected or impaired thereby.

 

SECTION 9.7                                             Representations, Warranties and Covenants.

 

9.7.1                     Representations and Warranties.  Each Party hereby represents and warrants to the other Party, as of the Effective Date, as follows:

 

(i)                                     Such Party is a corporation duly organized, validly existing and in good standing under the laws of the state in which it is incorporated;

 

(ii)                                  Such Party (a) has the corporate power and authority and legal right to enter into this Agreement, to perform its obligations and to grant the licenses hereunder, and (b) has taken all necessary corporate action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations hereunder;

 

(iii)                               This Agreement has been duly executed and delivered on behalf of such Party and constitutes a legal and valid obligation binding upon such Party and enforceable against it in accordance with its terms;

 

(iv)                              The execution, delivery and performance of this Agreement by such Party do not conflict with any agreement, instrument or understanding, oral or written, to which it is a party or by which it is bound, nor violate any applicable Law;

 

(v)                                 Such Party is aware of no action, suit, inquiry or investigation instituted by any Third Party that questions or threatens the validity of this Agreement;

 

(vi)                              All necessary consents, approvals and authorizations of all governmental authorities and other persons required to be obtained by such Party in connection with this Agreement have been obtained; and

 

(vii)                           No Joint Know-How (as such term is defined in the Original Agreement) was generated by the Parties in connection with their activities under the Original Agreement.

 

9.7.2                     Disclaimer.  EXCEPT AS EXPRESSLY SET FORTH IN SECTION 9.7 (REPRESENTATIONS, WARRANTIES AND COVENANTS), NEITHER PARTY MAKES ANY REPRESENTATIONS OR WARRANTIES, EXPRESS OR IMPLIED, OF ANY KIND, INCLUDING AS TO MERCHANTABILITY, FITNESS FOR A PARTICULAR USE OR NON-INFRINGEMENT.  SPECIFICALLY, NEITHER PARTY WARRANTS THE VALIDITY OR ENFORCEABILITY OF

 

32

 

THE PATENT RIGHTS LICENSED HEREUNDER, AND MAKES NO REPRESENTATIONS WHATSOEVER WITH REGARD TO THE SCOPE OF THE PATENT RIGHTS LICENSED HEREUNDER, OR THAT THE PATENT RIGHTS LICENSED HEREUNDER MAY BE EXPLOITED WITHOUT INFRINGING OTHER PATENTS OR OTHER INTELLECTUAL PROPERTY RIGHTS OF THIRD PARTIES.

 

9.7.3                     Covenants.  Each Party hereby covenants that it shall not enter into any agreement that is in conflict with this Agreement.  Further, AMT covenants it shall not knowingly use any employee or consultant who is or has been debarred by the FDA or other regulatory agency, or, to the best of AMT’s knowledge, is or has been the subject of debarment proceedings by the FDA or other regulatory agency.

 

9.7.4                     AMT Acknowledgement.  AMT hereby acknowledges that: (i) Amgen has granted certain rights under the Licensed Know-How and Licensed Patent Rights to MedGenesis Therapeutix Inc. and Biovail Laboratories International SRL outside of the Licensed Field; (ii) Amgen has granted certain academic institutions the right under material transfer agreements to conduct research (including preclinical and non-clinical activities but excluding in vivo and clinical activities) with respect to GDNF; and (iii) Amgen has placed a clinical hold order on its Regulatory Filings for the GDNF Product.

 

SECTION 9.8                                             Waiver.  A Party’s consent to or waiver, express or implied, of the other Party’s breach of its obligations hereunder shall not be deemed to be or construed as a consent to or waiver of any other breach of the same or any other obligations of the other Party.  A Party’s failure to complain of any act, or failure to act, by the other Party, to declare the other Party in default, to insist upon the strict performance of any obligation or condition of this Agreement or to exercise any right or remedy consequent upon a breach thereof, no matter how long such failure continues, shall not constitute a waiver by such Party of its rights hereunder, of any such breach, or of any other obligation or condition.  A Party’s consent in any one instance shall not limit or waive the necessity to obtain such Party’s consent in any future instance and in any event no consent or waiver shall be effective for any purpose hereunder unless such consent or waiver is in writing and signed by the Party granting such consent or waiver.

 

SECTION 9.9                                             Indemnity.

