Document:

Exhibit 10.13

 

Confidential Materials omitted and filed separately with the

Securities and Exchange Commission. Double asterisks denote omissions.

 

LICENSE AGREEMENT

 

by and among

 

FUNDACIÓN PARA LA INVESTIGACIÓN MÉDICA APPLICADA (1)

 

PONTEGADEA BIOTECHNOLOGICA, S.L. SOCIEDAD DE DESAROLLO DE NAVARA, S.A., CIERVANA, S.L., CINAMAR, S.A, MASAVEU DE INVESTIGACIONES Y DESAROLLO, S.L., INVESTIGACIONES 2001 CORPCAN, S.L., ALAZADY BIOTECNOLÓGICA, S.L., SOCIEDAD ANDALUZA DE INVESTIGACIÓN DE LA SALUD, S.L.U., INSTITUTO DE EDUCACIÓN E INVESTIGACIÓN S.A, LOYALTY SQUARE, S.L., UNICARTERA CAJA 2, S.L., CAJA RURAL DE NAVARRA, SOCIEDAD COOPERATIVA LIMITADA DE CREDITO, UNGRIA PATENTES Y MARCAS, S.A., FUERTES I MÁS D, S.L., GAINMÉDICA, S.L., UNIÓN TEMPORAL DE EMPRESES LEY 18/1982, DE 26 MAYO NÚM 1.334/2003 (2)

 

PROYECTO DE BIOMEDICINA CIMA S.L. (3)

 

DIGNA BIOTECH, S.L. (4)

 

AND

 

AMSTERDAM MOLECULAR THERAPEUTICS (AMT) B.V. (5),

 

dated as of 21st May, 2010

 

 

LICENSE AGREEMENT

 

THIS LICENSE AGREEMENT dated as of 21 May, 2010 (the “Agreement”) is made by and among:

 

(1)                                 Fundación para la Investigación Médica Applicada (“FIMA”) incorporated under the laws of Spain, by means of the public deed executed on December 10th, 1998, before the Notary Public of Madrid, Victor Manual Garrido de Palma, under the number 3001 of its protocol; with Tax Identification Number G82198524 and with registered offices at Calle Pintor Paret, 5, 1 F, Pamplona, Spain; duly represented by Mr Franciso Errasti Goenaga;

 

(2)                                 Pontegadea Biotecnologica, S.L, Sociedad de Desarrollo de Navarra, S.A., Ciervana, S.L., Cinamar, S.A., Masaveu de Investigaciones y Desarrollo, S.L., Investigaciones 2001 CORPCAN, S.L., Alazady Biotecnológica, S.L., Sociedad Andaluza de Investigación de la Salud, S.L.U., Instituto de Educación e Investigación S.A., Loyalty Square, S.L., Unicartera Caja 2, S.L., Caja Fural de Navarra, Sociedad Cooperativa Limitada de Credito, Ungria Patentes y Marcas, S.A., Fuertes I Más D, S.L., Gainmédica, S.L., Unión Temporal de Empresas Ley 18/1982, de 26 de Mayo, Núm. 1.334/2003, (the collaborative reseach consortium known as “UTE CIMA”), incorporated under the laws of Spain, by means of the public deed executed on June 3rd, 2003, before the Notary Public of Pamplona, Jose Javier Castiella Rodriques, under the number 1461 of its protocol, with Tax Identification Number G31790595 and with registered offices at Avda. De Carlos III, 36, 1 Dcha, Pamplona, Spain; duly represented by Mr Antonio Martin Catón;

 

(3)                                 Proyecto de Biomedicina CIMA S.L. (“Proyecto”) with corporate address at Avda. Carlos III. 36, 1 dcha., 31003 Pamplona, Navarra, Spain; duly represented by Mr Antonio Martin Canton;

 

(4)                                 Digna Biotech, S.L. (“Digna”) with corporate address at C/ Etxesakan 28, oficina 5, 31180 Cizur Maryo, Navarra, Spain, bearer of Tax Identification Number B-31778509, duly represented by Mr Pablo Ortiz Bétes;

 

(5)                                 Amsterdam Molecular Therapeutics (AMT) B.V. (“AMT”) a company with limited liability incorporated under the laws of The Netherlands with registered office at Meibergdreef 61, NL-1105 BA Amsterdam, The Netherlands, duly represented by Mr. Piers Morgan;

 

WHEREAS

 

(A)                               FIMA and UTE CIMA collaborate in a project called “CIMA Project” for medical investigation and research.  On June 3rd, 2003, FIMA and UTE CIMA entered into a Investigation Contract in the frame of a contractual joint venture (“Joint Venture”) by virtue of which FIMA, in consideration for the remuneration agreed between the parties, carries out those investigations required for the fulfillment of the purpose of CIMA Project, with the results derived from said investigations by FIMA being owned solely and automatically by UTE CIMA;

 

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(B)                               Pursuant to the Joint Venture, UTE CIMA undertook to assign to Proyecto, all of UTE CIMA’s right, title and interest in any results derived from the above investigations, when such results might be subject to protection and/or exploitation according to the intellectual property regulations;

 

(C)                               Proyecto has an agreement with Digna dated June 14th, 2005 under which Digna undertakes to carry out on behalf of Proyecto prosecution, maintenance, enforcement and defense tasks of the above intellectual property.  In addition, Proyecto has entered into an agreement with Digna dated June 25th, 2005, amended on December 20th, 2005, under which Digna is entitled to an exclusive worldwide license to develop and commercialize the above results;

 

(D)                               AMT is a biopharmaceutical company that owns or controls Patents, Know-How and Materials relating to the research, development, registration, manufacture and commercialization of therapies based on constructs including adeno-associated virus (“AAV”) vectors;

 

(E)                                In July 2005, FIMA, UTE CIMA and AMT entered into an agreement (“2005 Agreement”) for the conduct of a collaborative research and development program to construct an AAV vector which could be used in the therapy of porphyria which was since extended to include research and development into reducing the immunogenicity of the AAV therapies.  In anticipation of the successful generation of an AAV vector which could be used in the therapy of porphyria, the parties discussed potential opportunities for the further development and commercialization of Products (as defined in the 2005 Agreement);

 

(F)                                 On May 1, 2007, the Parties entered into a Commercialization Agreement (“2007 Commercialization Agreement”) pursuant to which, inter alia, (i) Digna relinquished its rights to develop and commercialize Products (as defined in the 2007 Commercialization Agreement) under such Intellectual Property to facilitate the 2007 Commercialization Agreement, (ii) AMT was granted exclusive rights to develop and commercialize Products (as defined in the 2007 Commercialization Agreement) and (iii) the 2005 Agreement was terminated;

 

(G)                               On July 25th, 2007, AMT, FIMA, UTE CIMA, PB CIMA and Digna entered into an agreement to give AMT and its Affiliates privileged access to the results of the research being conducted by or upon behalf of UTE CIMA and FIMA (“Privileged Access Agreement”) with an option for AMT to participate in the Development of Candidate Products (as those terms are defined in the Privileged Access Agreement) and, if this yielded positive results for AMT or its Affiliates to have the right to take an exclusive license under relevant intellectual property to further research, develop, make, register and commercialize such Candidate Product;

 

(H)                              In relation to the Candidate Product Virus encoded IGF-1 for the treatment of liver cirrhosis, AMT exercised its option to take an exclusive license pursuant to which Digna, Proyecto and AMT entered into a license agreement dated November 9th, 2007 (the “Virus encoded IGF License”);

 

(I)                                   The Parties now wish to modify their collaboration under aforementioned agreements and to refocus their efforts and resources to the further development and commercialization of a gene therapy treatment for acute intermittent porphyria under the terms and conditions set forth below;

 

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IT IS NOW AGREED AS FOLLOWS

 

ARTICLE 1                           DEFINITIONS

 

For purposes of this Agreement, the terms defined in this Article 1 shall have the meanings specified below.  Certain other capitalized terms are defined elsewhere in this Agreement.

 

1.1                               “Affiliate” any company, partnership or other business entity which Controls, is Controlled by or it under common Control with any of the Parties.  For the purposes of this definition “Control” refers to any of the following (i) the possession, directly or indirectly, of the power to direct the management or policies of an entity, whether through ownership of voting securities, by contract or otherwise; (ii) ownership of fifty percent (50%) or more of the voting securities entitled to vote for the election of directors in the case of a corporation, or of fifty percent (50%) or more of the equity interest in the case of any other type of legal entity; (iii) status as a general partner in any partnership, or any other arrangement whereby a Party controls or has the right to control the board of directors or equivalent governing body of a corporation or other entity.

 

1.2                               “Agreement” or “License Agreement” means this License Agreement.

 

1.3                               “AMT Background IP” means any IP owned or Controlled by AMT prior to the Effective Date or developed or acquired by AMT after the Effective Date, but excluding Joint Patent Rights and excluding any IP that has been developed prior to the Effective Date under the collaborative research programs jointly carried out by the Parties. AMT Background IP does, however include manufacturing knowhow developed by AMT within or outside said collaborative research programs.

 

1.4                               “Calendar Quarter” means each period of three months ending on 31 March, 30 June, 30 September or 31 December and “Quarterly” shall be construed accordingly.

 

1.5                               “Calendar Year” means each successive period of twelve calendar (12) months commencing on 1 January.

 

1.6                               “CIMA Parties” means FIMA, UTE CIMA, Proyecto and Digna jointly and a “CIMA Party” means FIMA, UTE CIMA, Proyecto or Digna.

 

1.7                               “CIMA Background IP” means any IP owned or Controlled by a CIMA Party at the Effective Date or developed or acquired by a CIMA Party after the Effective Date outside the scope of this Agreement and/or the Collaborative Development Agreement and that is useful for the development or Commercialization of the Product, but excluding Joint Patent Rights and excluding any IP that has been developed prior to the Effective Date under the collaborative research programs jointly carried out by the Parties.

 

1.8                               “Collaborative Development Agreement” means the agreement between Digna and ATM attached hereto as Exhibit 2.

 

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1.9                               “Commercialization”, “Commercializing” or “Commercialize” means all activities relating to the import, advertising, promotion and other marketing, pricing and reimbursement, detailing, distribution, storage, handling, offering for sale and selling, customer service and support, post Regulatory Approval regulatory activities including phase IV clinical trials and adverse event reporting in relation to the Product.

 

1.10                        “Commercially Reasonable Efforts” means in respect of AMT efforts and resources commonly used by biotechnology companies of a similar size to AMT based on funds raised.

 

1.11                        “Confidential Information” means, subject to the exceptions set forth in Article 8.3 (i) the terms and conditions of this Agreement and the Collaborative Development Agreement, for which each Party will be considered a Disclosing Party and a Recipient Party; and (ii) any non-public information, whether or not patentable, disclosed or provided by one Party to the other Party in connection with this Agreement, including, without limitation, any information which release is likely to prejudice the commercial interests of the parties, or is considered as a trade secret, including information regarding such Party’s strategy, business plans, objectives, research, technology, products, business affairs or finances including any non-public data relating to development or Commercialization of any Product and other information of the type that is customarily considered to be confidential information by parties engaged in activities that are substantially similar to the activities being engaged in by the Parties under this Agreement, for which the Party making such disclosure will be considered the Disclosing Party and the receiver will be the Recipient Party.

 

1.12                        “Control” (including variations such as “Controlled”) means with respect to any Intellectual Property, possession of the right, whether directly or indirectly, and whether by ownership, license or otherwise, to assign, or grant a license, sub-license or other right to or under, such Intellectual Property without violating the terms of any agreement or other arrangement with any Third Party.

 

1.13                        “Cover”, “Covered” or “Covering” means, with respect to a Patent Right that, but for a license under an issued Valid Claim included in such Patent Right, the manufacture, use, transportation, sale, offer for sale, or importation of the Product would infringe such Valid Claim or, in the case of a Patent Right that is a patent application, would infringe a Valid Claim in such patent application if it were to issue as a patent.

 

1.14                        Disclosing Party” means the Party which discloses Confidential Information to the other Party or Parties.

 

1.15                        “Disorder” means acute intermittent porphyria.

 

1.16                        “Documents” means analyses, books, CD-ROM, USB stick, charts, comments, computations, designs, discs, diskettes, files, graphs, ledgers, notebooks, paper, photographs, plans, records, recordings, reports, research notes, tapes and other graphic or written data or other media and other computer information storage means on which Know How is permanently stored and advertising and promotional materials of any nature whatsoever including preparatory materials for the same.

 

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1.17                        “Effective Date” means the date first set forth above.

 

1.18                        “Gene Therapy Field” means the use of genetic material in any of the following ways for the treatment or prophylaxis of a disease (a) delivery of a functional version of a mutant gene or any other DNA that encodes for a therapeutic molecule into the nucleus or mitochondiea of patient’s cells (b) by the insertion of a normal gene into a non-specific location within the genome to replace a non-functional gene; or (c) by swapping an abnormal gene for a normal gene (through homologous recombination); or (d) by repairing an abnormal gene through selective reverse mutation which returns the gene to its normal function; or (e) by altering the regulation (the degree to which a gene is turned on or off) of a particular gene.

 

1.19                        “Intellectual Property” or “IP” means Patent Rights, Know How and/or Materials.

 

1.20                        “Joint Patent Rights” means the patent application set forth in Exhibit 1 that is filed in the names of Amsterdam Molecular Therapeutics (AMT) IP B.V. and Proyecto de Biomedicina CIMA S.L jointly and any and all Patent Rights deriving from said patent application anywhere in the world.

 

1.21                        “Know-How” means technical and other information which is not in the public domain, including information comprising or relating to concepts, discoveries, data, designs, formulae, ideas, inventions, Materials, methods, models, research plans, procedures, designs for experiments and tests and results of experimentation and testing (including results of research or development) processes (including manufacturing processes, specifications and techniques), laboratory records, chemical, pharmacological, toxicological, clinical, analytical and quality control data, clinical and non-clinical trial data, case report forms, data analyses, reports, manufacturing data or summaries and information contained in submissions to and information from ethical committees and Regulatory Authorities. Know How includes Documents containing Know How, including but not limited to any rights including trade secrets, copyright, database or design rights protecting such Know How. The fact that an item is known to the public shall not be taken to preclude the possibility that a compilation including the item, and/or a development relating to the item, is not known to the public.

 

1.22                        “Launch” means the first arms-length commercial sale to a Third Party of the Product by AMT, its Affiliates or sub-licensees after grant of required Regulatory Approval and after pricing or reimbursement approval has been granted (if required in that country). Sales for test marketing, clinical trial purposes or compassionate or similar use do not constitute a Launch.

 

1.23                        “Losses” means any and all losses, damages, liabilities, costs and expenses (including, without limitation, reasonable attorneys’ fees and expenses). In calculating “Losses”, the duty to reasonably mitigate on the part of the Party suffering the Losses shall be taken into account.

 

1.24                        “Materials” means any chemical or biological substances including but not limited to blood samples, nucleotide or nucleotide sequence including DNA and RNA sequences, genes, vector or construct including plasmids, phages or viruses, host organism including bacteria, fungi, algae, protozoa and hybridoma’s, eukaryotic or prokaryotic cell line or expression system or any development strain or product of that cell line or expression system,

 

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protein including any peptide or amino acid sequence, enzyme, antibody or protein conferring targeting properties and any fragment of a protein or a peptide enzyme or antibody, assay or reagent, any other genetic or biological material or micro-organism.

