Document:

Exhibit 10.10

 

Confidential Materials omitted and filed separately with the

Securities and Exchange Commission. Double asterisks denote omissions.

 

EXCLUSIVE LICENSE AGREEMENT

 

THIS Exclusive License Agreement (“Agreement”), effective as of 07 July 2008 (“Effective Date”), is entered into by and between St. Jude Children’s Research Hospital, Inc., a Tennessee not-for-profit corporation located at 262 Danny Thomas Place, Memphis, Tennessee 38105 (“ST. JUDE”) and Amsterdam Molecular Therapeutics B.V., a closed limited liability company organized and existing under the laws of the Netherlands, with registered offices at Meibergdreef 61, 1105 BA Amsterdam, the Netherlands, (each a “Party” and together the “Parties”).

 

RECITALS

 

WHEREAS, ST. JUDE is the owner by assignment from Dr. John Gray of his entire right, title and interest in the Patent Rights and in the inventions described and claimed therein; and

 

WHEREAS, the Patent Rights relate to mechanisms for improving the expression of Factor IX in gene therapy vectors, including, the use of a specific Factor IX polynucleotide coding sequence designed for optimal expression, and, the use of transcriptional regulatory regions minimized in size so that they can be used to express Factor IX, as well as any other gene of interest, in a size-constrained environment such as in a self complementary gene therapy vector system; and

 

WHEREAS, under a separate agreement being entered into between the Parties on the same date as this Exclusive License Agreement (“Sponsored Research Agreement”), AMT engages ST. JUDE to develop a gene therapy vector incorporating certain features of the invention described in the Patent Rights but combined with certain technologies controlled by AMT (the “Vector”); and

 

WHEREAS, in order to carry out the work anticipated under the Sponsored Research Agreement, ST. JUDE will require access to technologies owned by AMT and AMT is willing to grant this access under a separate agreement being entered into between the Parties on the same date as this Exclusive License Agreement (“AMT Technology License Agreement”); and

 

SIGNATURE VERSION

 

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WHEREAS, the Vector will be further developed and commercialized by AMT and so AMT require a license under the Patent Rights; and

 

WHEREAS, AMT wishes to enter into an agreement with ST. JUDE to obtain a license under the Patent Rights and ST. JUDE is willing to grant such a license to AMT under the terms and conditions set forth in this Agreement.

 

NOW, THEREFORE, in consideration of the mutual promises contained herein and other good and valuable considerations, the Parties do hereby agree as follows:

 

1.                                      DEFINITIONS

 

1.1                               “Affiliate” shall mean any company, partnership or other business entity which Controls, is Controlled by or is under common Control with either Party.  For the purposes of this definition “Control” means 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                               “AMT” shall mean Amsterdam Molecular Therapeutics B.V. and any Affiliates of Amsterdam Molecular Therapeutics B.V.

 

1.3                               “Confidential Information” shall mean any confidential or proprietary non-public information furnished by one Party (the “Disclosing Party”) to the other Party (the “Receiving Party”) in connection with this Agreement.

 

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1.4                               “Commercialise”, “Commercialisation” or “Commercialising” shall mean 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 or post regulatory approval regulatory activities in relation to Licensed Product.

 

1.5                               “Commercially Reasonable Efforts” shall mean efforts and resources commonly used by biotechnology companies of a similar size to AMT based on funds raised to Develop and Commercialise a product owned by such a company or to which it has rights, which product is at a similar stage in its development or product life and is of similar market potential to the Licensed Product in question and taking into account the patent and other proprietary position of the product.

 

1.6                               “Development (and the corresponding verb “to Develop”)” shall mean all pre-regulatory approval development and regulatory activities regarding a product in a country conducted with the aim of obtaining such regulatory approval including:

 

(a)                                 studies on the toxicological, pharmacological, metabolical or clinical aspects of a product conducted internally or by individual investigators or consultants; and

 

(b)                                 process development, process improvement, scale-up and recovery, the manufacture of clinical supplies of product, including failed batches, manufacture of qualification lots; and

 

(c)                                  preparing, submitting, reviewing or developing data or information for the purpose of submission to a regulatory authority to obtain, maintain and/or expand manufacturing and/or regulatory approval of a product including data management, statistical designs and studies, document preparation, and other administration; and

 

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(d)                                 all post regulatory approval regulatory activities and adverse event reporting in relation to products.