 

9.9.1                     By Amgen.  Amgen agrees to defend AMT and its directors, officers, employees and agents (the “AMT Indemnified Parties”) at Amgen’s cost and expense, and will indemnify and hold AMT and the other AMT Indemnified Parties harmless from and against any claims, losses, costs, damages, fees or expenses (including legal fees and expenses) (collectively, “Losses”) resulting from any Third Party claim (including product liability claims and any claims made by any licensors under any Third Party Agreements described in Section 8.5.1.1) arising out of or otherwise relating to (i) the gross negligence or willful misconduct of Amgen, or (ii) breach of this Agreement or 

 

33

 

the representations and warranties made hereunder by Amgen or (iii) following the grant of the licenses to Amgen under Section 8.5, the Exploitation of any GDNF Product by or on behalf of Amgen or its Affiliates or Sublicensees; except, in each case, to the extent such Losses result from clause (i), (ii), or (iii) of Section 9.9.2 (By AMT).  In the event of any such claim against the AMT Indemnified Parties by a Third Party, AMT shall promptly notify Amgen in writing of the claim (provided, however, that any failure or delay to notify shall not excuse any obligations of Amgen except to the extent Amgen is actually prejudiced thereby) and Amgen shall solely manage and control, at its sole expense, the defense of the claim and its settlement; provided, however, that Amgen shall not settle any such claim without the prior written consent of AMT if such settlement does not include a complete release from liability or if such settlement would involve undertaking an obligation (including the payment of money by an AMT Indemnified Party), would bind or impair an AMT Indemnified Party, or includes any admission of wrongdoing or that any intellectual property or proprietary right of AMT is invalid or unenforceable.  The AMT Indemnified Parties shall cooperate with Amgen and may, at their option and expense, be represented in any such action or proceeding by counsel of their own choosing.

 

9.9.2                     By AMT.  AMT agrees to defend Amgen and its directors, officers, employees and agents (the “Amgen Indemnified Parties”) at AMT’s cost and expense, and will indemnify and hold Amgen and the other Amgen Indemnified Parties harmless from and against any Losses resulting from any Third Party claim (including product liability claims) arising out of or otherwise relating to (i) the gross negligence or willful misconduct of AMT, (ii) the Exploitation of any GDNF Product by or on behalf of AMT or its Affiliates, or (iii) breach of this Agreement or the representations and warranties made hereunder by AMT; except, in each case, to the extent such Losses result from clause (i) or (ii) of Section 9.9.1 (By Amgen).  In the event of any such claim against the Amgen Indemnified Parties by a Third Party, Amgen shall promptly notify AMT in writing of the claim (provided, however, that any failure or delay to notify shall not excuse any obligation of AMT except to the extent AMT is actually prejudiced thereby) and AMT shall solely manage and control, at its sole expense, the defense of the claim and its settlement; provided, however, that AMT shall not settle any such claim without the prior written consent of Amgen if such settlement does not include a complete release from liability or if such settlement would involve undertaking an obligation (including the payment of money by an Amgen Indemnified Party), would bind or impair an Amgen Indemnified Party, or includes any admission of wrongdoing or that any intellectual property or proprietary right of Amgen is invalid or unenforceable.  The Amgen Indemnified Parties shall cooperate with AMT and may, at their option and expense, be represented in any such action or proceeding by counsel of their own choosing.

 

9.9.3                     No Liability for Pre-Effective Date Losses.  Neither Party shall assume or be liable for any Losses (whether by way of indemnity or otherwise) resulting from or arising in connection with the activities of the other Party (or any agent, independent contractor 

 

34

 

or Third Party engaged by such other Party) or relating to such other Party’s intellectual property rights on or prior to the Effective Date.

 

9.9.4                     Insurance.  AMT shall at its own expense procure and maintain during the term of this Agreement and for [**] years thereafter, insurance policy/policies, including product liability insurance, adequate to cover its obligations hereunder and which are consistent with normal business practices of prudent pharmaceutical companies and with AAV gene therapy trials generally.  AMT’s insurance shall not be construed to create a limit of AMT’s liability with respect to its indemnification obligations under this Article 12 (General).  AMT’s insurance hereunder shall be primary with respect to the obligations for which it is liable hereunder.