 

1.25                        “Net Revenues” means:

 

(i)                                     Any signature fee or other up-front fee due to be received by AMT or any of its Affiliates from a licensee being appointed by AMT or any of its Affiliates to further develop and/or Commercialize a Product; and

 

(ii)                                  Any milestone or other payments due to be received by AMT or any of its Affiliates from a licensee being appointed by AMT or any of its Affiliates to further develop and/or Commercialize a Product which payments are payable on an event to occur in relation to the development or Commercialization thereof but always excluding sums received by AMT or any of its Affiliates from such licensee which reimburse AMT for the cost and expense (but only the cost and expenses and no profit element) of research or development work to be undertaken by or upon behalf of AMT of its Affiliate directly related to the development of Product; and

 

(iii)                               Any sums due to be received by AMT or any of its Affiliates from a licensee appointed by AMT or any of its Affiliates to Commercialize a Product which sums are calculated by reference to the sales volumes of the Product by such licensee as a percentage of a net sales or similar definition, but always excluding any sums received by AMT or its Affiliates for sales of Products by AMT or Affiliates to distributors or other Third Parties, provided that those sums are accounted as “Net Sales”.

 

In the event that AMT, or its Affiliate, receives non-monetary consideration from a licensee to further develop and/or Commercialize a Product, Net Revenues shall be calculated based on the fair market value of such consideration.

 

1.26                        “Net Sales” means the gross amount invoiced for sales of Product, in arm’s length sales by AMT or its Affiliates to Third Parties, less the following deductions from such gross amounts which are actually incurred, allowed, accrued or specifically allocated:

 

(i)                                     normal and customary trade cash and quantity discounts actually given, credits, price adjustments or allowances for damaged Products, returns or rejections of Products;

 

(ii)                                  chargeback payments and rebates (or the equivalent thereof) for Product granted on a customary trade basis to group purchasing organizations, managed health care organizations or to federal, state/provincial, local and other governments, including their agencies, or to trade customers;

 

(iii)                               reasonable and customary freight, shipping insurance and other transportation expenses directly related to the sale of Product (if actually borne by AMT or its Affiliates without reimbursement from any Third Party);

 

(iv)                              required distribution commissions/fees payable to any Third Party providing distribution services to AMT;

 

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(v)                                 sales, value-added, excise taxes, tariffs and duties, and other taxes and governmental charges directly related to the sale, to the extent that such items are included in the gross invoice price of Product and are actually borne by AMT, its Affiliates, without reimbursement from any Third Party (but not including taxes assessed against the income derived from such sale); and

 

(vi)                              actual uncollectible amounts for Product where collectability is determined in accordance with IFRS consistently applied to all AMT products.

 

In the event that AMT, or its Affiliate, receives non-monetary consideration from a Third Party for sale of Product, Net Sales shall be calculated based on the fair market value of such consideration.

 

1.27                        “Parties” means the parties to this Agreement and “Party” means a party to this Agreement.

 

1.28                        “Patent Rights” means a (i) all national, regional and international patents and patent applications, including provisional patent applications, (ii) all patent applications filed either from such patents, patent applications or provisional applications or from an application claiming priority from any of these, including divisional, continuations, continuations-in-part, provisions, convened provisionals and continued prosecution applications, (iii) any and all patents that have issued or in the future issue from the foregoing patent applications (i) and (ii), including author certificates, inventor certificates, utility models, petty patents and design patents and certificates of invention, (iv) any and all extensions or restorations by existing or future extension or restoration mechanisms, including revalidations, reissues, re-examinations and extensions (including any supplementary protection certificates and the like) of the foregoing patents or patent applications (i), (ii) and (iii), and (v) any similar rights, including so-called pipeline protection, or any importation, revalidation, confirmation or introduction patent or registration patent or patent of additions to any such foregoing patent applications and patents.

 

1.29                        “Product” means any product that is, or that utilizes technology Covered by the Joint Patent Rights.

 

1.30                        “Previous Agreements” means the 2005 Agreement, the Privileged Access Agreement, the Virus encoded IGF License and the 2007 Commercialization Agreement jointly.

 

1.31                        “Receiving Party” means any Party receiving Confidential Information from another Party;

 

1.32                        “Regulatory Approval” means all approvals from Regulatory Authorities in any country in the Territory required lawfully to develop, clinically test, manufacture and market the Product in any such country, any establishment license application filed with the FDA or other Regulatory Authority to obtain approval of the facilities and equipment to be used to manufacture a Product, any Investigational New Drug or other investigational filing, including but not limited to any authorization for the import, manufacture and clinical testing of the Product (whether or not in filled and finished form), and any product pricing approvals where applicable.

 

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1.33                        “Regulatory Authority” means any relevant national (e.g., the FDA, EU member states authorities), supra-national (e.g., the European Commission, the Council of the European Union, or the EMEA), or other relevant governmental entity in any jurisdiction of the world involved in the granting of Regulatory Approvals for pharmaceutical product.

 

1.34                        “Territory” means the world.

 

1.35                        “Third Party” means a party other than any of the Parties or any of their respective Affiliates.

 

1.36                        “Valid Claim” means either a claim of (a) an issued, unexpired patent which has not been revoked or held unenforceable or invalid by a decision of a court or governmental agency of competent jurisdiction from which no appeal can be taken, or with respect to which an appeal is not taken within the time allowed for appeal, and which has not been disclaimed, denied or admitted to be invalid or unenforceable through reissue, disclaimer or otherwise, or (b) any patent application which has not been cancelled, withdrawn, or abandoned, or been pending for more than [**] years from the earliest priority date claimed for such application, unless and until such claim becomes an issued claim of an issued patent.

 

ARTICLE 2                           TERMINATION OF PREVIOUS AGREEMENTS

 

2.1                               General.  The Parties agree that with effect from the Effective Date all the terms of the Previous Agreements (including but not limited to the financial obligations of AMT thereunder, whether or not already due and outstanding prior to the termination of the Previous Agreements) are terminated and to be replaced in their entirety by the terms of this Agreement, save for the clauses that will survive as set forth in Section 2.2 hereof and that each Party has no claim against each other Party in connection with the termination of the Previous Agreements agreed herein but for the surviving clauses set forth below.

 

2.2                               Surviving clauses. The following clauses in the Previous Agreements will survive:

 

2.2.1                     Privileged Access Agreement

 

(a)                                 Article 5 (Confidentiality, Publicity and Press Releases)

 

(b)                                 Article 9 (Governing Law)

 

(c)                                  Article 10 (Jurisdiction)

 

2.2.2                     2007 Commercialization Agreement

 

(a)                                 Article 2 (termination of, inter alia, 2005 Agreement)

 

(b)                                 Section 3.1 (ownership of Collaborative Research IP, as defined in the 2007 Commercialization Agreement)

 

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(c)                                  Section 3.4 (waiver and release of Digna regarding the development or Commercialization of Products (as defined in the 2007 Commercialization Agreement)

 

(d)                                 Article 6 (Confidentiality)

 

(e)                                  Sections 7 (Representations and Warranties)

 

(f)                                   Article 11 (Dispute Resolution)

 

2.2.3                     Virus Encoded IGF License

 

(a)                                 Article 6 (Confidentiality)

 

(b)                                 Article 10 (Governing Law)

 

(c)                                  Article 11 (Jurisdiction)

 

2.3                               For the avoidance of doubt:  (i) as per the Effective Date of this Agreement, the license granted to AMT under Optioned IP (as defined in the Virus Encoded IGF License) shall terminate, the costs of further maintenance, prosecution, enforcement and defense of the Optioned IP shall be borne by Digna and AMT shall cease the development, manufacture and Commercialization of Virus Encoded IGF, (ii) the license granted to AMT under the 2007 Commercialization Agreement to develop and Commercialize Products (as defined in the 2007 Commercialization Agreement) is replaced by the license granted to AMT under Article 3 of this Agreement subject to the terms and conditions of this Agreement and (iii) any amount due and outstanding by AMT under the Virus Encoded IFG License is waived by the CIMA Parties with effect as from the Effective Date.

 

ARTICLE 3                           OWNERSHIP AND LICENSE

 

3.1                               Ownership of Background. AMT is and remains the sole owner of the AMT Background IP. The CIMA Parties are and remain the sole owner of the CIMA Background IP. The Joint Patent Rights are and remain jointly owned by Amsterdam Molecular Therapeutics (AMT) IP B.V. and Proyecto de Biomedicina CIMA S.L.

 

3.2                               Grant of Rights from the CIMA Parties to AMT. As appropriate, UTE CIMA and Proyecto hereby grant to AMT and its Affiliates:

 

3.2.1                     an exclusive right and license, with the right to grant sublicenses, under Proyecto’s interest, right and title in the Joint Patent Rights to use, develop, make, have made and Commercialize Products within the Territory; and

 

3.2.2                     a non-exclusive, fully paid up, royalty free, right and license, with the right to grant sublicenses, under the CIMA Background IP required for the use, development, manufacture and/or Commercialization of the Product within the Territory and in the Gene Therapy Field and only to the extent required for said purpose. The CIMA Parties shall notify

 

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AMT in writing regularly (at least [**]) on any CIMA Background IP developed after the Effective Date, describing such new developed CIMA Background IP.

 

3.3                               Registration of license. The CIMA Parties shall upon first request of AMT cooperate in the registration of the licenses granted to AMT hereunder in the patent registers of the applicable patent offices, at AMT’s expense.

 

3.4                               Commercially Reasonable Efforts. AMT agrees to use Commercially Reasonable Efforts to further develop, manufacture and Commercialize Products as soon as reasonably practicable. If AMT does not fulfill its financial obligations under the Collaborative Development Agreement and/or in any other way does not use Commercially Reasonable Efforts to further develop, manufacture and Commercialize Products as soon as reasonably practicable,, DIGNA might revoke the license.

 

ARTICLE 4                           COLLABORATIVE DEVELOPMENT AGREEMENT

 

4.1                               Development Plan. The Parties acknowledge that Digna and AMT have entered into that certain Collaborative Development Agreement of even date herewith (attached hereto as Exhibit 2, the “Collaborative Development Agreement”) aimed at the further developed of a Product for treatment or prevention of acute intermittent porphyria.

 

ARTICLE 5                           ROYALTIES ON NET SALES AND NET REVENUES

 

5.1                               Royalties on Net Sales. If the Product is Commercialized by AMT, AMT shall pay a [**] percent royalty on Net Sales on all Products on a Product-by-Product and country-by-country basis for the longer of the two following periods: (i) for so long as there are Valid Claims of Joint Patent Rights in such country of sale; or (ii) for the period of orphan drug marketing exclusivity granted by the applicable regulatory authority on a country by country basis, being ten (10) years in the European Union or seven (7) years in the United States post Launch of the Product, as applicable.

 

5.2                               Royalties on Net Revenues. If the further development and/or Commercialization of a Product is licensed to a Third Party, AMT shall pay a [**] percent of Net Revenues received by AMT from any licensee under any license granted by AMT under the Joint Patent Rights for so long as such Net Revenues are received.

 

5.3                               Payment to Digna. All royalties shall be paid to Digna. Digna shall be responsible for the apportionment of the sums paid to Digna hereunder to the respective CIMA Parties, pursuant to the agreements executed between them, and for payment of the same according to that apportionment. All other CIMA Parties agree with payment of the royalties by AMT to Digna.

 

5.4                               Additional licenses. The Parties acknowledge that any vector license required by AMT from NIH to use, develop, make, have made or Commercialize Products will be borne by AMT. In the event that a license, sublicense or similar right from one or more Third Parties is necessary in order to make, have made, use, offer to sell, sell or import Product other than said licenses from NIH, then, upon notification to the CIMA Parties, AMT, its Affiliates or licensees may acquire such a license, sublicense or similar right and AMT may offset a total of [**]percent

 

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([**]%) of any royalty or other payments paid in connection therewith against any royalty payments due to Digna under this Article 5; provided, however, that in no event shall the total royalty payable to Digna on any Product be less than [**] percent ([**] %) of the Net Sales of such Product sold by AMT, its Affiliates or licensees as a result of such off-set.

 

5.5                               Quarterly Basis. All sums due to Digna under Sections 5.1 and 5.2 shall be calculated and payable on a Quarterly basis, and shall be paid in EURO within [**] days following the end of each Calendar Quarter. Each such payment shall be accompanied by a written report indicating the amount of Net Sales in the Territory and Net Revenues during such Calendar Quarter (including quantity of Product sold by party -i.e AMT, its Affiliates and licensees), the gross amounts that correspond to such Net Sales and Net Revenues, the currency conversion rates used (if any) and a calculation of the sums due.

 

5.6                               Currency. Whenever for the purpose of calculating royalties conversion from any foreign currency shall be required, such conversion shall be made as follows. When calculating the Net Sales, the amount of such sales in foreign currencies shall be converted into EURO using the average monthly rate of exchange for such currencies at the time published in Financial Times in accordance with current standard practices in the market. AMT shall make all payments under this Agreement in EURO. If AMT becomes obliged by law to make a deduction or withholding in respect of tax from any amount payable under this Agreement it shall make this deduction.

 

5.7                               Records. AMT and its Affiliates shall keep and AMT shall require its licensees to keep, full, true and accurate records and books of account containing all particulars that may be necessary for the purpose of calculating all royalties payable to Digna for a minimum period of [**] years after each payment. Upon timely notice by Digna, AMT shall permit an independent certified public accountant selected by Digna and acceptable to AMT, which acceptance shall not be unreasonably withheld, to have access during normal business hours to such records of AMT and its Affiliates as may be reasonably necessary to verify the accuracy of the royalty reports described herein. Any such certified public accountant shall first be required to enter into a confidentiality agreement in form reasonably acceptable to AMT. AMT shall use commercially reasonable efforts to schedule all such verifications within [**] days after Digna makes its written request. Such verifications shall be conducted not more than [**]. If Digna’s independent certified public accountant concludes that additional royalties were owed to Digna during such period, the additional fees shall be paid by AMT within [**] days after the date Digna delivers to AMT such independent certified public accountant’s written report so concluding, unless AMT shall have a good faith dispute as to the conclusions set forth in such written report, in which case AMT shall provide written notice to Digna within such [**] day period of the nature of its disagreement with such written report. In the event Digna’s independent certified public accountant concludes that there was an overpayment of royalties to Digna during such period, the overpayment shall be repaid by Digna within [**] days after the date AMT received such independent certified public accountant’s written report so concluding or, at the election of AMT, be credited against future royalties, unless Digna shall have a good faith dispute as to the conclusions set forth in such written report, in which case Digna shall provide written notice to AMT within such [**] day period of the nature of its disagreement with such written report. In the event a Party provides written notice of such a dispute hereunder, the Parties shall thereafter, for a period of [**] days, attempt in good faith to resolve such dispute and if they are unable to

 

11

 

do so then either Party may take appropriate legal actions to enforce its rights hereunder. The fees charged by such independent certified public accountant shall be paid by Digna unless the audit discloses an underpayment of the fees payable by AMT for the audited period of more than [**] percent ([**]%) or more than [**] EURO (€ [**]), in which case AMT shall pay the reasonable fees and expenses charged by such accountant.

 

5.8                               Taxes. All payments to Digna under the terms of the Agreement are expressed to be exclusive of value added tax howsoever arising and AMT shall pay to Digna in addition to those payments all value added tax for which Digna is liable to account in relation to any supply made or deemed to be made for value added tax purposed to this Agreement on receipt of a tax invoice or invoices from Digna.