 

1.7                               “Field” shall mean gene therapy for the therapy or prophylaxis of Haemophilia B.

 

1.8                               “Investigational New Drug Application (“INDA”) shall mean an application submitted to the FDA or a foreign equivalent requesting permission to conduct human clinical studies with an investigational new drug or to conduct human clinical studies with an existing drug for a new use.

 

1.9                               “Licensed Product” shall mean all products containing Factor IX that are covered by Valid Claims of the Patent Rights to any extent.

 

1.10                        “Net Sales” shall mean the sum of all amounts actually invoiced by AMT (or Sublicensees as appropriate) from persons or entities for sales of Licensed Products, less the following deductions and offsets, to the extent such sums are actually incurred, paid or credited by AMT (or Sublicensees as appropriate) and not otherwise reimbursed:

 

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

 

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

 

(c)                                  reasonable and customary freight, shipping insurance and other transportation expenses directly related to the sale of product (if actually borne by AMT or Sublicensees without reimbursement from any third party);

 

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(d)                                 required distribution commissions/fees payable to any third party providing distribution services to AMT or Sublicensees;

 

(e)                                  sales, value-added, excise taxes, tariffs and duties, and other taxes and government 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 or its Sublicensees without reimbursement from any third party (but not including taxes assessed against the income derived from such sale); and

 

(f)                                   actual uncollectible amounts for product where collectibility is determined in accordance with IFRS consistently applied to all AMT products.

 

Sales of products intended for resale to third parties, and made internally amongst AMT and Sublicensees shall not be deemed sales for purposes of calculating “Net Sales” (however, sales to a third party other than a Sublicensee or Affiliate shall be included in the calculation of “Net Sales”).

 

1.11                        “Patent Rights” shall mean (i) U.S. Provisional Patent Application No. 60/612,135 filed September 22, 2004 entitled “Improved Expression of Factor IX in Gene Therapy Vectors” (ST. JUDE reference no. SJ-04-0024); (ii) all patent applications filed claiming priority from the above including all provisional patent applications and all national, regional and international patents and patent applications; (iii) all patent applications filed claiming priority from any of the above including any divisional, continuation, or continuation-in-part; (iv) any patent issued on any of the foregoing; (v) any reissue or extension of such patent; and (vi) any foreign counterparts to such patents and patent applications and applications and/or patents or the equivalent thereof claiming priority to or from any of the above.

 

1.12                        “Phase I Clinical Trial” shall mean a human clinical trial, the principal purpose of which is a preliminary determination of safety in healthy individuals or patients as required in 21

 

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C.F.R. §312, or a similar clinical study prescribed by the regulatory authorities in a country other than the United States.

 

1.13                        “Phase II Clinical Trial” shall mean (i) a human clinical trial, for which a primary endpoint is a preliminary determination of efficacy or dose ranges in patients with the disease target being studied as required in 21 C.F.R. §312.21(b), as maybe amended from time to time, or a similar clinical study prescribed by the regulatory authorities in a country other than the United States, or (ii) a combined Phase II and Phase III Clinical Trial which enrolls at least forty (40) patients, or any Phase III Clinical Trial performed in lieu of a Phase II study.

 

1.14                        “Phase III Clinical Trial” shall mean a human clinical trial, the principal purpose of which is to establish safety and efficacy in patients with the disease target being studied as required in 21 C.F.R. §312, or similar clinical study prescribed by the regulatory authorities in a country other than the United States.  A Phase III Clinical Trial shall also include any other human clinical trial intended as a pivotal study, whether or not such study is a traditional Phase III study.

 

1.15                        “Royalty Reporting Period” shall mean the partial calendar half year commencing on the date on which a Licensed Product is first sold and every complete or partial calendar half year thereafter during which royalty payment obligations under this Agreement remain in effect.

 

1.16                        “Sublicensee” shall mean any sublicensee of the rights granted to AMT under this Agreement, as further described in Section 2.1(i).

 

1.17                        “ST. JUDE Improvements” shall mean any improvement or enhancement (whether patentable or not) to the inventions of a Valid Claim of the Patent Rights in the Field that is discovered, developed or otherwise acquired by ST. JUDE after the Effective Date

 

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pursuant to Section 2.1(v) (but, for clarity, outside the scope of the Sponsored Research Agreement) and in relation to which a patent application is filed by ST. JUDE.