 

SECTION 9.10                                      LIMITATION OF DAMAGES.  IN NO EVENT SHALL EITHER PARTY BE LIABLE HEREUNDER TO THE OTHER PARTY FOR ANY INDIRECT, SPECIAL, INCIDENTAL EXLEMPARY OR CONSEQUENTIAL DAMAGES (INCLUDING LOST REVENUE, LOST PROFITS, OR LOST SAVINGS), EVEN IF IT HAS NOTICE OF THE POSSIBILITY OF SUCH DAMAGES.  The limitations set forth in this Section 9.10 (Limitation of Damages) shall not apply with respect to (i) any breach of Section 9.5 (Confidential Information) or (ii) the willful misconduct of a Party.  NOTHING IN THIS SECTION 9.10 (LIMITATION OF DAMAGES) IS INTENDED TO LIMIT OR RESTRICT THE INDEMNIFICATION RIGHTS OR OBLIGATIONS OF EITHER PARTY UNDER SECTION 9.9 (INDEMNITY) WITH RESPECT TO ANY DAMAGES PAID BY THE OTHER PARTY TO A THIRD PARTY IN CONNECTION WITH A THIRD PARTY CLAIM.

 

SECTION 9.11                                      The limitations of liability and exclusion of damages herein, shall apply even if a Party had or should have had knowledge, actual or constructive, of the possibility of such damages.  In addition, such limitations of liability and exclusion of damages, and the sole and exclusive remedies provided herein: (i) are fundamental elements of this Agreement, which would not be entered into without such limitations, exclusions and sole/exclusive remedies; (ii) shall apply whether a claim is based on breach of contract, breach of warranty, tort (excluding fraud or intentional misconduct) or otherwise; and (iii) shall apply even if the breach is a total and/or fundamental breach of this Agreement and regardless of whether the limited damages or remedies fail of their essential purpose and/or fail to provide relief to a Party.

 

SECTION 9.12                                      Assignment.  Neither this Agreement nor any right or obligation hereunder may be assigned or otherwise transferred by a Party (whether voluntarily, by operation of law or otherwise), without the prior express written consent of the other Party; provided, however, that either Party may, without the other’s consent, assign this Agreement and its rights and obligations hereunder in connection with the transfer or sale of all or substantially all of its business related to this Agreement whether in a merger, consolidation, acquisition or similar transaction.  Notwithstanding anything contained in the foregoing to the contrary, either Party may assign this Agreement to its Affiliates.  Any permitted assignee shall assume all obligations of its assignor under this Agreement.  Any purported assignment or transfer in violation of this Section 9.12 (Assignment) shall be void.

 

35

 

SECTION 9.13                                      Non-Use of Names.  Amgen shall not use the name, trademark, logo, physical likeness or name of AMT or any of its officers, directors or employees, or any adaptation of any of them, in any advertising, promotional or sales literature, without AMT’s prior written consent.  Amgen shall require its Affiliates and Sublicensees to comply with the foregoing.  AMT shall not use the name, trademark, logo, physical likeness or name of Amgen or any of its officers, directors or employees, or any adaptation of any of them, in any advertising, promotional or sales literature, without Amgen’s prior written consent.  AMT shall require its Affiliates and Sublicensees to comply with the foregoing.

 

SECTION 9.14                                      Publicity.  Neither Party shall originate any publicity, news release or other public announcement, written or oral, of this Agreement or its terms, without the prior approval of the other Party except solely to the extent a Party reasonably believes same is otherwise required by Law.  Any Press Release in connection with the signing of this Agreement is set out in Schedule 9.14.  Each Party shall to the extent consistent with applicable Laws and regulations limit the disclosure of the financial terms set forth in this Agreement (such as by requesting confidential treatment of such terms in documents required to be filed with the U.S. Securities and Exchange Commission).  AMT shall provide a proposed draft to Amgen of any intended press releases or other public disclosure, which AMT is required to make under applicable Law or stock exchange rule to the extent relating to this Agreement or the activities contemplated under this Agreement as soon as practicable and when possible at least [**] business days in advance of its proposed release.  Amgen shall consider AMT’s request to make such press release or statement and within [**] business days of receiving such press release or statement or sooner if reasonably requested by AMT, indicate to AMT whether Amgen requires any changes to be made prior to the release thereof, which changes AMT shall be required to make prior to making such press release or other public disclosure, unless the making of such changes would, in AMT’s reasonable belief, put AMT in violation of a legal requirement to disclose a material fact pursuant to applicable Law or stock exchange rules.  Notwithstanding the foregoing, if applicable Law or stock exchange rules, in the opinion of counsel, require disclosure in a time frame that makes prior disclosure by AMT to Amgen in accordance with the foregoing procedures impractical under the circumstances, AMT may make such disclosure provided that it promptly provide such disclosure to Amgen.