 

5.9                               Transfer of amounts. Payments made to Digna under this Agreement shall be made by wire transfer to the following account of Digna:

 

Bank: BBVA,
 Bank address: Avda. Carlos III, 33, 31004 Pamplona 
 Swift Code: BBVAESMMXXX 
 IBAN: ES89 0182 5000 8802 0156 0335

 

or any other bank account that may be notified by Digna to AMT from time to time.

 

ARTICLE 6                           FILING, MAINTENANCE AND PROSECUTION OF PATENT RIGHTS

 

6.1                               AMT Background IP. AMT shall have the exclusive responsibility, at its sole expense, to file, maintain, prosecute, defend and enforce Patent Rights including within the AMT Background IP, using patent counsel at its election.

 

6.2                               CIMA Background IP. Digna or a CIMA Party designated by Digna shall have the exclusive responsibility, at its sole expense, to file, maintain, prosecute, defend and enforce Patent Rights including within the CIMA Background IP, using patent counsel at its election.

 

6.3                               Joint Patent Rights.

 

6.3.1                     Filing, Maintenance and Prosecution. AMT shall have the exclusive responsibility to file, maintain and prosecute the Joint Patent Rights, using patent counsel at its election. The costs thereof shall be jointly borne by Proyecto and AMT. AMT will consult with Digna, keep Digna reasonably informed and obtain the prior approval from Digna regarding the status and strategies associated with any Patent Rights included in the Joint Patent Rights. Digna, in turn, will keep the other CIMA Parties reasonable informed. If AMT elects, in its sole discretion, not to initiate or continue to pursue the further prosecution of one or more Patent Rights included in the Joint Patent Rights in any particular country, then it shall, subject to any contractual obligations to Third Parties, notify Digna in writing of such election at least [**] days prior to the last available date to allow Digna to take action to preserve such Patent Rights included in the Joint Patent Rights at Digna’s expense.

 

6.3.2                     Enforcement. In the event that either Party identifies activities of Third Parties that (allegedly) infringe the Joint Patent Rights, it will notify the other Party and AMT shall decide whether it is necessary to commence proceedings as claimant and it shall be entitled

 

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to request each and any of the CIMA Parties to join AMT as co-claimant, and the CIMA Parties shall decide whether to join or not at its sole election. If AMT succeeds in any such infringement proceedings whether at trial or by way of settlement, the first charge on any costs, damages or profits in such proceedings or settlement shall be the costs incurred by AMT and the CIMA Parties that have acted as co-claimants. If such sums are less than the costs incurred they shall be apportioned between AMT and the CIMA Parties in the proportion to the Parties’ expenditure. Where the sums exceed the costs incurred, AMT on the one hand and the CIMA Parties that acted as co-claimant together on the other hand shall allocate the balance between them in the same proportion as the allocation of net revenues described in section 5.2. AMT is not entitled to settle such dispute without Digna’s prior written consent. In case AMT decides not to commence proceedings as claimant, the CIMA Parties shall be entitled to commence them at its sole cost. In such a case, any sum derived from said infringement proceedings shall be for the CIMA Parties. The CIMA Parties shall not be entitled to settle such dispute without AMT’s prior written consent.

 

6.3.3                     Defense. In the event that one or more patents or patent applications included in the Joint Patent Rights are challenged by a Third Party (by way of interference, opposition, invalidity actions or otherwise), the Parties shall decide whether they want to jointly defend such patents or patent applications included in the Joint Patent Rights and jointly bear the costs. If the CIMA Parties do not want to bear half of the costs of such defense, AMT shall have the right (but not the obligation) to take the appropriate actions to defend such patents and patent application included in the Joint Patent Rights. In such event, AMT shall be entitled to deduct up to [**]% of the costs incurred by AMT regarding such defense actions from the royalty payable by AMT to the CIMA Parties hereunder. Any awards will be allocated in accordance with Section 6.3.2. AMT (or the CIMA Parties, as the case may be) shall not be entitled to settle any challenge dispute without the other Party’s prior written consent.

 

6.4                               Cooperation. Each of the Parties shall make available to the other (or to the other’s authorized attorneys, agents or representatives) its employees, agents or consultants to the extent necessary or appropriate to enable the appropriate Party to file, prosecute and maintain patent applications and resulting patents with respect to inventions owned by a Party, at the expense of this Party and for periods of time sufficient for such Party to obtain the assistance it needs from such personnel. Where appropriate, each of the Parties shall sign or cause to have signed all documents relating to said patent applications or patents at no charge to the other Party.

 

6.5                               Third Party Claims of Infringement. If during the period of this Agreement, either Party receives any notice, claim or proceedings from any Third Party alleging infringement of that Third Party’s intellectual property by reason of development or Commercialization of the Product, the Party receiving that notice shall (i) forthwith notify the other Party of the notice, claim or proceeding and (ii) neither Party shall make any admission of liability and notwithstanding that one of CIMA Parties may have received the notice, AMT shall at its own cost and expense be responsible for and shall have conduct of any and sole authority to defend or settle such claims or proceedings. If AMT reasonable believes that Third Party rights are valid and that infringement may be occurring, or believes that it is economically or otherwise advantageous to seek a license, it may, subject to Section 5.4, seek a license from such Third Party on appropriate commercial terms.

 

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ARTICLE 7                           ACCESS RIGHTS

 

7.1                               General. The Parties contemplate to collaborate on the identification and development of future products (other than the Products) within the Gene Therapy Field. Therefore, the Parties have agreed as follows:

 

7.1.1                     Disclosure. During term of this License Agreement, the CIMA Parties shall disclose to AMT inventions such CIMA Party has, whether or not together with other CIMA Parties, conceived, developed or reduced to practice within the Gene Therapy Field (“Inventions”). Such inventions shall be disclosed in writing to AMT within reasonable time (no longer than [**] months) after such invention has been conceived, developed or reduced to practice. The reports describing such inventions shall be deemed to be Confidential Information of the CIMA Parties.

 

7.1.2                     The CIMA Parties herewith grant to AMT the exclusive first right to negotiate a license to Inventions and any IP associated therewith under market prevailing terms and conditions. The relevant CIMA Party shall be owner of any right, title and interest in such Invention.

 

7.1.3                     In the event that AMT is interested in the further development and Commercialization of an Invention, AMT shall notify the CIMA Party that has sent the written report describing the Invention to AMT in writing within [**] months after receipt of such report. In such event, the Parties shall in good faith negotiate the terms and conditions for an exclusive license to such Invention and any IP associated therewith. In case AMT has not notified in writing to the corresponding CIMA Party its interest in the Invention within the above [**] months period, the CIMA Parties shall be entitled to offer such Invention to Third Parties (whether as a license, assignment or any other agreement), without any further right for AMT.

 

7.1.4                     In case AMT has notified its interest within said [**] months, but the Parties are not able to reach an agreement on the terms of such exclusive license for such Invention and IP rights associated therewith within [**] months after the notification of its interest by AMT, the CIMA Parties may freely offer such Invention to Third Parties provided that they shall not accept an offer from a Third Party for such Invention unless they have first offered AMT the right to match such offer and AMT has not notified by writing within [**] days its will to match such offer (and on the understanding that if AMT matches such offer, the CIMA Parties will grant an exclusive license under the Invention and IP rights associated therewith under the thus matched terms and conditions).

 

ARTICLE 8                           CONFIDENTIALITY

 

8.1                               General. Each Party undertakes to keep strictly confidential the Confidential Information and to use it only for the purpose of this Agreement.

 

8.2                                   No disclosure / restriction to use. Each Receiving Party undertakes to not disclose the Confidential Information to any third party except to those of its officers and employees who need to have access to the same. Each Party shall before disclosing any Confidential Information to any of its officers or employees make each such person aware of such restrictions and to use and disclosure and shall procure that such persons comply with such restrictions. If the Receiving Party wishes to disclose Confidential Information to any consultant or advisor who is

 

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not an officer or employee it shall obtain the Disclosing Party’s prior written consent and shall furnish to the Disclosing Party with a confidentiality agreement signed by such consultant or advisor on the same terms and conditions of this Agreement.

 

8.3                                   Exceptions. The obligations to maintain confidentiality and to respect the restriction of the use shall not apply where, as properly evidenced by documentation: (i) is or becomes patented, published or otherwise becomes publicly known other than by acts of the Party obligated not to disclose such Confidential Information in contravention of this Agreement; (ii) can be shown by written documents to have been disclosed to the Receiving Party by a Third Party, provided, that such information was not obtained by such Third Party directly or indirectly from the other Party under this Agreement; (iii) prior to disclosure under this Agreement, was already in the possession of the Receiving Party; or (iv) can be shown by written documents to have been independently developed by the Receiving Party without use of the other Party’s Confidential Information or breach of any of the provisions of this Agreement.

 

8.4                               Permitted disclosure. Notwithstanding the above obligations of confidentiality and non-use a Recipient Party may:

 

8.4.1                     disclose Confidential Information to a Regulatory Authority as reasonably necessary to obtain Regulatory Approval in a particular jurisdiction to the extent consistent with the licenses granted under terms of this Agreement; and

 

8.4.2                     disclose Confidential Information: (a) to the extent such disclosure is reasonably necessary to comply with the order of a court; or (b) to the extent such disclosure is required to comply with a legal requirement, including to the extent such disclosure is required in publicly filed financial statements or other public statements under rules governing a stock exchange (e.g. the rules of the Netherlands, United States Securities and Exchange Commission, NASDAQ, NYSE, UKLA or any other stock exchange on which securities issued by either Party may be listed); provided, to the extent possible bearing in mind such legal requirements and subject to the next subsequent sentence of this Section 8.4, such Party shall provide the other Party with a copy of the proposed text of such statements or disclosure [**] Business Days in advance of the date on which the disclosure is to be made to enable the other Party to review and provide comments, which shall be followed as long as they are reasonable, unless a shorter review time is agreed. If the compliance with a legal requirements requires filing of this Agreement, the filing Party shall to the extent possible seek confidential treatment of portions of this Agreement from the relevant competent authority and shall provide the other Party with a copy of the proposed filings at least [**] Business Days prior to filing for the other Party to review any such proposed filing. Each Party agrees that it will obtain its own legal advice with regard to its compliance with legal requirements and will not rely on any statements made by the other Party relating to such legal requirements

 

8.4.3                     disclose Confidential Information by filing or prosecuting Patent Rights, the filing or prosecution of which is contemplated by this Agreement, without violating the above secrecy provision; it being understood that publication of such filings occurs in some jurisdictions within [**] months of filing, and that such publication shall not violate the above secrecy provision;

 

8.4.4                     disclose Confidential Information to such Recipient Party’s Affiliates, contractors (including clinical researchers) distributors, licensee’s, agents, consultants, as such

 

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Recipient Party reasonably determines is necessary to receive the benefit of this Agreement or to fulfill its obligations pursuant to this Agreement; provided, however, any such persons must be obligated to substantially the same extent as set forth in Section 8.2 to hold in confidence and not make use of such Confidential Information for any purpose other than those permitted by this Agreement;

 

8.4.5                     disclose Confidential Information, only to the extent reasonably required (i) to its actual or potential investment bankers; (ii) to existing and potential investors in connection with an offering or placement of securities for purposes of obtaining financing for its business and to actual and prospective lenders for the purpose of obtaining financing for its business; and (iii) to a bona fide potential acquirer or merger partner for the purposes of evaluating entering into a merger or acquisition, provided, however, any such persons must be obligated to substantially the same extent as set forth in Section 8.2 to hold in confidence and not make use of such Confidential Information for any purpose other than those permitted by this Agreement; and

 

8.4.6                     Disclose Confidential Information to its legal advisers for the purpose of seeking advice.

 

8.5                               Press Release. Neither Party shall make any public announcement or statement to the public containing Confidential Information without the prior written consent of the other Parties. No such public announcement or statements shall be made without the prior review and consent of the appropriate individual designated for the purpose by the other Parties.

 

ARTICLE 9                           REPRESENTATIONS AND WARRANTIES

 

9.1                               Mutual Warranties. Each Party represents and warrants to the other Parties that:

 

(a)                                 It has full power to extend the rights and licenses granted hereunder and perform its obligations hereunder;

 

(b)                                 It has full power and authority to enter into this Agreement and has taken all necessary action on its part required to authorize the execution and delivery of this Agreement;

 

(c)                                  The execution, delivery and performance of this Agreement and its compliance with the terms and provisions hereof does not conflict with, or result in a breach of any of the terms and provisions of, or constitute a default under any agreement to which any Party is a party; and

 

(d)                                 The execution, delivery and performance of this Agreement by each Party does not require the consent, approval or authorization of or notice, filing or registration with Regulatory Authority.

 

9.2                               Warranties of CIMA Parties. The CIMA Parties jointly and severally represent and warrant to AMT that, at the Effective Date, (i) Proyecto is the owner of the undivided interest in the Joint Patent Rights; and that (ii) they have not previously entered into any agreement, whether written or oral, with respect to, or otherwise assigned, licensed, transferred,

 

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conveyed or otherwise encumbered its/their rights, title or interest in or to the Joint Patent Rights (including by granting any covenant not to sue with respect thereto).

 

9.3                               Indemnification. AMT shall defend, indemnify and hold the CIMA Parties harmless from and against any Losses arising out of Third Party claims, suits or demands based on alleged or actual bodily injury or death or any other damage resulting from the development of Product or Commercialization of Product by AMT, its Affiliates or licensees. Losses shall not include any liability, claims, lawsuits, losses, damages, costs or expenses to the extent the same are determined to be the result of any CIMA Parties, their Affiliates, any Third Party engaged by Digna under the Collaborative Development Agreement and/or their directors officers, employees and agents negligence or willful misconduct.

 

AMT shall obtain and maintain insurance coverage in respect of the development and commercialization of the Product (notwithstanding Digna’s obligation to obtain and maintain insurance coverage as set forth in the Collaborative Development Agreement). Evidence of the existence and continuation of such insurance shall be provided to the CIMA Parties and AMT, respectively, upon request.

 

9.4                               The CIMA Parties shall immediately notify AMT (and each of the other CIMA Parties) in writing of any Third Party claim or action that may give rise to Losses (a “Claim Notice”) for which AMT has to indemnify pursuant to Section 9.3. AMT undertakes at its expense, to assume sole control and responsibility for dealing with the Third Party and the Third Party claim, including the right to settle the Third Party claim on any terms AMT chooses, by giving written notice to Digna without [**] days after receipt of a Claim Notice. The CIMA Parties shall be entitled to participate in. but not control, the defense of a Third Party claim by having their view regularly solicited by Digna who shall in turn liaise with AMT regarding the conduct of the Third Party Claim. Where proceedings are commenced, the CIMA Parties shall be entitled to retain counsel of their choice for such purpose, provided, however, that such retention shall be at each of the CIMA Parties’ own cost and expense.

 

ARTICLE 10                    TERM / TERMINATION

 

10.1                        This License Agreement shall commence on the Effective Date and shall continue until the payment obligations set out in Article 5 expire following which the Parties agree that the Agreement will have been fully performed. All licenses granted under this Agreement shall become perpetual, irrevocable, fully paid-up and royalty free on a country-by-country basis when there are not outstanding payment obligations in relation to such country.