 

1.18                        “Valid Claim” shall mean a claim of an issued and unexpired patent or pending published patent application included within Patent Rights, which has not been held permanently revoked, unenforceable or invalid by a decision of a court or other governmental agency of competent jurisdiction, unappealable or un-appealed within the time allowed for appeal, and which has not been admitted to be invalid or unenforceable through reissue or disclaimer or otherwise.

 

2.                                      GRANT

 

2.1                               License Grant

 

(i)                                     ST. JUDE hereby grants to AMT and AMT accepts, subject to the terms and conditions herein, an exclusive worldwide license under the Patent Rights to research, have researched, Develop, have Developed, make, have made, import, distribute, use and Commercialise Licensed Products in the Field.  Such license shall include the right to grant sublicenses provided that AMT shall remain responsible for compliance by Sublicensees with the terms and conditions of this Agreement.  Within [**] days of the grant of each sublicense under this Agreement, AMT shall inform ST. JUDE in writing of the identity of the Sublicensee and provide a copy of the sublicense agreement but showing only those terms directly pertaining to the sublicense itself, with all other terms including financial terms redacted.

 

(ii)                                  The license granted herein is subject to the rights, conditions and limitations imposed by U.S. law on inventions and discoveries conceived or first actually reduced to practice during the course of research funded by a U.S. federal agency that are relevant to the Patent Rights.  The words “exclusive license” as used herein

 

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shall mean exclusive except for the royalty-free non-exclusive license granted to the U.S. government by ST. JUDE pursuant to 35 USC Section 202 (c) (4) for any Patent Rights claiming any invention subject to such license as defined under 35 USC Section 201 and any other federal laws and applicable regulations.

 

(iii)                               To the extent that Licensed Products embody Patent Rights conceived or first actually reduced to practice during the course of research funded by a U.S. federal agency, AMT agrees that such Licensed Products shall be manufactured substantially in the United States in accordance with 35 U.S.C. Section 204.

 

(iv)                              Title to the Patent Rights shall remain with ST. JUDE and ST. JUDE retains the right to license the Patent Rights to other entities outside the Field and to use the Patent Rights for internal and collaborative research outside the Field.

 

(v)                                 The license granted under Section 2.1(i) of this Agreement is subject to the non-transferable right of ST. JUDE under the Patent Rights solely to perform internal and collaborative research and education in the Field with academic collaborators.  To the extent that such research involves pre-clinical or clinical research the data and other results of such research, including any IND package and a copy of any interim or final clinical research report shall be made available by ST. JUDE to AMT and AMT shall be permitted to utilise the same only for lawful purposes in its dealings with the FDA.  ST. JUDE will at its own cost procure that this is possible under the terms of any agreement between it and such academic collaborations.

 

2.2                               ST. JUDE Improvements.  If any ST. JUDE Improvements are made by ST. JUDE during the term of this Agreement, AMT shall have the first right of refusal to such ST. JUDE Improvements.  ST. JUDE will disclose any such ST. JUDE Improvement to AMT by notice in writing.  AMT shall treat any such disclosure as Confidential Information and

 

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shall only use such disclosure to consider its licensing interest.   AMT shall have [**] days from the date of such disclosure in which to indicate to ST. JUDE by notice in writing whether it wishes to negotiate a license with grant terms the same as those set out in Section 2.1.  If AMT does so indicate that it wishes to take a license within the notice period, the Parties shall negotiate in good faith the financial and other terms of such license during the subsequent period of [**] days.  If the Parties cannot reach agreement during the negotiation period, ST. JUDE will be free to deal with third parties in respect of the said ST. JUDE Improvements in the Field.  During the period from first notification by ST. JUDE of the ST. JUDE Improvement to AMT until the expiration of the aforesaid [**] day period, the ST. JUDE shall not enter into arrangements or agreements with any third party concerning the ST. JUDE Improvements in the Field.

 

3.                                      DILIGENCE OBLIGATIONS AND ANNUAL PROGRESS REPORT

 

3.1                               Use of Commercially Reasonable Efforts.  With effect from completion or termination of the Research Program under the Sponsored Research Agreement (“Commencement Date”) AMT  shall  use  Commercially  Reasonable  Efforts  to  diligently  Develop and Commercialize Licensed Products whether by itself or through its Sublicensee(s).

 

3.2                               Annual Progress Reports.  Within [**] days after each anniversary of the Commencement Date, AMT shall furnish ST. JUDE with a written report summarizing efforts and achievements toward Developing and Commercializing Licensed Products, including the status of any regulatory submissions, clinical trials and sublicensing activities.  This report shall also include a statement regarding insurance coverage in accordance with Section 8.1 (iii) below.