 

SECTION 9.15                                      Construction.  The Parties agree that each Party has reviewed this Agreement and that any rule of construction to the effect that ambiguities are to be resolved against the drafting Party shall not apply to the interpretation of this Agreement.  As used herein, the terms “include”, “includes” and “including” shall be deemed to be immediately followed by “without limitation”.

 

SECTION 9.16                                      Headings.  The headings for each Article and Section in this Agreement have been inserted for convenience of reference only and are not intended to limit or expand on the meaning of the language contained in the particular Article or Section.  Unless otherwise specified, (i) references in this Agreement to any Article, Section, or Schedule shall mean references to such Article, Section, or Schedule of this Agreement, (ii) references in any Section to any clause are references to such clause of such Section, and (iii) references to any agreement, instrument or other document in this Agreement refer to such agreement, instrument or other document as originally 

 

36

 

executed or, if subsequently varied, replaced or supplemented from time to time, as so varied, replaced or supplemented and in effect at the relevant time of reference thereto.

 

SECTION 9.17                                      Further Actions.  Each Party agrees to execute, acknowledge and deliver such further instruments and to do all such other acts as may be necessary or appropriate in order to carry out the purposes and intent of this Agreement.

 

SECTION 9.18                                      Independent Contractors.  The relationship between AMT and Amgen created by this Agreement is solely that of independent contractors.  This Agreement does not create any agency, distributorship, employee-employer, partnership, joint venture or similar business relationship between the Parties.  Neither Party is a legal representative of the other Party, and neither Party can assume or create any obligation, representation, warranty or guarantee, express or implied, on behalf of the other Party for any purpose whatsoever.  Each Party shall use its own discretion and shall have complete and authoritative control over its employees and the details of performing its obligations under this Agreement.

 

SECTION 9.19                                      No Benefit of Third Parties.  The representations, warranties, covenants and agreements set forth in this Agreement are for the sole benefit of the Parties hereto and their successors and permitted assigns, and they shall not be construed as conferring any rights on any Third Parties (with the exception of AMT Indemnified Parties and Amgen Indemnified Parties under Sections 9.9.1 and 9.9.2, respectively).

 

SECTION 9.20                                      Counterparts.  This Agreement may be executed in any number of counterparts, each of which need not contain the signature of more than one Party but all such counterparts taken together shall constitute one and the same agreement, and may be executed through the use of facsimiles.

 

SECTION 9.21                                      License to Intellectual Property.  The Parties acknowledge that this Agreement constitutes a license to “intellectual property” as such term is used in §365(n) of the United States Bankruptcy Code (“Bankruptcy Code”).  The Parties shall retain and may fully exercise all of their respective rights and elections under the Bankruptcy Code.  Following the commencement of a bankruptcy proceeding of a Party, the non-bankrupt Party shall further be entitled to a complete duplicate of (or complete access to, as appropriate) any such intellectual property, and such, if not already in its possession, shall be promptly delivered to the non-bankrupt Party, unless the bankrupt Party elects to continue, and continues, to perform its obligations under this Agreement.

 

SECTION 9.22                                      English Language.  This Agreement, including all Schedules, is being executed in the English language only, which language shall be controlling in all respects, and all versions hereof in any other language shall be for accommodation only and shall not be binding upon the Parties hereto.  All communications to be made or given pursuant to this Agreement shall be made in the English language.

 

[The rest of this page left intentionally blank.]

 

37

 

IN WITNESS WHEREOF, the Parties have each caused a duly authorized officer to sign this Agreement to be effective as of the Effective Date.

 

	
AMGEN   INC.
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
By:
    	
/s/   Roger M. Perlmutter
    	
 
    	
 
    
	
Name:
    	
Roger   M. Perlmutter
    	
 
    	
 
    
	
Title:
    	
EVP   Research & Development
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
AMSTERDAM   MOLECULAR THERAPEUTICS
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
By:
    	
/s/   P.J. Morgan CFO
    	
 
    	
 
    
	
Name:
    	
Jörn   Aldag
    	
 
    	
 
    
	
Title:
    	
Chief   Executive Officer
    	
 
    	
 
    

 

38

 

SCHEDULE 1.10

 

(AMT Licensed Patent Rights)

 

	
Country
    	
 
    	
Official No.
    	