 

10.2                        Termination for breach or insolvency. Notwithstanding any other provision hereof, each Party may forthwith terminate this Agreement:

 

(a)                                 as a result of a material breach or default in the performance of any obligation, condition or covenant of this Agreement by the other Party or Parties, if such default or noncompliance shall not have been remedied within [**] days after receipt by the defaulting Party of a notice thereof from the other Party; or

 

(b)                                 if the other Party receives suspension of payment or, whether voluntarily or involuntarily, is declared bankrupt, or if such Party becomes permanently unable

 

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to perform its obligations hereunder for reasons other than suspension of payment or bankruptcy, such as, for example, liquidation, dissolution or winding-up.

 

10.3                        Termination for termination of the Collaborative Development Agreement. Each Party may terminate this Agreement in the event that the Collaborative Development Agreement is terminated.

 

10.4                        Termination by AMT for convenience. AMT may terminate this Agreement for convenience upon 2 months written notice.

 

10.5                        Effect of Termination.

 

10.5.1              In the event of termination, the licenses granted by the CIMA Parties to AMT as set forth in Article 3 of this Agreement shall terminate. In the event of termination by Digna pursuant to Section 10.2, by Digna or AMT pursuant to Section 10.3 (other than termination of the Collaborative Development Agreement by AMT for breach or insolvency of Digna) or Section 10.4, the CIMA Parties shall have the exclusive rights, with the right to grant sublicenses, to use the Joint Patent Rights for the further development and Commercialization of Products as treatment or prevention of the Disorder without financial obligations to AMT, and each of the CIMA Parties collectively on the one hand and AMT on the other hand shall have the non-exclusive rights, without the right to sublicense, to use the Joint Patent Rights for the development and Commercialization of products as treatment or preventions of disorders other than the Disorder without financial obligations to the other Party or Parties. In the event of termination by AMT pursuant to Section 10.2 or by Digna or AMT pursuant to Section 10.3 (other than termination of the Collaborative Development Agreement by Digna for breach or insolvency of AMT), AMT shall have the exclusive rights, with the right to grant sublicenses, to use the Joint Patent Rights for the further development and Commercialization of Products or products as treatment or prevention of the Disorder, or disorders other than the Disorder without financial obligations to CIMA Parties.

 

10.6                        The Articles 2, 3.1, 5.7, 6, 8, 9, 12, 13 and 14 survive expiration or termination of this Agreement for any reason (subject to Section 10.5).

 

ARTICLE 11                    ASSIGNMENT

 

Save as otherwise provided in this Agreement no Party shall without the prior written consent of the other assign the benefit and/or burden of this Agreement provided always that any Party may assign this Agreement to an Affiliate of said Party or any purchaser of the whole or part of said Party’s assets or to a company with which said Party is merging, provided that such Affiliate, purchaser or merger company undertakes to the other Parties to be bound by the terms of this Agreement. The CIMA Parties shall not transfer, assign or encumber (their interest in the) ownership of the CIMA Background IP or the Joint Patent Rights without AMT’s prior written consent, other than to an Affiliate or in connection with an above permitted assignment of its rights. AMT shall not transfer, assign or encumber its interest in the ownership of the Joint Patent Rights without Digna’s prior written consent other than to an Affiliate or in connection with an above permitted assignment of its rights.

 

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ARTICLE 12                    NOTICES

 

Any notices required or provided under this Agreement shall be in writing and shall be given by facsimile or by certified mail addressed to the applicable Party as set out below:

 

	
AMT
    	
Mr. Piers Morgan
    
	
 
    	
PO Box 22506
    
	
 
    	
1100DA Amsterdam
    
	
 
    	
The Netherlands
    
	
 
    	
 
    
	
UTE   CIMA
    	
Mr. Antonio   Martin Cantón
    
	
 
    	
UTE   PROYECTO CIMA AVDA. PÍO XII, 22, OFICINA 1. 31008
    
	
 
    	
PAMPLONA,   NAVARRA
    
	
 
    	
Spain
    
	
 
    	
 
    
	
FIMA
    	
Mr. Franciso   Errasti Goenaga
    
	
 
    	
Calle   Pintor Paret 5,1° F Pamplona,
    
	
 
    	
Spain
    
	
 
    	
 
    
	
DIGNA
    	
Mr. Pablo   Ortiz Betes
    
	
 
    	
DIGNA   BIOTECH S.L.AVDA. PÍO XII, 22, OFICINA 2. 31008 PAMPLONA,
    
	
 
    	
NAVARRA
    
	
 
    	
Spain
    
	
 
    	
 
    
	
PROYECTO
    	
Mr. Antonio   Martin Cantón
    
	
 
    	
PROYECTO DE   BIOMEDIC1NA CIMA AVDA. PÍO XII, 22, OFICINA I.
    
	
 
    	
31008   PAMPLONA, NAVARRA
    
	
 
    	
Spain
    

 

ARTICLE 13                    GOVERNING LAW

 

The validity construction and performance of this Agreement shall be governed by the laws of The Netherlands.

 

ARTICLE 14                    JURISDICTION

 

All disputes arising out of or in connection with this Agreement shall be finally settled under the Rules of Arbitration of the International Chamber of Commerce by one or more arbitrators appointed in accordance with said Rules. The arbitration to take place in Paris and to be conducted in English.

 

ARTICLE 15                    MISCELLANEOUS

 

15.1                        Interpretation.

 

15.1.1              If an ambiguity or a question of intent or interpretation arises with respect to this Agreement, this Agreement shall be construed as if drafted jointly by the Parties and no presumption or burden of proof shall arise favoring or disfavoring any Party by virtue of the authorship of any provisions of this Agreement.

 

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15.1.2     Whenever the context may require, any pronoun shall include the corresponding masculine, feminine and neuter forms. The words “include”, “includes” and “including” shall be deemed to be followed by the phrase “without limitation.” The word “will” shall be construed to have the same meaning and effect as the word “shall.” Unless the context requires otherwise, (A) any definition of or reference to any agreement, instrument or other document herein shall be construed as referring to such agreement, instrument or other document as from time to time amended, supplemented or otherwise modified (subject to any restrictions on such amendments, supplements or modifications set forth herein or therein), (B) any reference to any laws herein shall be construed as referring to such laws as from time to time enacted, repealed or amended, (C) any reference herein to any Person shall be construed to include the Person’s successors and assigns, (D) the words “herein”, “hereof and “hereunder”, and words of similar import, shall be construed to refer to this Agreement in its entirety and not to any particular provision hereof, (E) any reference herein to the words “mutually agree” or “mutual written agreement” shall not impose any obligation on either Party to agree to any terms relating thereto or to engage in discussions relating to such terms except as such Party may determine in such Party’s sole discretion and; (F) all references herein to Articles, Sections or Schedules shall be construed to refer to Articles, Sections and Schedules of this Agreement.

 

15.2        Force Majeure. Neither Party shall be held liable or responsible to the other Party nor be deemed to have defaulted under or breached this Agreement for failure or delay in fulfilling or performing any term of this Agreement when such failure or delay is caused by or results from causes beyond the reasonable control of the affected Party, including fire, floods, embargoes, war, acts of war (whether war is declared or not), insurrections, riots, civil commotions, strikes, lockouts or other labor disturbances, acts of God or acts, omissions or delays in acting by any governmental authority or the other Party; provided, however, that the Party so affected shall use Commercially Reasonable Efforts to avoid or remove such causes of non-performance, and shall continue performance hereunder with reasonable dispatch wherever such causes are removed. Each Party shall provide the other Parties with prompt written notice of any delay or failure to perform that occurs by reason of force majeure. The Parties shall mutually seek a resolution of the delay or the failure to perform in good faith.

 

15.3        Severability. Each Party hereby agrees that it does not intend to violate any public policy, statutory or common laws, rules, regulations, treaty or decision of any government agency or executive body thereof of any country or community or association of countries. Should one or more provisions of this Agreement be or become invalid, the Parties hereto shall substitute, by mutual consent, valid provisions for such invalid provisions which valid provisions in their economic effect are sufficiently similar to the invalid provisions that it can be reasonably assumed that the Parties would have entered into this Agreement with such valid provisions. In case such valid provisions cannot be agreed upon, the invalidity of one or several provisions of this Agreement shall not affect the validity of this Agreement as a whole, unless the invalid provisions are of such essential importance to this Agreement that it is to be reasonably assumed that the Parties would not have entered into this Agreement without the invalid provisions.

 

15.4        Exhibits. The Exhibits to this Agreement form an integral part of this Agreement.

 

15.5        Entire Agreement. This Agreement (including the Exhibits thereto) contains the entire understanding of the Parties with respect to the subject matter hereof and supersedes all

 

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prior or contemporaneous oral or written agreements of the Parties with respect to the subject matter hereof, including the Previous Agreements. This Agreement may be amended, or any term hereof modified, only by a written instrument duly executed by both Parties hereto.

 

15.6        Headings. The captions to the several Articles and Sections hereof are not a part of this Agreement, but are merely guides or labels to assist in locating and reading the several Articles and Sections hereof.

 

15.7        Independent Contractors. It is expressly agreed that the Parties to this Agreement shall be independent contractors and that the relationship between the Parties shall not constitute a partnership, joint venture or agency. Neither Party shall have the authority to make any statements, representations or commitments of any kind, or to take any action, which shall be binding on the other(s), without the prior consent of the other Parties to do so.

 

15.8        Waiver. Except as expressly provided herein, the waiver by either Party hereto of any right hereunder or of any failure to perform or any breach by the other Party shall not be deemed a waiver of any other right hereunder or of any other failure to perform or breach by said other Party, whether of a similar nature or otherwise, nor shall any singular or partial exercise of such right preclude any further exercise thereof or the exercise of any other such right.

 

15.9        Counterparts. This Agreement may be executed in one more counterparts, each of which shall be deemed an original, but all of which together shall constitute one and the same instrument.

 

15.10      Benefit. Nothing in this Agreement or the agreements referred to herein, expressed or implied, shall confer on any person other than the Parties hereto or thereto, or their respective permitted successors or assigns, any rights remedies, obligations or liabilities under or by reason of this Agreement, the agreements referred to herein, or the transactions contemplated herein or therein.

 

15.11      Further Assurances. Each Party shall, as and when requested by another Party, do all acts and execute all documents as may be reasonably necessary to give effect to the provisions of this Agreement.

 

[Remainder of page intentionally left blank]

 

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IN WITNESS WHEREOF, the Parties have executed this Collaboration Agreement as of the date first written above.

 

 

	
 
    	
 
    
	
FIMA
    	
 
    
	
By: Mr. Franciso Errasti Goenaga
    	
 
    
	
Title: Presidente
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
/s/ Antonio   Martin Cantón
    	
 
    
	
UTE CIMA
    	
 
    
	
By: Antonio   Martin Cantón
    	
 
    
	
Title:   Gerente – Manager
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
/s/   Mr. Antonio Martin Cantón
    	
 
    
	
Proyecto de   Biomedicina CIMA S.L.
    	
 
    
	
By:   Mr. Antonio Martin Cantón
    	
 
    
	
Title:   Director General – General Manager
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
/s/ Pablo Ortiz Betés
    	
 
    
	
Digna Biotech S.L.
    	
 
    
	
By: Mr. Pablo Ortiz Betés
    	
 
    
	
Title: Director General
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
/s/ Piers Morgan
    	
 
    
	
Amsterdam Molecular Therapeutics (AMT) B,V.
    	
 
    
	
By: Mr. Piers Morgan
    	
 
    
	
Title: Chief Financial Officer
    	
 
    

 

22

 

Exhibit 1

 

JOINT PATENT RIGHTS

 

[**]

 

23

 

Exhibit 2

 

COLLABORATIVE DEVELOPMENT AGREEMENT BETWEEN DIGNA AND AMT

 

24

 

COLLABORATIVE DEVELOPMENT AGREEMENT

 

by and among

 

DIGNA BIOTECH, S.L.

 

AND

 

AMSTERDAM MOLECULAR THERAPEUTICS (AMT) B.V.

 

dated as of 21st of May, 2010

 

 

COLLABORATIVE DEVELOPMENT AGREEMENT

 

THIS COLLABORATIVE DEVELOPMENT AGREEMENT dated as of 21 May, 2010 (the “Agreement”) is made by and among:

 

(1)                                 Digna Biotech, S.L.  (“Digna”) with corporate address at C/ Etxesakan 28, oficina 5, 31180 Cizur Maryo, Navarra, Spain, beare of Tax Identification Number B-31778509, duly represented by Mr.  Pablo Ortiz Betés.

 

and

 

(2)                                 Amsterdam Molecular Therapeutics (AMT) B.V.  (“AMT”) a company with limited liability incorporated under the laws of The Netherlands with registered office at Meibergdreef 61, NL-1105 BA Amsterdam, The Netherlands, duly represented by Mr. Piers Morgan

 

WHEREAS

 

(A)          Digna and AMT, together with FIMA, UTE CIMA and Proyecto (as defined in the License Agreement), have entered into a License Agreement of even date herewith;

 

(B)          Digna has broad expertise and Know How in the field of acute intermittent porphyria and has, through hospitals with which it collaborates, access to relevant patient populations;

 

(C)          AMT has broad expertise and Know How in the field of development and manufacturing of products as gene therapy treatment;

 

(D)          the Parties now want to combine their expertise and knowledge aimed at the preclinical and clinical development of a gene therapy product as treatment for and/or prevention of acute intermittent porphyria under the terms and conditions set forth below;

 

IT IS NOW AGREED AS FOLLOWS

 

ARTICLE 1                                                   DEFINITIONS

 

For purposes of this Agreement, the terms defined in this Article 1 shall have the meanings specified below.  Certain other capitalized terms are defined elsewhere in this Agreement.

 

1.1          “Affiliate” any company, partnership or other business entity which Controls, is Controlled by or it under common Control with any of the Parties.  For the purposes of this definition “Control” refers to any of the following (i) the possession, directly or indirectly, of the power to direct the management or policies of an entity, whether through ownership of voting securities, by contract or otherwise; (ii) ownership of more than fifty percent (50%) of the voting securities entitled to vote for the election of directors in the case of a corporation, or of more than fifty percent (50%) of the equity interest in the case of any other type of legal entity; (iii) status as a general partner in any partnership, or any other arrangement whereby a Party controls or has

 

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the right to control the board of directors or equivalent governing body of a corporation or other entity.

 

1.2          “Agreement” means this Collaborative Development Agreement.

 

1.3          “AMT Background IP” has the same meaning as assigned to it in the License Agreement.

 

1.4          “CIMA Background IP” has the same meaning as assigned to it in the License Agreement.

 

1.5          “CIMA Parties” has the meaning assigned to it in the License Agreement.

 

1.6          “Clinical Trial” means each and any clinical trial and/or other study where the Product is administered to humans or that involves human subjects carried out in the context of the current Agreement, as set out in the Development Plan and Protocol.  Specifically, Clinical Trial refers to Phase I/II clinical trial.  Any other clinical trial not set out in the Development Plan but added to the Development Plan by decision of the Joint Steering Committee will be covered by a separate Agreement.  .

 

1.7          “Confidential Information” means, subject to the exceptions set forth in Article 10.3 (i) the terms and conditions of this Agreement, for which each Party will be considered a Disclosing Party and a Recipient Party; and (ii) any non-public information, whether or not patentable, disclosed or provided by one Party to the other Party in connection with this Agreement, including, without limitation, any information which release is likely to prejudice the commercial interests of the parties, or is considered as a trade secret, including information regarding such Party’s strategy, business plans, objectives, research, technology, products, business affairs or finances including any non-public data relating to development or Commercialization of any Product and other information of the type that is customarily considered to be confidential information by parties engaged in activities that are substantially similar to the activities being engaged in by the Parties under this Agreement, for which the Party making such disclosure will be considered the Disclosing Party and the receiver will be the Recipient Party.