 

4.                                      PAYMENTS

 

4.1                               License Fee.  In partial consideration of the rights granted to AMT under this Agreement and to reimburse ST. JUDE for patent expenses already incurred in pursuing the Patent

 

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Rights, AMT shall pay [**] U.S. dollars to ST. JUDE within [**] days of the full execution of this Agreement.  This license fee payment is nonrefundable and not creditable against any other payments due to ST. JUDE under this Agreement.

 

4.2                               Annual Maintenance Fee.  AMT shall pay ST. JUDE an annual fee of Ten Thousand ($10,000) U.S. dollars within [**] days of January 1.  This fee shall be creditable to royalties and milestones which are due in the same calendar year.

 

4.3                               Milestone Payments.  AMT shall pay ST. JUDE the following milestone payments on the first occurrence of the following milestone events:

 

(i)                                     [**] U.S. dollars upon [**];

 

(ii)                                  [**] U.S. dollars upon [**]; and

 

(iii)                               [**] U.S. dollars upon [**].

 

Each of the milestone payments the subject of this Section shall only be payable by AMT upon the first occurrence of the applicable event whenever it occurs.

 

4.4                               Royalties.  AMT shall pay ST. JUDE [**] percent ([**]%) of Net Sales of Licensed Products sold by AMT itself or Sublicensees on a country by country basis until expiry of the Valid Claims of the Patent Rights in the country of sale that cover the product and render it a Licensed Product.

 

4.5                               Sublicense Consideration.  In addition to the royalty obligation as set forth under Section 4.4, AMT shall pay to ST. JUDE the following percentages of consideration received for sublicenses under this Agreement:

 

(i)                                     [**] percent ([**]%) for a sublicense granted [**];

 

(ii)                                  [**] percent ([**]%) for a sublicense granted [**]; and

 

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(iii)                               [**] percent ([**]%) for a sublicense granted [**].

 

This payment shall be due, without the need for invoice from ST. JUDE, within [**] days of the receipt the payment made to AMT by a Sublicensee under a sublicense agreement.  Such sublicense consideration shall include consideration of any kind received by AMT from a Sublicensee for the grant of a sublicense under this Agreement, such as upfront fees or milestone fees and including any premium paid by the Sublicensee over the Fair Market Value (as such term is defined in subsection (iii) below) for stock of AMT in consideration for such sublicense. However, not included in such sublicense consideration are:

 

(i)                                     Support for research, Development and/or manufacturing activities corresponding directly to the Development of Licensed Products, which do not exceed the fully-burdened cost for undertaking such research, Development, and/or manufacturing performed by or for AMT (including third parties on AMT’s behalf), each pursuant to a specific agreement including a performance plan and commensurate budget;

 

(ii)                                  Proceeds derived from debt financing, to the extent that such financing is at market rates, and any loans to AMT by the Sublicensee:

 

(iii)                               Consideration received for the purchase of an equity interest in AMT to the extent that the price per share for such equity does not exceed by more than [**] percent ([**]%) the Fair Market Value of AMT’s stock.  The term Fair Market Value shall mean the average price that the stock in question is publicly trading at for twenty (20) days prior to the announcement of its purchase by the Sublicensee or if the stock is not publicly traded, the value of such stock as determined by the most recent private financing through a financial investor (an entity whose sole interest in AMT is financial);

 

(iv)                              Reimbursement of AMT’s patent costs related to Patent Rights; and

 

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(v)                                 Any and all amounts paid to AMT by a Sublicensee as royalties on sales of Licensed Product sold by the Sublicensee under a sublicense.

 

4.6                               Late Payment.  For any late payment AMT shall pay an interest penalty based on the amount owed at a daily accrual rate equal to the lesser of [**] percent ([**]%) per annum or the highest rate permissible by law.

 

5.                                      ROYALTY REPORTS; PAYMENTS; RECORDS

 

5.1                               First Sale.  AMT shall report to ST. JUDE the date of first commercial sale of a Licensed Product within [**] days of its occurrence.