 
    	
Filing Date
    	
 
    	
Case Status
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Confidential Materials omitted and filed separately with the Securities and Exchange Commission. A total of one page was omitted. [**]

 

39

 

SCHEDULE 1.50

 

(Licensed Patent Rights)

 

GDNF Related IP

 

	
Country
    	
 
    	
Filing Number
    	
 
    	
Filing
    	
 
    	
Status
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    

 

Confidential Materials omitted and filed separately with the Securities and Exchange Commission. A total of four pages were omitted. [**]

 

40

 

SCHEDULE 9.14

 

(Press Release)

 

Amsterdam Molecular Therapeutics Amends Amgen GDNF Gene License Agreement

 

Amsterdam, The Netherlands, DATE, 2010-Amsterdam Molecular Therapeutics (AMT) Holding N.V. (Euronext: AMT), a leader in the development of gene based therapies, today announced that it has amended and restated its licensing agreement with Amgen (Nasdaq: AMGN) for gene therapy applications incorporating the GDNF (glial cell derived neurotrophic factor) gene to which Amgen holds rights.  Financial terms were not disclosed.

 

The GDNF gene contains the information to produce a protein necessary for the development and survival of nerve cells.  The positive effect of GDNF on nerve cells has already been demonstrated in early research.  Studies with a GDNF gene therapy, AMT-090, in a Parkinson’s disease model are being conducted by AMT in collaboration with the University of Lund, Sweden.  AMT also plans to combine the GDNF gene with its proprietary adeno-associated virus (AAV) technology to develop gene therapies for a range of CNS applications, such as Huntington’s disease and amyotrophic lateral sclerosis (ALS), with an aim to protect and enhance the function of the affected nerve cells.

 

“Based on the promising early results of our GDNF gene therapy product in Parkinson’s disease models, we believe there is an opportunity for a similar approach in other debilitating CNS disorders.  For many of these disorders, current therapies are limited and tend only to treat symptoms.  Treatment with our gene therapies has the potential to halt or reverse disease progress,” said Jurn Aldag, CEO of AMT, “This agreement will allow us to progress the program for Parkinson’s Disease forward and at the same time find a partner who will support the funding of our GDNF programs in alternative indications.  Expanding the partnering opportunities could mean even greater interest as the widened therapeutic applications offer more chances of success, potentially less complex product development paths and in many cases fewer patients to enroll in clinical trials.”

 

About Amsterdam Molecular Therapeutics

 

AMT is a leader in the development of human gene based therapies.  Using adeno-associated viral (AAV) derived vectors as the delivery vehicle of choice for therapeutic genes, the company has been able to design and validate what is probably the first stable and scalable AAV production platform.  This proprietary platform can be applied to a large number of rare (orphan) diseases that are caused by one faulty gene.  Currently, AMT has a product pipeline with several AAV-based gene therapy products in LPLD, Hemophilia B, Duchenne Muscular Dystrophy, Acute Intermittent Porphyria, and Parkinson’s Disease at different stages of research or development.  AMT was founded in 1998 and is based in Amsterdam.

 

41

 

For further enquiries:

 

	
Jörn   Aldag
    	
Mike   Sinclair
    
	
CEO
    	
Partner
    
	
AMT
    	
Halsin   Partners
    
	
Tel:   +31 20 566 7394
    	
Tel:   +44 20 7318 2955
    
	
j.aldag@amtbiopharma.com
    	
msinclair@halsin.com
    

 

Certain statements in this press release are “forward-looking statements” including those that refer to management’s plans and expectations for future operations, prospects and financial condition.  Words such as “strategy,” “expects,” “plans,” “anticipates,” “believes,” “will,” “continues,” “estimates,” “intends,” “projects,” “goals,” “targets” and other words of similar meaning are intended to identify such forward-looking statements.  Such statements are based on the current expectations of the management of AMT only.  Undue reliance should not be placed on these statements because, by their nature, they are subject to known and unknown risks and can be affected by factors that are beyond the control of AMT. Actual results could differ materially from current expectations due to a number of factors and uncertainties affecting AMT’s business.  AMT expressly disclaims any intent or obligation to update any forward-looking statements herein except as required by law.

 

42

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