 

1.8          “Development Plan” means the comprehensive plan (including activities assigned to each of Digna and AMT, timelines and budget) for the preclinical and clinical development of the Product aimed at obtaining Regulatory Approval for the Product, attached hereto as Exhibit 1.

 

1.9          Disclosing Party” means the Party which discloses Confidential Information to the other Party or Parties.

 

1.10        “Disorder” means acute intermittent porphyria

 

1.11        “Documents” means analyses, books, CD-ROM, USB stick, charts, comments, computations, designs, discs, diskettes, files, graphs, ledgers, notebooks, paper, photographs, plans, records, recordings, reports, research notes, tapes and other graphic or written data or other media and other computer information storage means on which Know How is permanently

 

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stored and advertising and promotional materials of any nature whatsoever including preparatory materials for the same.

 

1.12        “Effective Date” means the date first set forth above.

 

1.13        “EU Clinical Trial Directive” means Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use” and all legislation of the EU member states implementing this directive.

 

1.14        “GCP” means the ICH Harmonized Tripartite Guideline for Good Clinical Practice together with such other good clinical practice requirements as are specified in Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 relating to medicinal products for human use and in guidance published by the European Commission pursuant to such Directive and including the EU detailed guidelines on good clinical practice specific to advanced therapy medicinal products of December 3, 2009.

 

1.15        “Hospital” means Clínica Universidad de Navarra and any other premises as designated by the Joint Steering Committee to conduct the Clinical Trial.

 

1.16        “IMPD” means Investigational Medicinal Product Dossier as defined in Clinical Trials Directive (2001/20/EC).

 

1.17        “Intellectual Property” or “IP” means Patent Rights, Know How and Materials together.

 

1.18        “Joint Steering Committee” means the committee to be established by the Parties to manage the Development Program pursuant to Section 7.1.

 

1.19        “Know-How” means technical and other information which is not in the public domain, including information comprising or relating to concepts, discoveries, data, designs, formulae, ideas, inventions, Materials, methods, models, research plans, procedures, designs for experiments and tests and results of experimentation and testing (including results of research or development) processes (including manufacturing processes, specifications and techniques), laboratory records, chemical, pharmacological, toxicological, clinical, analytical and quality control data, clinical and non-clinical trial data, case report forms, data analyses, reports, manufacturing data or summaries and information contained in submissions to and information from ethical committees and Regulatory Authorities.  Know How includes Documents containing Know How, including but not limited to any rights including trade secrets, copyright, database or design rights protecting such Know How.  The fact that an item is known to the public shall not be taken to preclude the possibility that a compilation including the item, and/or a development relating to the item, is not known to the public.

 

1.20        “License Agreement” means the license agreement of even date herewith between Digna, AMT, UTE CIMA, FIMA and Proyecto.

 

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1.21        “Losses” means any and all losses, damages, liabilities, costs and expenses (including, without limitation, reasonable attorneys’ fees and expenses).  In calculating “Losses”, the duty to reasonably mitigate on the part of the Party suffering the Losses shall be taken into account.

 

1.22        Marketing Authorisation Application” or “MAA” means a new drug license application filed with the competent European Regulatory Authorities to obtain Regulatory Approval for a pharmaceutical product in Europe, or any equivalent application filed with the Regulatory Authority in or for a country or group of countries to obtain Regulatory Approval for a pharmaceutical product in or for that country or with that group of countries.

 

1.23        “Materials” means any chemical or biological substances including but not limited to blood samples, nucleotide or nucleotide sequence including DNA and RNA sequences, genes, vector or construct including plasmids, phages or viruses, host organism including bacteria, fungi, algae, protozoa and hybridoma’s, eukaryotic or prokaryotic cell line or expression system or any development strain or product of that cell line or expression system, protein including any peptide or amino acid sequence, enzyme, antibody or protein conferring targeting properties and any fragment of a protein or a peptide enzyme or antibody, assay or reagent, any other genetic or biological material or micro-organism.

 

1.24        “Monitor” means one or more persons appointed by Digna to monitor compliance of the Clinical Trials with GCP and to conduct source data verification.

 

1.25        “Observational Study” means a Clinical Trial aimed at assessing baseline parameters of patients with the Disorder as further described in the Development Plan.

 

1.26        “Parties” means the parties to this Agreement and “Party” means a party to this Agreement.

 

1.27        “Patent Rights” means a (i) all national, regional and international patents and patent applications, including provisional patent applications, (ii) all patent applications filed either from such patents, patent applications or provisional applications or from an application claiming priority from any of these, including divisional, continuations, continuations-in-part, provisions, converted provisionals and continued prosecution applications, (iii) any and all patents that have issued or in the future issue from the foregoing patent applications (i) and (ii), including author certificates, inventor certificates, utility models, petty patents and design patents and certificates of invention, (iv) any and all extensions or restorations by existing or future extension or restoration mechanisms, including revalidations, reissues, re-examinations and extensions (including any supplementary protection certificates and the like) of the foregoing patents or patent applications (i), (ii) and (iii), and (v) any similar rights, including so-called pipeline protection, or any importation, revalidation, confirmation or introduction patent or registration patent or patent of additions to any such foregoing patent applications and patents.

 

1.28        “Phase I/II” means, for the purpose of this Agreement, a Clinical Trial conducted by a Qualified Service Provider aimed at preliminary determination of safety in patients affected by the Disorder and (ii) determination of dose ranges and a preliminary determination of efficacy in patients affected by the Disorder as further described in the Development Plan.

 

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1.29                        “Phase II/ III” means pivotal human clinical trials conducted at multiple sites, which are sufficiently powered and designed to establish safety and efficacy of one or more particular doses in patients being studied and to provide the statistical basis for marketing approval for the respective drug (for example, as described in 21 C.F.R. § 312.21, or similar clinical study legislation or guidelines in a country other than the United States).

 

1.30                        “Principal Investigator” means Prof. Jesus Prieto or any other person agreed by the Parties to replace him.

 

1.31                        “Product” means a AAV vector containing porphobilinogen deaminase (PBGD) manufactured by AMT or its Affiliates for use within the scope of the Development Plan.

 

1.32                        “Protocol” means the description of a Clinical Trial to be conducted under the Development Plan and all amendments thereto as the Joint Steering Committee may from time to time agree.  The Protocol, once determined by the Joint Steering Committee, will be attached to this Agreement as Exhibit 2.  Any amendments will be signed by the Parties and form a part of this Agreement.

 

1.33                        “Qualified Service Providers” means Third Parties engaged by Digna in the execution of its preclinical or clinical activities under the Development Plan, including CIMA, the Hospital and the Principal Investigator, and that (i) are discussed in the meeting of the Joint Steering Committee prior to its engagement and to which AMT has not imposed reasonable and substantiated objections (ii) meet the quality and other criteria imposed by Spanish legislation regarding Clinical Trial and/or the Spanish Regulatory Authorities for the execution of such activities and (iii) are, if other than CIMA, the Hospital and/or the Principal Investigator, under a written obligation between Digna and the Qualified Service Provider to comply with the obligations of Digna set forth in this Agreement regarding confidentiality, publication and ownership of Results as if they were a Party thereto or, if relating to the conduct of a Clinical Trial, have entered into a written agreement with Digna.

 

1.34                        “Receiving Party” means any Party receiving Confidential Information from another Party;

 

1.35                        “Regulatory Approval” means all approvals from Regulatory Authorities in any country in the Territory required lawfully to develop, clinically test, manufacture and market the Product in any such country, any establishment license application filed with the FDA or other Regulatory Authority to obtain approval of the facilities and equipment to be used to manufacture a Product, any Investigational New Drug or other investigational filing, including but not limited to any authorization for the import, manufacture and clinical testing of the Product (whether or not in filled and finished form), and any product pricing approvals where applicable.

 

1.36                        “Regulatory Authority” means any relevant national (e.g., the FDA, EU member states authorities), supra-national (e.g., the European Commission, the Council of the European Union, or the EMEA), or other relevant governmental entity in any jurisdiction of the world involved in the granting of Regulatory Approvals for pharmaceutical product.

 

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1.37                        “Results” means data, Know How, Materials, inventions, Patent Rights and all other information resulting from the activities by Digna or its Qualified Service Providers under this Agreement, excluding the Joint Patent Rights (as defined in the License Agreement), excluding any IP that has been developed prior to the Effective Date under the collaborative research programs jointly carried out by the Parties, excluding the AMT Background IP and excluding the CIMA Background IP.

 

1.38                        “Territory” means the world.

 

1.39                        “Third Party” means a party other than any of the Parties or any of their respective Affiliates.

 

ARTICLE 2                                                   DEVELOPMENT PLAN GENERAL

 

2.1                               Development Plan.  The activities assigned to each of Digna and AMT with regard to the preclinical and (once successful) clinical development of the Product are set forth in the Development Plan attached hereto as Exhibit 1.  The Development Plan sets forth in detail (i) the proposed overall program of development for the Product, including pre-clinical studies, toxicology, formulation, manufacturing, Clinical Trials and regulatory plans up to and including Phase I/II Clinical Trials, (ii) a summary of estimated costs expected to be incurred by each Party hereunder in performing its activities under the Development Plan and (iii) the timelines.  In general terms (i) AMT shall be responsible for the production of the Product for preclinical studies and Clinical Trials in accordance with all local and European legislation and the Good manufacturing practice (GMP) Guidelines., (ii) Digna shall be responsible for the execution of the preclinical studies and the drafting of the Protocol(s) and (iii) Digna shall act as Sponsor of the Clinical Trial.

 

2.2                               Updated Development Plan.  The Joint Steering Committee may decide to update the Development Program at a later date to revise or expand the Development Program, provided, however, that the Joint Steering Committee shall not assign additional activities to Digna unless (i) AMT agrees to increase its funding for the Development Plan accordingly or (ii) such additional activities are covered under a government grant or subsidy.

 

2.3                               Qualified Service Providers.  Digna may not subcontract its activities under the Development Plan to Third Parties unless such Third Party qualifies as a Qualified Service Provider as defined herein.

 

2.4                               Execution of Development Plan.  Digna and AMT shall use reasonable efforts to execute and substantially perform (or have performed by Qualified Service Providers) the activities assigned to each Party under the Development Program in accordance with the budget and timelines set forth in the Development Plan.

 

ARTICLE 3                                                   CLINICAL TRIAL

 

3.1                               General.  Digna shall act as the Sponsor of the Clinical Trial to be conducted by the Hospital and the Principal Investigator.

 

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3.2                               Separate Clinical Trial Agreement.  Digna shall enter into a separate Clinical Trial agreement with the Hospital, the Principal Investigator and each Qualified Service Provider under terms and conditions that are customary for the kind of services to be provided with regard to human clinical trials, wherein Digna shall impose on the Hospital, the Principal Investigator and other Qualified Service Providers the obligations as set forth in this Article 3, 4.3, 5.1, 9, 10 and 11 and wherein AMT shall be named as third party beneficiary..  AMT shall have the right to review such draft agreements before they are entered into to verify that the obligations of Hospital, Principal Investigator and other Qualified Service Providers as reflected in this Article 3, 4.3, 5.1, 9, 10 and 11 are properly included.

 

3.3                               Trial Site.  The Phase I/II Clinical Trial shall be conducted at the site of the Hospital under supervision of the Principal Investigator.  AMT may, however, require Digna to add additional Hospitals for the conduct of the Clinical Trials pursuant to Section 3.9 hereof.

 

3.4                               Obligations Digna.  Digna shall use reasonable efforts to procure compliance of the Hospital and the Principal Investigator conducting the Clinical Trial with all obligations imposed on Digna under this Agreement to the extent they relate to the conduct of the Clinical Trial as well as the obligations regarding confidentiality, publications and ownership of Results.

 

3.5                               Obligations AMT:  AMT shall share with Digna its expertise and experience in the field of conducting clinical trials with gene therapy products and shall assist Digna in the preparation of the investigator’s brochure, whereby Digna, however, acknowledges that Digna is, as sponsor of the Clinical Trials, responsible for the proper conduct thereof.  AMT shall be responsible for including in the IMPD all required information regarding the manufacture of the Product.  .

 

3.6                               Protocol.  Digna shall be in the lead as to the design of the Protocol for the Clinical Trial, provided that (i) the Protocol is in accordance with the Development Plan and (ii) furthermore provided that any Protocol and any deviation to the Protocol (whether or not instigated by the Regulatory Authorities in Spain) will be agreed with AMT before (re)submitting.  Digna will make its best efforts to ensure that the Hospital and the Principal Investigator shall conduct the Clinical Trial in accordance with: (i) the Protocol (once established by the Joint Steering Committee) for such Clinical Trial; (ii) the terms and conditions of the approval of the relevant ethics committee and (iii) instruction by AMT as to the handling and use of the Product.  The Principal Investigator and the Hospital shall not consent to any change in the Protocol requested by a relevant ethics committee without the prior written consent of Digna and AMT.

 

3.7                               Medical Ethical Approval.  Digna will make its best efforts to ensure that the Hospital and Principal Investigator shall not administer Product to any Clinical Trial subject and that no other clinical intervention mandated by the Protocol takes place in relation to any such Clinical Trial subject until it is satisfied that all relevant regulatory and ethics committee approvals have been obtained.

 

3.8                               Regulatory and GCP Compliance.  Digna shall comply with all laws and regulations applicable to the performance of the Clinical Trial including, but not limited to the GCP, the World Medical Association Declaration of Helsinki and any and all local applicable

 

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laws and regulations, as amended from time to time including but not limited to, where applicable, Spanish regulations regarding gene therapy, informed consent and privacy regulations and shall use reasonable efforts to ensure that the Hospital, the Principal Investigator and any other Qualifed Service Provider will comply with such laws and regulations as well..

 

3.9                               Use of Product.  Digna shall use reasonable efforts to ensure that Hospital and Principal Investigator will not use the Product for any purpose other than the conduct of the Clinical Trial and upon termination or expiration of this Agreement all unused Product shall, at AMT’s option, either be returned to AMT or disposed of in accordance with the Protocol.

 

3.10                        Recruitment.  Digna shall oblige the Hospital and Principal Investigator to use their best efforts to recruit the number of Clinical Trial subjects as set forth in the Development Plan (or, if deviating, the Protocol for such Clinical Trial) and shall conduct the Clinical Trial in accordance with the timelines set forth in the Development Plan and the Protocol.  If, for reasons other than AMT’s breach of its obligations under this Agreement, recruitment of Clinical Trial subjects for the Phase I/II Clinical Trial is proceeding at a rate below that, at the discretion of the Joint Steering Committee, required to enable the relevant timeline in the Development Plan to be met, AMT may by notice to Digna require recruitment by the Hospital to cease and/or to add additional hospitals as designed by the Joint Steering Committee, for the conduct of such Clinical Trial.  The terms of the Agreement shall thereafter relate to the number of Clinical Trial subjects who have been accepted for treatment in the Clinical Trial by the Hospital at the date of such notice and the funding as set forth in Article 8 hereof, to the extent it relates to such Clinical Trial, shall be allocated by Digna between the Hospital and such other hospitals involved in such Clinical Trial.