 

5.2                               Reports and Payments.  Within [**] days after the conclusion of each Royalty Reporting Period, AMT shall deliver to ST. JUDE a report of Net Sales for each Licensed Product during the prior Royalty Reporting Period on a country-by-country basis. Such report shall include the amount of gross sales and the amount of all deductions and reductions taken in each category identified in the definition of Net Sales in sufficient detail to allow ST. JUDE to verify the Net Sales calculation, the amount of Net Sales, and the total royalty payable on Net Sales in U.S. dollars, together with the exchange rates used for conversion.  All such reports shall be considered Confidential Information of which AMT is the Disclosing Party and the provisions of Section 7 of this Agreement shall apply to such reports.  If no royalties are due to ST. JUDE for any Royalty Reporting Period, the report shall so state. Concurrent with the report, AMT shall remit to ST. JUDE any payment due for the applicable Royalty Reporting Period. Unless other arrangements are made, payment shall be remitted to the following address:

 

St. Jude Children’s Research Hospital

P.O. Box 1000, Department # 516

Memphis, TN 38148-0516

 

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5.3                               Records.

 

(i)                                     AMT shall maintain, and shall require its Sublicensees to maintain complete and accurate records of all Net Sales under this Agreement which records shall contain sufficient information to permit auditors to confirm the accuracy of any reports delivered to ST. JUDE under Section 5.2.  The relevant party shall retain such records relating to a given Royalty Reporting Period for at least [**] years after the conclusion of that Royalty Reporting Period.

 

(ii)                                  Upon [**] working days notice by ST. JUDE, ST. JUDE shall have the right, at its expense, to cause accountants from a nationally-recognized accounting firm to inspect the records of AMT (but not Sublicensees) for the period covering Royalty Reporting Periods ending no more than [**] years prior to the date of the inspection (including records of royalty accounting received from their Sublicensees) during normal business hours for the sole purpose of verifying any reports and payments delivered under this Section 5.2. ST. JUDE may exercise its rights under this Section 5.3 only [**].

 

(iii)                               The Parties shall reconcile any underpayment or overpayment within [**] days after the auditor delivers the results of the audit. In the event that any audit performed under this Section reveals an underpayment in excess of [**] percent ([**]%) in any Royalty Reporting Period, AMT shall bear the full cost of such audit.

 

(iv)                              Prior to any such audit taking place, such firm of accountants shall undertake to AMT that they shall keep all information and data contained in the records of AMT strictly confidential and shall not disclose such information or copies of such records to any third person including ST. JUDE, but shall only use the same for the

 

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purpose of the reviews and/or calculations which they need to perform in order to verify the reports delivered under Section 5.2 of this Agreement.

 

(v)                                 Upon timely request by ST. JUDE, AMT shall, at the expense of ST. JUDE, have any Sublicensee accounting to AMT for royalties audited under the audit provisions agreed between AMT and the Sublicensee, and AMT shall report to ST. JUDE the outcome. If there is a discrepancy identified upon such an audit the provisions of Section 5.3(iii) shall apply in like manner.

 

6.                                      PATENTS AND INFRINGEMENT

 

6.1                               Responsibility for Patent Rights.  Title to all Patent Rights shall remain with ST. JUDE and ST. JUDE shall retain primary responsibility for the drafting, filing, prosecution, and maintenance of all Patent Rights.  ST. JUDE shall appoint and retain external patent counsel approved by AMT.  ST. JUDE shall keep AMT informed of all developments including promptly furnishing AMT with all patent office communications.  ST. JUDE shall, to the satisfaction of AMT, implement all reasonable requests of AMT with respect to the drafting, filing, prosecution, and maintenance of all Patent Rights.

 

6.2                               Reimbursement of Patent Expenses.  AMT shall reimburse ST. JUDE for all out of pocket patent-related expenses incurred by ST. JUDE pursuant to Section 6.1 related to Patent Rights during the term of this Agreement within [**] days after ST. JUDE invoices AMT subject to the provisions of this Section.  Such invoice shall contain a breakdown of the expenses and be accompanied by supporting evidence of such expenses as appropriate including copies of invoices from external patent counsel.  ST JUDE shall instruct its patent counsel to communicate with AMT directly on all matters pertaining to the activities of patent counsel, including the giving of forward cost estimates, but copying ST JUDE on all e-mails and other correspondence.

 

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6.2.1                     If ST. JUDE grants an exclusive license under the Patent Rights outside of the Field, ST. JUDE shall promptly notify AMT. In such an event, from the effective date of that license, AMT shall be responsible for [**] percent ([**]%) of the patent-related expenses only.