 

3.11                        Monitor.  Digna ensures that the Hospital and Principal Investigator shall permit the Monitor access to the records of Clinical Trial subjects for monitoring and source data verification, such access to be arranged at mutually convenient times and on reasonable notice.  Each of Digna and AMT will alert the Hospital and Principal Investigator promptly to significant issues (in the opinion of the Monitor) relating to the conduct of the Clinical Trial.  In the event that AMT reasonably believes there has been any research misconduct in relation to the Clinical Trial, Digna shall use reasonable efforts to procure that the Hospital and Principal Investigator shall provide all reasonable assistance to any investigation into any alleged research misconduct undertaken by or on behalf of AMT.  At its conclusion, AMT, Digna, the Hospital and Principal Investigator shall review the conduct of the Clinical Trial at the trial site set forth in Section 3.3 hereof, such review to take place within [**] months of trial site close-out.  Digna shall send copies of the reports of the Monitor to the members of the Joint Steering Committee.

 

3.12                        Samples.  Digna shall use reasonable efforts to procure that Hospital and Principal Investigator shall test any clinical samples required to be tested during the course of the Clinical Trial in accordance with the Protocol and at a laboratory that qualifies as a Qualified Service Provider.

 

3.13                        Follow-up.  Digna shall use reasonable efforts to provide that Hospital and Principal Investigator shall give follow-up to subjects for at least the time that is required under the relevant laws and regulations pertaining to (preclinical and clinical trials with) gene therapy products.

 

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3.14                        Not debarred.  Digna shall use its best efforts to ensure that neither the Investigator nor any other person involved in the conduct of the Clinical Trials is or has been debarred.

 

3.15                        No adverse activities.  Digna shall use reasonable efforts to procure that neither the Hospital nor the Principal Investigator shall during the term of this Agreement conduct any human clinical trial which might adversely affect the Hospital’s or Principal Investigator’s ability to perform its obligations under this Agreement within the timelines set forth in the Development Plan.  Digna, furthermore, will negotiate in order to procure a commitment by both the Hospital and the Principal Investigator in the sense that they shall not be engaged in human clinical trials involving gene therapy and/or enzyme replacement therapy and/or any product aimed at treatment or prevention of the Disorder, during the term of this Agreement.

 

ARTICLE 4                                                   REGULATORY FILINGS

 

4.1                               Filing of the IMPD.,  Digna shall file an IMPD for the Product with the Regulatory Authority in Spain.  Without prejudice to the fact that Digna will act as sponsor of the Clinical Trials AMT shall be responsible for the IMPD to the extent it relates to the Product and the manufacturing thereof.  Digna acknowledges that AMT’s information regarding the manufacture of the Product is highly sensitive and proprietary and that AMT will, to the extent allowed by the Regulatory Authorities in Spain, provide such information to the Regulatory Authority in Spain without allowing Digna access thereto.  Digna shall be responsible for the IMPD to the extent it relates to the information relating the Disorder and the Clinical Trials.  For the avoidance of doubt: AMT shall be the sole Party entitled to use, develop and commercialize the Product and to file any additional Regulatory filings for the Product, including an MAA.  To the extent required, Digna herewith assigns in advance (and shall, if such assignment in advance is not possible, upon first request of AMT assign), any and all of its rights that may be obtained by Digna by virtue of filing the IMPD, to AMT.

 

4.2                               Other regulatory interactions.  Digna shall, to the extent permitted by the Regulatory Authorities in Spain, act to communicate with the Regulatory Authority in Spain with regard to the Clinical Trials and the IMPD save for the part of the IMPD that relates to the Product and the manufacturing of the Product.  AMT shall act to communicate with the Regulatory Authorities with regard to the Product and the manufacturing of the Product.  No party will approach, consult and/or negotiate with regulatory authorities without an expressed consent from the other party.  Any regulatory authority interaction will be jointly prepared and agreed between Digna and AMT in advance of any such interactions (without prejudice to AMT’s legitimate interest to keep the information regarding the manufacture of the Product confidential and to minimize access by Digna thereto to the extent allowed by the relevant laws and regulations.

 

4.3                               Local ethical committee approvals.  Ethics Committee.  Digna shall use reasonable efforts to ensure that the Hospital and the Principal Investigator shall collaborate for obtaining and maintaining all approvals from the relevant local research ethics committee of the Hospital (so other than the IMPD) for the conduct of the Clinical Trial and that the Hospital and the Principal Investigator shall keep Digna and AMT fully apprised of the progress of ethics

 

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committee submissions and that they shall provide Digna with all correspondence relating to such submissions.

 

4.4                               Digna shall provide the members of the Joint Steering Committee with all information obtained by Digna from the Qualified Service Providers.

 

ARTICLE 5                                                   AUDIT

 

5.1                               Audit Rights.  AMT shall be entitled to have reasonable access to the facilities of Digna and its Qualified Service Providers (including the Hospital) during regular business hours with reasonable frequency (which shall not be in any case more than [**] per facility per organization) and upon reasonable advance notice and, with regard to each Qualified Service Provider, prior to the execution of the agreement between Digna and such Qualified Service Provider (pre-audit), at AMT’s own expense and during the term of this Agreement, to records and facilities of Digna and its Qualified Service Providers (including the Hospital) relating to the Development Program, but only to the extent reasonably necessary for AMT to ensure compliance by Digna and its Qualified Service Providers with the Development Plan, the Protocol, GCP and other applicable laws and regulations.  In no event shall personal data (as defined in the Spanish Data Protection Act), be disclosed to AMT.

 

ARTICLE 6                                                   MANUFACTURING

 

6.1                               Manufacturing and Supply Product.  AMT shall be solely responsible for the manufacture and supply of the Product for use in the activities under the Development Plan.  To the extent Product is to be used for Clinical Trial, AMT shall supply Product that meets the requirements of the Regulatory Authorities that are competent to obtain Regulatory Approval for the IMPD referred to in Section 4.1.  AMT may, in its sole discretion, subcontract with Third Parties for the manufacture, supply or packaging of the Product.  AMT shall not supply the Product directly to the Hospital without the prior written instruction of Digna to do so.

 

6.2                               AMT will be solely responsible for obtaining and maintaining all the necessary authorizations or clearances set forth in the national and supra-national legislation regarding the manufacturing of the Investigational Medicinal Product and shall provide Digna (or the Hospital directly) with sufficient quantities of Product to execute the preclinical work and/or the Clinical Trials, free of charge.

 

6.3                               AMT shall, upon request of Digna, provide reasonable assistance to Digna in order to comply with all the relevant obligations that are required in its condition of Sponsor as stated in the enforceable legislation, the regulation of clinical good practices or the obligations which may be required at any time by the Regulatory Authority and, if were the case, by the Hospital or the Principal Investigator provided, however, that Digna (and not AMT) shall be responsible that the Clinical Trials and other activities in the course of the development of the Product (other than the manufacture of the Product) is in compliance with applicable laws and regulations.

 

6.4                               DIGNA will have the right to reject the Product if it does not meet the quality, safety and stability specifications previously agreed by the Joint Steering Committee.

 

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6.5                               The Product will be transported by AMT (at AMT’s expense and under AMT’s responsibility) to the clinical site of the Hospital referred to in Section 3.3 hereof or at such other place as Digna and AMT may jointly decide.

 

ARTICLE 7                                                   JOINT STEERING COMMITTEE

 

7.1                               Joint Steering Committee.

 

7.1.1                     Formation and Composition.  Forthwith upon signing this Agreement, Digna and AMT will establish a committee to oversee and manage the activities pursuant to this Agreement (the “Joint Steering Committee”).  The Steering Committee shall be composed of [**] representatives appointed by Digna and [**] representatives appointed by AMT, provided that the size of the Joint Steering Committee may be increased by unanimous agreement of the Joint Steering Committee members so long as the membership has equal representation by Digna and AMT.  The initial representatives on the Joint Steering Committee of Digna shall be [**], and AMT’s initial representatives on the Joint Steering Committee shall be [**] shall designate one (1) of its representatives on the Joint Steering Committee to act as Chair, and the Joint Steering Committee shall appoint one (1) of its members to act as Secretary.  Members of the Joint Steering Committee may be represented at any meeting by another member of the Joint Steering Committee or by a deputy.  Each Party may change one or more of its representatives to the Joint Steering Committee at any time, provided that any such representatives will be senior officers and/or managers of the respective Party, its Affiliates, divisions or business units.  Additionally, each of the Parties may appoint a non-voting special advisor to the Joint Steering Committee.  Each of Parties shall bear all expenses of its respective representatives and other participants in connection with Joint Steering Committee participation, including in connection with the attendance of any meetings thereof.

 

7.1.2                     Functions The Joint Steering Committee shall perform the following functions: (a) coordinate the activities of the Parties and the Qualified Service Providers under the Development Plan; (b) recommend changes to the Development Plan, if applicable; (c) establish scientific and development teams for the execution of the Development Program as it sees fit, and settle any disputes or disagreements that are unresolved by any such teams; (d) serve as the governing body of all activities under this Agreement; and (e) perform such other functions as appropriate to further the purposes of the collaboration under this Agreement as determined by the Parties.

 

7.1.3                     Meetings; Action by Written Consent.  The Joint Steering Committee will meet as needed, but not less than [**], and the members shall determine the form (e.g., in-person, telephone or video conference), timing, frequency and location of meetings.  In principle, the meetings shall alternately take place in Amsterdam and Madrid.  Representatives of either AMT or Digna or their Affiliates who are not members of the Joint Steering Committee may attend meetings of the Joint Steering Committee as agreed to by a representative member of the other Party.  Any action required or permitted to be taken at any meeting of the Joint Steering Committee may be taken without a meeting if all members of the Joint Steering Committee consent thereto in writing, and such writing is filed with the minutes of proceedings of the Joint Steering Committee.

 

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7.1.4                     Decision Making.  Any approval, determination or other action agreed to by unanimous consent of the members of the Joint Steering Committee or their deputies present at the relevant Joint Steering Committee meeting shall be the approval, determination or other action of the Joint Steering Committee, provided at least one representative of each of Digna and of AMT are present at such meeting.  The Joint Steering Committee will work in good faith to resolve any disputes that may arise among its members, provided that in the event any deadlock cannot be resolved in good faith by the Joint Steering Committee during a [**] business day period following initial submission of any approval, determination or other action to the Joint Steering Committee, then the issue shall be submitted to the Chief Executive Officers of AMT and Digna jointly who shall work in good faith to resolve any such dispute within [**] business days.  The joint decision of the Chief Executive Officers of AMT and Digna shall be deemed the approval, determination or action of the Joint Steering Committee.  Any issue that cannot be resolved in good faith by the Chief Executive Officers of AMT and Digna within [**] business days after the Joint Steering Committee has submitted the issue to them, shall be submitted to arbitration in accordance with Article 17 of this Agreement.

 

7.1.5                     Minutes.  The Joint Steering Committee shall keep accurate minutes of its deliberations which shall record all proposed decisions and all actions recommended or taken.  The Secretary shall be responsible for the preparation of draft minutes.  Draft minutes shall be sent to all members of the Joint Steering committee within [**] business days after each meeting.  All records of the Joint Steering Committee shall at all times be available to both Digna and AMT.

 

ARTICLE 8                                                   FUNDING OF DEVELOPMENT PROGRAM

 

8.1                               Development Program.  In consideration for the execution of the Development Program by Digna and its Qualified Service Providers (including the Hospital), AMT shall pay to Digna an aggregate amount of € 1,000,000 (one million euro) to be paid in installments as follows:

 

	
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[**]
    	
 
    	
[**]
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    
	
Total
    	
 
    	
€1,000,000
    	
 
    

 

8.2                               The funding set forth in Section 8.1 does not take into account the costs of Phase II/III Clinical Trials which are not within the scope of this Agreement and are subject to further agreement between the Parties (acknowledging that AMT may decide to have the Phase II/III Clinical Trials conduct by Third Parties).  The funding set forth in Section 8.1, furthermore, does not take into account any preclinical work or Clinical Trials not described in the Development Plan that the Joint Steering Committee may decide to execute in order to facilitate the filing for Regulatory Approvals for the Product.  In the event that the Joint Steering Committee decides to

 

12

 

have such additional preclinical work or Clinical Trials conducted by Digna or its Qualified Service Providers, the Parties shall in good faith agree on the amount of the additional funding to be paid by AMT to Digna.

 

8.3                               Payment to Digna.  All amounts under this Article 8 shall be paid by AMT to Digna within [**] days after receipt of the respective invoice.  Digna shall be responsible for the apportionment of the sums paid to Digna hereunder to the Qualified Service Providers engaged by Digna in the execution of the Development Plan pursuant to the agreements executed between Digna and such Qualified Service Providers and for payment of the same according to that apportionment.

 

8.4                               Taxes.  All payments to Digna under the terms of the Agreement are expressed to be exclusive of value added tax howsoever arising and AMT shall, if required, pay to Digna in addition to those payments all value added tax for which Digna is liable to account in relation to any supply made or deemed to be made for value added tax purposed to this Agreement on receipt of a tax invoice or invoices from Digna.  The Parties shall in such event closely cooperate to have such tax amounts refunded to AMT under applicable tax treaties.

 

Transfer of amounts.  Payments made to Digna under this Agreement shall be made by wire transfer to the following account of Digna:

 

Bank: BBVA,
 Bank address: Avda.  Carlos III, 33, 31004 Pamplona 
 Swift Code: BBVAESMMXXX 
 IBAN: ES89 0182 5000 8802 0156 0335

 

or any other bank account that may be notified by Digna to AMT from time to time.

 

8.5                               EU Funding.  The Parties acknowledge that they have applied for a so called European FP7 grant to cover (part of) the costs of the Clinical Trials.  Digna acknowledges that the terms and conditions of the consortium agreement to be entered into between the partners to that FP7 project should not negatively affect the rights of AMT under this Agreement.  Therefore, Digna and AMT shall negotiate and agree with all partners under said FP7 project clauses in the consortium agreement to the effect that Foreground (as defined in the FP7 grant agreement) generated by such partners shall be transferred to AMT.  Any Foreground generated by Digna and [Hospital] under the FP7 project shall be considered Results as defined in this Agreement and AMT shall be the exclusive owner thereof.

 

ARTICLE 9                                                   SOPS / REPORTING / RESULTS

 

9.1                               SOPs.  Digna shall provide AMT with its own Standard Operation Procedures (SOPs) regarding the (organization) of preclinical studies and Clinical Trials within [**] days after the Effective Date.  Digna, furthermore, shall give AMT the right to review the SOPs of each Qualified Service Provider that Digna wishes to engage for the execution of its activities.  AMT acknowledges that such SOPs are proprietary and confidential information of the respective Qualified Service Provider.

 

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9.2                               Report / Data.  Digna shall within [**] months after completion of each activity under the Development Plan, provide the members of the Joint Steering Committee (or ensure that the Qualified Service Provider provides the members of the Joint Steering Committee) with a written report describing in sufficient detail the methodology used, the Results generated, an analysis of the Results and conclusions drawn from the Results.

 

9.3                               Keeping data and records.  Digna shall ensure that the Qualified Service Provider that execute the activities assigned to Digna under the Development Plan prepares and provides AMT with a database of accumulated data from all preclinical studies and/or Clinical Trials of the Product and of adverse information for the Product.  AMT shall keep the trial master file with the essential documents relating to the Clinical Trial as well as any relevant records for at least [**] years after the completion of such activity / Clinical Trial in accordance with the most recent guidelines and regulations on clinical trials in the field of gene therapy (including the detailed EU guidelines on good clinical practice specific to advanced therapy medicinal products of December 3, 2009).  The documents to be included in the trial master file shall, for each preclinical study and/or Clinical Trial, be provided by Digna to AMT within [**] months after completion of the final report relating to such preclinical study and/or Clinical Trial.