 

6.3                               Abandonment.  AMT may elect, upon [**] days written notice to ST. JUDE, to cease payment of the expenses associated with obtaining or maintaining patent protection for one or more patents or applications within the Patent Rights in one or more countries.  In such event, AMT shall forfeit all rights under this Agreement with respect to such patent within the Patent Rights in such country(ies). ST. JUDE shall have the right, at its sole expense, to prepare, file, prosecute, and maintain any patents or patent applications under Patent Rights abandoned by AMT.

 

6.4                               Infringement.

 

(i)                                     Notification of Infringement.  Each Party agrees to provide written notice to the other Party promptly (i) after becoming aware of or having a reasonable suspicion of any infringement of the Patent Rights in the Field or (ii) upon becoming aware of any action alleging invalidity or non-infringement of the Patent Rights in the Field.

 

(ii)                                  AMT Right to Enforce Patent Rights in the Field.  AMT shall have the right, under its own control and at its own expense, to prosecute any third party infringement of the Patent Rights in the Field including negotiating sublicense agreements with such third parties at its discretion.  At least [**] days prior to a potential claim, AMT shall notify ST. JUDE in writing of the nature of the anticipated action and the party(ies) against whom the anticipated action may be taken.  It is understood that any sublicense rights granted hereunder shall not forgive any royalty payments that would otherwise be due to ST. JUDE based on sales of Licensed Products by the Sublicensee without consultation with ST. JUDE.  If AMT succeeds in any such

 

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infringement proceedings whether at trial or by way of settlement, any recovery by AMT in such proceedings brought by AMT shall first be used to reimburse AMT for all reasonable out-of-pocket costs and legal fees incurred to conduct such proceedings.  Out of any remaining damages actually received by AMT relating to infringement of the Patent Rights, AMT shall pay to ST. JUDE an amount equivalent to the payment which would have been due to ST. JUDE on the balance as if they were Net Sales, along with an accounting of the recovery and the reasonable out-of-pocket costs and legal fees.

 

In the event that AMT fails to initiate an infringement action within [**] months after it first becomes aware of such infringement or notifies ST. JUDE that it does not intend to initiate such action, ST. JUDE shall have the right to prosecute such infringement, under its sole control and its sole expense, and any recovery obtained shall be retained by ST. JUDE. AMT shall provide all necessary assistance to ST. JUDE in relation to such proceedings and ST. JUDE shall on demand by AMT indemnify AMT against the costs of such activity, unless AMT elects to be separately represented (which shall be at AMT’s discretion), in which case such separate representation shall be at AMT’s cost and expense.

 

(iii)                               ST. JUDE as Indispensable Party.  If, in the reasonable opinion of AMT’s counsel, ST. JUDE should be a named party to any such suit, AMT may name ST. JUDE as a party, provided that AMT shall hold ST. JUDE harmless from, and if necessary indemnify ST. JUDE against, any costs (including attorney fees), expenses or liability that ST. JUDE may incur in connection with such action unless ST. JUDE elects to be separately represented in which case such separate representation shall be at ST. JUDE’s own cost and expense.

 

(iv)                              Cooperation.  Each Party agrees to cooperate fully in any action under this Section 6.4, which is controlled by the other Party, provided that the controlling Party

 

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reimburses the cooperating Party promptly for any costs and expenses incurred by the cooperating Party in connection with providing such assistance.

 

6.5                               Third Party Patent Rights.  Each Party shall promptly notify the other Party of any third party patent rights relevant to the Development or Commercialisation of the Licensed Product of which it becomes aware including by making appropriate searches for these as and when it considers appropriate.  To the extent possible, whilst preserving attorney-client privilege, the Parties’ patent counsel shall share copies of all external and internal opinions on the likelihood of grant and/or validity of relevant third party patent rights

 

7.                                      CONFIDENTIAL INFORMATION; PUBLICITY

 

7.1                               Confidential Information.

 

(i)                                     Obligations.  Except to the extent authorized in Section 7.1(i) of this Agreement, and for so long as the exceptions set out below in Section 7.1(ii) do not apply, the Receiving Party shall, in relation to any Confidential Information (i) maintain such Confidential Information in confidence using the same duty of care it would use to protect its own information of a like kind (and in any event no less than reasonable care), except that the Receiving Party may disclose or permit the disclosure of any Confidential Information to its Sublicensees (to the extent necessary to effect the relevant Sublicense) and its trustees, directors, officers, employees, consultants, and advisors who are obligated to maintain the confidential nature of such Confidential Information and who need to know such Confidential Information for the purpose of this Agreement and for other purposes that may be required or necessary pursuant to this Agreement such as communication with collaborators or regulatory agencies; (ii) use such Confidential Information solely for the purposes of this Agreement; and (iii) allow its Sublicensees, trustees or directors, officers, employees, consultants, and advisors to reproduce the Confidential Information

 

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only to the extent necessary for the purposes of this Agreement, with all such reproductions being considered Confidential Information.