 

9.4                               Access.  To the extent permitted by the Spanish Data Protection Act, Digna shall ensure that all Qualified Service Providers and Affiliates provide AMT access to all such data, to the extent necessary to meet or comply with any regulations or other requirements of the FDA, EMEA or other Regulatory Authorities, in each case with respect to Regulatory Approvals or other regulatory purposes

 

9.5                               Ownership of Results.  AMT shall exclusively own and have title, right and interest in and to the Results.  AMT may, at its discretion, file patent applications for the Results in its name and at its expense.

 

ARTICLE 10                                            CONFIDENTIALITY / PUBLICATION

 

10.1                        General.  Each Party undertakes to keep strictly confidential the Confidential Information and to use it only for the purpose of this Agreement.

 

10.2                        No disclosure / restriction to use.  Each Receiving Party undertakes to not disclose the Confidential Information to any third party except to those of its officers and employees who need to have access to the same.  Each Party shall, before disclosing any Confidential Information to any of its officers or employees, make each such person aware of such restrictions and shall procure that such persons comply with such restrictions.  If the Receiving Party wishes to disclose Confidential Information to any consultant or advisor who is not an officer or employee it shall obtain the Disclosing Party’s prior written consent and shall furnish to the Disclosing Party with a confidentiality agreement signed by such consultant or advisor on the same terms and conditions of this Agreement.

 

10.3                        Exceptions.  The obligations to maintain confidentiality and to respect the restriction of the use shall not apply where, as properly evidenced by documentation: (a) is or becomes patented, published or otherwise becomes publicly known other than by acts of the Party obligated not to disclose such Confidential Information in contravention of this Agreement;

 

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(ii) can be shown by written documents to have been disclosed to the Receiving Party by a Third Party, provided, that such information was not obtained by such Third Party directly or indirectly from the other Party under this Agreement; (iii) prior to disclosure under this Agreement, was already in the possession of the Receiving Party; or (iv) can be shown by written documents to have been independently developed by the Receiving Party without use of the other Party’s Confidential Information or breach of any of the provisions of this Agreement.

 

10.4                        Permitted disclosure.  Notwithstanding the above obligations of confidentiality and non-use a Recipient Party may:

 

10.4.1              disclose Confidential Information to a Regulatory Authority as reasonably necessary to obtain Regulatory Approval in a particular jurisdiction to the extent consistent with the licenses granted under terms of this Agreement; and

 

10.4.2              disclose Confidential Information: (a) to the extent such disclosure is reasonably necessary to comply with the order of a court; or (b) to the extent such disclosure is required to comply with a legal requirement, including to the extent such disclosure is required in publicly filed financial statements or other public statements under rules governing a stock exchange (e.g.  the rules of the Netherlands, United States Securities and Exchange Commission, NASDAQ, NYSE, UKLA or any other stock exchange on which securities issued by either Party may be listed); provided, to the extent possible bearing in mind such legal requirements and subject to the next subsequent sentence of this Section 10.4, such Party shall provide the other Party with a copy of the proposed text of such statements or disclosure [**] Business Days in advance of the date on which the disclosure is to be made to enable the other Party to review and provide comments, which shall be followed as long as they are reasonable, unless a shorter review time is agreed.  If the compliance with a legal requirements requires filing of this Agreement, the filing Party shall to the extent possible seek confidential treatment of portions of this Agreement from the relevant competent authority and shall provide the other Party with a copy of the proposed filings at least [**] Business Days prior to filing for the other Party to review any such proposed filing.  Each Party agrees that it will obtain its own legal advice with regard to its compliance with legal requirements and will not rely on any statements made by the other Party relating to such legal requirements

 

10.4.3              disclose Confidential Information by filing or prosecuting Patent Rights, the filing or prosecution of which is contemplated by this Agreement, without violating the above secrecy provision; it being understood that publication of such filings occurs in some jurisdictions within [**] months of filing, and that such publication shall not violate the above secrecy provision;

 

10.4.4              disclose Confidential Information to such Recipient Party’s Affiliates, contractors (including clinical researchers) distributors, licensee’s, agents, consultants, as such Recipient Party reasonably determines is necessary to receive the benefit of this Agreement or to fulfill its obligations pursuant to this Agreement; provided, however, any such persons must be obligated to substantially the same extent as set forth in Section 10.2 to hold in confidence and not make use of such Confidential Information for any purpose other than those permitted by this Agreement;

 

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10.4.5              disclose Confidential Information , only to the extent reasonably required, (i) to its actual or potential investment bankers; (ii) to existing and potential investors in connection with an offering or placement of securities for purposes of obtaining financing for its business and to actual and prospective lenders for the purpose of obtaining financing for its business; and (iii) to a bona fide potential acquirer or merger partner for the purposes of evaluating entering into a merger or acquisition, provided, however, any such persons must be obligated to substantially the same extent as set forth in Section 10.2 to hold in confidence and not make use of such Confidential Information for any purpose other than those permitted by this Agreement; and

 

10.4.6              Disclose Confidential Information to its legal advisers for the purpose of seeking advice.

 

ARTICLE 11                                            PUBLICATION

 

11.1                        Publication of Background IP and Confidential Information.  Neither Digna nor AMT shall submit for written or oral scientific publication any manuscript, abstract or the like which includes Confidential Information or Background IP of the other Party (including joint IP) without first obtaining the prior written consent of the other Party, which consent shall not be unreasonably withheld and Digna shall ensure best reasonable efforts to procure that CIMA Parties comply with the provisions of this Article 11.  The contribution of each Party, if any, shall be mentioned in all publications or presentations by acknowledgement or co-authorship, whichever is appropriate.

 

11.2                        Publication of Results.  The Party wishing to submit any manuscript, abstract or the like regarding the Results for publication shall provide the other Party (the “Reviewing Party”) with a copy of any proposed publication which contains Results to the Reviewing Party at least [**] days before the date of submission of the proposed publication to any publisher.

 

11.3                        Within [**] days of receipt of the proposed publication under Section 11.2, the Reviewing Party shall either:

 

(a)                                 provide written consent to the proposed publication; or

 

(b)                                 reasonably require to remove the Reviewing Party’s Confidential Information or Background IP whereby AMT shall always have the right to remove Confidential Information regarding its production and manufacturing processes;

 

(c)                                  reasonably require that the proposed publication be delayed or amended (without altering the scientific meaning of the publication) to enable a patent application to be filed regarding any Results contained in the proposed publication.  The delay or amendment required by the Reviewing Party shall be reasonable and in any event, any delay required shall be no longer than three months from the date the other Party provided a copy of the proposed publication to the Reviewing Party.; and/or

 

(d)                                 provide comments and/or amendments in relation to the proposed publication which will be reasonably considered and incorporated by the other party into the publication.

 

16

 

11.4                        In the event of any dispute regarding the proposed publication, the Parties shall resolve such differences in good faith through the Joint Steering Committee as provided for in Article 7.

 

11.5                        If within [**] days of receipt of the proposed publication the Reviewing Party does not:

 

11.5.1              provide consent under Section 11.3(a); or

 

11.5.2              request a delay or amendment under Section 11.3(c),

 

the Reviewing Party shall be deemed to have given consent for the proposed publication for the purposes of Section 11.5(a), always provided that no Party is entitled to publish Confidential Information or Background IP of the other Party, even in absence of a reasonable request as referred to in Section 11.3(b).

 

11.6                        Digna ensures that the CIMA Parties shall comply with this Article 11 as if they were a Party thereto.

 

11.7                        Digna shall use its best efforts to include in the agreements with the Qualified Service Providers clauses regarding publications rights that substantially resemble the ones set forth in this Article 11, including a reasonable review time by Digna (and consequently, AMT) of any proposed scientific publication on the Clinical Trial by such Qualified Service Provider.

 

ARTICLE 12                                            REPRESENTATIONS AND WARRANTIES / INDEMNIFICATION / INSURANCE

 

12.1                        Mutual Warranties.  Each Party represents and warrants to the other Parties that:

 

(a)                                 It has full power to extend the granted hereunder and perform its obligations hereunder;

 

(b)                                 It has full power and authority to enter into this Agreement and has taken all necessary action on its part required to authorize the execution and delivery of this Agreement;

 

(c)                                  The execution, delivery and performance of this Agreement and its compliance with the terms and provisions hereof does not conflict with, or result in a breach of any of the terms and provisions of, or constitute a default under any agreement to which any Party is a party; and

 

(d)                                 The execution, delivery and performance of this Agreement by each Party does not require the consent, approval or authorization of or notice, filing or registration with Regulatory Authority.

 

12.2                        Indemnification by AMT.  AMT indemnifies and holds harmless Digna, its Qualified Service Providers (including the Hospital and the Principal Investigator) and their employees against all claims and proceedings (to include any settlements or ex gratia payments

 

17

 

made with the consent of the Parties hereto and reasonable legal and expert costs and expenses) made or brought (whether successfully or otherwise) by or on behalf of Clinical Trial subjects and (or their dependants) against Digna or a Qualified Service Provider or their employees for personal injury (including death) to Clinical Trial subjects arising out of or relating to the administration of the Product under investigation or any clinical intervention or procedure provided for or required by the Protocol to which the Clinical Trial subjects would not have been exposed but for their participation in the Clinical Trial.  The above indemnity by AMT shall not apply to any such claim or proceeding (i) to the extent that such personal injury (including death) is caused by the negligent or willful misconduct of Digna or a Qualified Service Provider, their employees or agents and/or (ii) to the extent that such personal injury (including death) is caused by the failure of a Qualified Service Provider or its employees to conduct the Clinical Trial in accordance with the Protocol and/or GCP,.

 

12.3                        Indemnification by Digna.  Digna, as Sponsor, indemnifies and holds harmless AMT and its employees against all claims and proceedings (to include any settlements or ex gratia payments made with the consent of the Parties hereto and reasonable legal and expert costs and expenses) made or brought (whether successfully or otherwise) (i) to the extent that such personal injury (including death) is caused by the gross negligent or willful misconduct of Digna, a Qualified Service Provider or their employees and/or (ii) to the extent that such personal injury (including death) is caused by the failure of Digna or a Qualified Service Provider to conduct the Clinical Trial in accordance with the Protocol and/or GCP.

 

Digna’s liability arising out or in connection with any breach of this contract or any act or omission of Digna or its Qualified Service Providers in connection with the Clinical Trial shall, save for willful misconduct or gross negligence of Digna or its Qualified Service Providers, in no event exceed the amount of fees paid by AMT according to clause 8.

 

12.4                        The indemnified Party hereunder shall as soon as reasonably practicable following receipt of notice of such claim or proceeding, notify the indemnifying Party hereunder in writing of a claim and shall, upon the indemnifying Party’s request permit the indemnifying Party to have full care and control of the claim or proceeding using legal representation of its own choosing.

 

12.5                        Insurance.  Each of AMT and Digna will take out appropriate insurance cover their potential liability under this Article 12 (including, Digna in its capacity of Sponsor of the Clinical Trials, an clinical trial insurance as required by the Spanish Regulatory Authorities).  Each Party shall produce to the Qualified Service Provider and to each other on request, copies of insurance policies or other evidence thereof together with evidence that such policies remain in full force and effect.  The terms of any insurance or the amount of cover shall not relieve AMT or Digna of any liabilities under this Agreement.

 

ARTICLE 13                                            TERM / TERMINATION

 

13.1                        Term.  This Agreement shall commence on the Effective Date and shall continue until completion of the Development Plan, save for premature termination in accordance with this Article 13.

 

18

 

13.2                        Termination.  Notwithstanding any other provision hereof, each Party may forthwith terminate this Agreement:

 

(a)                                 as a result of a material breach or default in the performance of any obligation, condition or covenant of this Agreement by the other Party or Parties, if such default or noncompliance shall not have been remedied within [**] days after receipt by the defaulting Party of a notice thereof from the other Party (whereby it is agreed that failure to comply with the Protocol or GCP by Hospital and/or the Principal Investigator is deemed to be a material breach by Digna); or

 

(b)                                 if the other Party is declared insolvent or, whether voluntarily or involuntarily, is declared bankrupt, or if such Party becomes permanently unable to perform its obligations hereunder for reasons other than suspension of payment or bankruptcy, such as, for example, liquidation, dissolution or winding-up.

 

13.3                        Termination by AMT for other reasons.  AMT may, furthermore, terminate this Agreement upon two (2) months written notice in the event that the Joint Steering Committee (subject to Section 7.1.4.) decides to cease further development of the Product for safety, efficacy or technical feasibility or commercial reasons.

 

13.4                        Effect of Termination.

 

13.4.1              Effects of termination by AMT pursuant to Section 13.2.  In the event of termination by AMT pursuant to Section 13.2 the following applies (notwithstanding AMT’s rights by law or equity):

 

(a)                                 AMT remains sole owner of the Results.

 

(b)                                 The Development Plan will be terminated as per the earliest possible date and the funding obligations of AMT as set forth in Article 8 will terminate.  AMT will be free to further develop and Commercialize by itself or with Third Parties at its discretion and is released from any further payments to Digna under this Agreement.

 

13.4.2              Effects of termination by Digna pursuant to Section 13.2 or by AMT pursuant to Section 13.3.  In the event of termination by Digna pursuant to Section 13.2 of by AMT pursuant to Section 13.3, the following applies (notwithstanding Digna’s rights by law or equity):

 

(a)                                 AMT shall assign to Digna co-ownership of the Results.  Digna shall be exclusively entitled to use and Commercialize the Results on a royalty-free basis for the further development and Commercialization of a product for the treatment or prevention of the Disorder.  This right is with the right to sublicense.  Each of AMT and Digna may, on a royalty-free and non-exclusive basis, without the right to sublicense, use the Results for the treatment or prevention of disorders other than the Disorder.  User rights of the Joint Patent Rights in the event of termination of this Agreement are set forth in the License Agreement.

 

(b)                                 AMT shall cease development, manufacture and Commercialization of Products as treatment or prevention of the Disorder;

 

19

 

(c)                                  The Development Plan will be terminated as per the earliest possible date.  The funding obligations of AMT as set forth in Article 8 will terminate as per the effective date of termination of this Agreement.

 

(d)                                 AMT will, if so requested by Digna, enter into good faith discussions with Digna regarding the terms and conditions under which AMT, or a third party engaged by AMT, would be willing to manufacture the Product for Digna or its sublicensee.

 

13.5                        Surviving Articles.  Articles 10, 11, 12, 16 and 17 shall survive expiration or termination of this Agreement for any reason.

 

ARTICLE 14                                            ASSIGNMENT

 

Save as otherwise provided in this Agreement no Party shall without the prior written consent of the other assign the benefit and/or burden of this Agreement provided always that AMT may assign this Agreement to an Affiliate of AMT or any purchaser of the whole or part of AMT’s assets or to a company with which AMT is merging, provided that such Affiliate, purchaser or merger company undertakes to Digna to be bound by the terms of this Agreement.

 

ARTICLE 15                                            NOTICES

 

Any notices required or provided under this Agreement shall be in writing and shall be given by facsimile or by certified mail addressed to the applicable Party as set out below:

 

AMT

 

Mr. Piers Morgan 
 PO Box 22506 
 1100DA Amsterdam 
 The Netherlands

 

Digna

 

Mr. Pablo Ortiz Betés
 DIGNA BIOTECH S.L.AVDA.  PÍO XII, 22, OFICINA 2.31008 PAMPLONA,
 NAVARRA
 Spain

 

ARTICLE 16                                            GOVERNING LAW

 

The validity construction and performance of this Agreement shall be governed by the laws of The Netherlands.

 

ARTICLE 17                                            JURISDICTION

 

All disputes arising out of or in connection with this Agreement shall be finally settled under the Rules of Arbitration of the International Chamber of Commerce by one or more arbitrators

 

20

 

appointed in accordance with said Rules.  The arbitration to take place in Paris and to be conducted in English.

 

ARTICLE 18                                            MISCELLANEOUS

 

18.1                        Interpretation.

 

18.1.1              If an ambiguity or a question of intent or interpretation arises with respect to this Agreement, this Agreement shall be construed as if drafted jointly by the Parties and no presumption or burden of proof shall arise favoring or disfavoring any Party by virtue of the authorship of any provisions of this Agreement.

 

18.1.2              Whenever the context may require, any pronoun shall include the corresponding masculine, feminine and neuter forms.  The words “include”, “includes” and “including” shall be deemed to be followed by the phrase “without limitation.” The word “will” shall be construed to have the same meaning and effect as the word “shall.” Unless the context requires otherwise, (A) any definition of or reference to any agreement, instrument or other document herein shall be construed as referring to such agreement, instrument or other document as from time to time amended, supplemented or otherwise modified (subject to any restrictions on such amendments, supplements or modifications set forth herein or therein), (B) any reference to any laws herein shall be construed as referring to such laws as from time to time enacted, repealed or amended, (C) any reference herein to any Person shall be construed to include the Person’s successors and assigns, (D) the words “herein”, “hereof and “hereunder”, and words of similar import, shall be construed to refer to this Agreement in its entirety and not to any particular provision hereof, (E) any reference herein to the words “mutually agree” or “mutual written agreement” shall not impose any obligation on either Party to agree to any terms relating thereto or to engage in discussions relating to such terms except as such Party may determine in such Party’s sole discretion and; (F) all references herein to Articles, Sections or Schedules shall be construed to refer to Articles, Sections and Schedules of this Agreement.

 

18.2                        Force Majeure.  Neither Party shall be held liable or responsible to the other Party nor be deemed to have defaulted under or breached this Agreement for failure or delay in fulfilling or performing any term of this Agreement when such failure or delay is caused by or results from causes beyond the reasonable control of the affected Party, including fire, floods, embargoes, war, acts of war (whether war is declared or not), insurrections, riots, civil commotions, strikes, lockouts or other labor disturbances, acts of God or acts, omissions or delays in acting by any governmental authority or the other Party; provided, however, that the Party so affected shall use Commercially Reasonable Efforts to avoid or remove such causes of non-performance, and shall continue performance hereunder with reasonable dispatch wherever such causes are removed.  Each Party shall provide the other Parties with prompt written notice of any delay or failure to perform that occurs by reason of force majeure.  The Parties shall mutually seek a resolution of the delay or the failure to perform in good faith.

 

18.3                        Severability.  Each Party hereby agrees that it does not intend to violate any public policy, statutory or common laws, rules, regulations, treaty or decision of any government agency or executive body thereof of any country or community or association of countries.  Should one or more provisions of this Agreement be or become invalid, the Parties hereto shall

 

21

 

substitute, by mutual consent, valid provisions for such invalid provisions which valid provisions in their economic effect are sufficiently similar to the invalid provisions that it can be reasonably assumed that the Parties would have entered into this Agreement with such valid provisions.  In case such valid provisions cannot be agreed upon, the invalidity of one or several provisions of this Agreement shall not affect the validity of this Agreement as a whole, unless the invalid provisions are of such essential importance to this Agreement that it is to be reasonably assumed that the Parties would not have entered into this Agreement without the invalid provisions.

 

18.4                        Exhibits.  The Exhibits to this Agreement form an integral part of this Agreement.

 

18.5                        Entire Agreement.  This Agreement (including the Exhibits thereto) contains the entire understanding of the Parties with respect to the subject matter hereof and supersedes all prior or contemporaneous oral or written agreements of the Parties with respect to the subject matter hereof, including the Previous Agreements.  This Agreement may be amended, or any term hereof modified, only by a written instrument duly executed by both Parties hereto.

 

18.6                        Headings.  The captions to the several Articles and Sections hereof are not a part of this Agreement, but are merely guides or labels to assist in locating and reading the several Articles and Sections hereof.

 

18.7                        Independent Contractors.  It is expressly agreed that the Parties to this Agreement shall be independent contractors and that the relationship between the Parties shall not constitute a partnership, joint venture or agency.  Neither Party shall have the authority to make any statements, representations or commitments of any kind, or to take any action, which shall be binding on the other(s), without the prior consent of the other Parties to do so.

 

18.8                        Waiver.  Except as expressly provided herein, the waiver by either Party hereto of any right hereunder or of any failure to perform or any breach by the other Party shall not be deemed a waiver of any other right hereunder or of any other failure to perform or breach by said other Party, whether of a similar nature or otherwise, nor shall any singular or partial exercise of such right preclude any further exercise thereof or the exercise of any other such right.

 

18.9                        Counterparts.  This Agreement may be executed in one more counterparts, each of which shall be deemed an original, but all of which together shall constitute one and the same instrument.

 

18.10                 Benefit.  Nothing in this Agreement or the agreements referred to herein, expressed or implied, shall confer on any person other than the Parties hereto or thereto, or their respective permitted successors or assigns, any rights remedies, obligations or liabilities under or by reason of this Agreement, the agreements referred to herein, or the transactions contemplated herein or therein.

 

18.11                 Further Assurances.  Each Party shall, as and when requested by another Party, do all acts and execute all documents as may be reasonably necessary to give effect to the provisions of this Agreement.

 

[Remainder of page intentionally left blank]

 

22

 

IN WITNESS WHEREOF, the Parties have executed this Collaborative Development Agreement as of the date first written above.

 

 

	
/s/ Pablo Ortiz Betés
    	
 
    	
 
    
	
Digna Biotech S.L.
    	
 
    	
 
    
	
By: Pablo Ortiz Betés
    	
 
    	
 
    
	
Title: Director General
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
/s/ Piers Morgan
    	
 
    	
 
    
	
Amsterdam Molecular Therapeutics (AMT) B.V.
    	
 
    	
 
    
	
By: Piers Morgan
    	
 
    	
 
    
	
Title: Chief Financial Officer
    	
 
    	
 
    

 

23

 

EXHIBIT 1

DEVELOPMENT PLAN

 

Project Plan:

 

The aim of this collaboration is to develop an AIP product and to deliver a data package for the product that is suitable for the submission and approval by the European and North American regulatory authorities.  The product should be approved for the general treatment of AIP (both males and females.) The quality of the project has to comply with the national and internationally accepted quality standards.  A quality plan, defining the CRO selection, quality inspections, auditing etc will be agreed between the parties.  It is acknowledged by the Parties that the timelines set out below were drafted at the beginning of the negotiation process on this Agreement and the License Agreement and that, in view of the fact that several months passed since then, the Joint Steering Committee will update the timelines as soon as possible after the signature of this Agreement.

 

	
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Conditions and Specifications

 

PoC in pre-clinical models

 

·                  PoC in rodent disease model

·                  PoC in non-human primates, based on agreed protocol

·                  Go-no-go

·                  efficacy in rodent disease model

·                  10% hepatic transduction and/or PBDG levels [**] fold above normal in rodents

·                  10% hepatic transduction in non-human primates

 

GLP Toxicology

 

·                  Scientific advice from a regulatory body (AEMPS and/or EMA) for safety and toxicology package (duration, number of species, biodistribution, inclusion of immunosuppressants, risk of integration, germ line transmission)

·                  GLP toxicology study in rodents rats or mice (transduction will be compared between mice and rats, only if transduction levels are equal in rats to the transduction levels in mice, rats will be used), 180 days according to relevant EU guideline (EMEA/CHMP/GTWP/125459/2006) with interim sacrifices for acute toxicity [**], and delayed toxicity at early time point [**].  The need for an additional late time point [**] will be discussed.  Biodistribution studies (including gonadal tissues) should provide data on all organs, whether target or not, needs Scientific advice.

·                  Toxicology data in a non-rodent species, using the route of administration intended in the clinic duration similar to rodent study, including bio-distribution (including gonadal tissues) and efficacy endpoints.  This work is not included in the amount payable by AMT to DIGNA under section 8.1.  Costs hereof will be agreed by the Joint Steering Committee and will be funded by AMT.  Needs Scientific advice.  Details to be agreed by the Joint Steering Committee.

·                  GLP germline transmission in female and maternal transmission study in mice, according to the relevant European guidelines, will be conducted in case DNA is found in gonadal tissue.  Details to be agreed by the Joint Steering Committee.  (AMT may decide to conduct additional germline transmission in female and maternal transmission study in mice even if these are not strictly required for the Phase I/II trial, in such case, AMT, at its own choice, would have the option to fund such a study and DIGNA will ensure that such a study is done as agreed).

·                  GLP germ line transmission study in male rabbits (duration exceeding [**] cycles of spermatogenesis, [**]) will be conducted at additional cost.  (The quotation is required prior the final contract signature).

 

Toxicology study design will take into account:

·                  Identification of potential target organs of biological activity (for efficacy studies- i.e.  liver) and of potential target organs of toxicity,

·                  Eventual concomitant medication (e.g.  immunosuppressants, standard co-medication),

·                  Environmental risk/shedding, has to be included in the tox studies.  The Joint Steering Committee will evaluate and agree whether this would be required for the for Phase I/II trial

 

25

 

·                  Analysis of appropriateness of surrogate markers of efficacy/safety,

·                  Any other relevant issues as agreed by the Joint Steering Committee.

 

Deliverable: Toxicology study report suitable for the submission the regulatory authority.

 

Observational, pre-intervention study/studies

 

·                  DIGNA and AMT agree on the need of good quality patient’s data (clinical and biochemical) before entering the interventional study in order to adequately assess the efficacy of the product.  For this reason, patient’s to be included in the Phase I/II clinical trial will be followed for a period between [**] months before entering into the trial.  The type of data to be collected, clinical and analytical, will be agreed by the Joint Steering Committee.

 

·                  Little is known of the natural history of this disease.  The medical history, phenotypic presentation, natural evolution of AIP patients has to be explored and documented (for the ‘group of AIP patients’) over an adequate time period.  In addition, a baseline against which to measure intra-individual post-administration efficacy and safety has to be established per individual study subject.  Main investigator of University Clinic will conduct a observational preparatory study to provide baseline information on the course of the disease by recording episodes AIP, abdominal pain, hospitalizations, extent of any possible known or unknown to be related to AIP symptomatology, incidence of (adverse) clinical events per year, etc., sufficient to provide a clinical picture to obtain a baseline data and to determine how efficacy will be show during the trial.  Also, to allow for inclusion of [**] eligible and willing subjects into the subsequent interventional trial, a sufficient number of subjects needs to included in the observational preparatory study (not everybody would be suitable or willing to progress).  The Joint Steering Committee will evaluate and agree how it can best ensure that sufficient number of subjects is included.

 

·                  The period of observation of the first observational trial should be at an estimated minimum of [**] months on an individual basis, and at least [**] months for the group/cohort (of to-be treated subjects) average.  In parallel to the intervention study, subjects entered into the observational study but not enrolled in the intervention study should continue in the observational study up to [**] months.

 

·                  Observational study needs to comply with the nationally and internationally accepted standard, to make sure that the data are suitable for the regulatory submission for marketing authorisation.  This will be done if so requested by AMT at an additional cost of [**] euros.  The following conditions should be met:

·                  The study should conform to all industry standards, to guidance of Institutional Review Board/Independent Ethics Committee (“IRB/IEC”) approval(s), to all relevant guidance relating to medicines and clinical trials from time to time in force including, but not limited to, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices (E6).

·                  AMT to be provided with a full list of clinical SOPs and copies of the applicable SOPs as requested by AMT prior to the conduct of the study.

·                  Both parties to agree on the content of the study audit plan prior to the start of the study, including any relevant quality plan.

·                  The Principle Investigator (PI) will attempt to secure timely consent from all patients, to be rolled over into an AMT owned by AIP Registry, in which among others natural evolution and long term safety and efficacy after gene therapy will be captured, at a point to be determined.

·                  Go/no go for subsequent intervention study/studies: sufficient disease presentation, manifestation & complication data and sufficient information on natural disease evolution is collected and sufficient individual patient baseline data is acquired, to allow the conclusion that any data to be collected in the interventional study can be used to judge interventional product safety and gauge clinical efficacy using suitable, determinable endpoints.  The go/no go criteria will also include:

 

·                  Site and protocol feasibility that supports the conduct and execution of the proposed study according the agreed timeline

 

26

 

·                  Regulatory and ethical approval and

·                  Actual progress that is consistent with achieving agreed accrual targets and timelines

 

Phase I/II

 

·                  GCP & guidelines compliant as per above

 

·                  The clinical phase I/II should include an estimated minimum [**] patients that are administered the gene therapy drug, and are followed up and clinically assessed for at least [**] months following drug administration.

 

·                  The formal study follow up will be at least [**] years post administration per individual subject; interim analysis and reporting will be planned for, at a minimum once immediately after all subjects have had their [**] months study visit.

 

·                  The PI has to commit to a [**] year follow up of those [**] treated patients, at minimum for safety and efficacy assessments each year during the first [**] years and [**] thereafter, and needs to commit upfront to maintaining adequate study and patient data documentation, and to keep any source documents secure, for [**] years after study drug administration.

 

·                  The clinical trial must include all biochemical, imaging, clinical and functional assays, as well as any other relevant additional assays, to assess the disease state and change therein over time, as well as the phenotypic disease variation, as well as the overall clinical and psychosocial or other health status or change therein over time of the individual trial subjects, both before, during and following drug administration.

 

·                  Study monitoring and source data verification will be carried out and documented to industry accepted standards.

 

·                  AMT will have, at the latest [**] months after the obtaining of each individual data point, access to and exclusive use of the data for the purposes of ultimately obtaining marketing authorizations, in Europe and/or any other country or region in the world.  This data access is needed early on to engage in discussion with relevant regulatory bodies representatives.

 

·                  Within [**] months after the completion of each individual study or study phase, AMT will receive a copy of the essential documents on request and copies of the study database.  Upon completion, AMT will receive a copy of the final, audited, clinical trial database, with data, and those aspects of the Trial Master File that are necessary to file for MAA.

 

·                  Study data only published with approval and agreement of the Liaison Committee

 

27

 

EXHIBIT 2
  PROTOCOL (to be attached once final)

 

Confidential Materials omitted and filed separately with the Securities and Exchange Commission.  A total of 137 pages were omitted. [**]

 

28Exhibit 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”)

 

2

 

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.

 

3

 

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.

 

4

 

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.

 

5

 

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:

 

6

 

(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:

 

7

 

(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.

 

8

 

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).

 

9

 

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
    

 

10

 

	
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

 

11

 

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

 

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(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 

 

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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

 

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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

 

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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

 

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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.

 

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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.

 

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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

 

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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

 

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

 

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 [**]:

 

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

 

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

 

Stability acceptance criteria

 

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

 

10

 

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

 

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