 

(ii)                                  Exceptions.  The obligations of the Receiving Party under Section 7.1(i) above shall not apply to the extent that the Receiving Party can demonstrate by written evidence that certain Confidential Information (a) was in the public domain prior to the time of its disclosure under this Agreement; (b) entered the public domain after the time of its disclosure under the Agreement through means other than an unauthorized disclosure resulting from an act or omission by the Receiving Party; (c) was independently developed or discovered by the Receiving Party without use of the Confidential Information; (d) is or was disclosed to the Receiving Party at any time, whether prior to or after the time of its disclosure under this Agreement, by a third party having no fiduciary relationship with the Disclosing Party and having no obligation to confidentiality with respect to such Confidential Information; or (e) was previously known to the Receiving Party from sources other than the Disclosing Party at the time of disclosure under this Agreement other than under an obligation of confidentiality.

 

(iii)                               Allowed Disclosure.  Notwithstanding the above obligations of confidentiality and non-use a Receiving Party may:

 

(a)                                 disclose Confidential Information to a competent 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

 

(b)                                 disclose Confidential Information: (i) to the extent such disclosure is reasonably necessary to comply with the order of a court; or (ii) to the extent such disclosure is required to comply with a legal requirement,

 

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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., EURONEXT, the rules of the United States Securities and Exchange Commission, NASDAQ, NYSE, 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 sentence of this Section, 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, unless a shorter review time is agreed.  If the compliance with a legal requirement 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; and

 

(c)                                  disclose Confidential Information by filing or prosecuting the Patent Rights, the filing or prosecution of which is contemplated by this Agreement, without violating the above confidentiality provisions; it being understood that publication of such filings occurs in some jurisdictions within [**] months of filing; and

 

(d)                                 in the case where AMT is the Receiving Party disclose Confidential Information to AMT’s contractors (including clinical researchers) distributors, Sublicensee’s, agents, consultants, as such Receiving Party 

 

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reasonably determines is necessary to receive the benefit of the licenses and rights granted or available to it under this Agreement or to fulfil its obligations pursuant to this Agreement; provided, however, any such persons must be obligated to substantially the same extent as set forth in this Section to hold in confidence and not make use of such Confidential Information for any purpose other than that permitted by this Agreement; and

 

(e)                                  disclose Confidential Information: (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 acquiror 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 this Section to hold in confidence and not make use of such Confidential Information for any purpose other than those permitted by this Agreement; and

 

(f)                                   disclose Confidential Information to its legal advisers for the purpose of seeking advice.

 

7.2                               Use of Names.

 

(i)                                     AMT and its Sublicensees shall not use the name “St. Jude Children’s Research Hospital” or any variation of that name, or any trademarks or logos belong to ST. JUDE, or the names of any of ST. JUDE’s trustees, officers, faculty, students, employees, or agents, or any adaptation of such names, or any term of this Agreement in any promotional material or other public announcement or disclosure 

 

20

 

or in connection with the marketing or sale of any Licensed Product without the prior written approval of ST. JUDE; except: (a) in annual reports or as part of required regulatory or financial disclosures to the FDA, Securities Exchange Commission or other federal or foreign agencies; and (b) where otherwise required by law, provided that AMT shall notify ST. JUDE in advance of any disclosure to be made under these exceptions.

 

(ii)                                  ST. JUDE shall not use the name “ Amsterdam Molecular Therapeutics B.V.” or any variation of that name, or any term of this Agreement in any promotional material or other public announcement or disclosure without the prior written approval of AMT; except: (a) as part of required reports to state or federal government entities; and (b) where otherwise required by law, provided that ST. JUDE shall notify AMT in advance of any disclosure to be made under these exceptions.

 

7.3                               Publication.  If ST. JUDE wishes to publish or otherwise publically disclose results obtained from its internal research under the Patent Rights in the Field, ST. JUDE shall submit to AMT a confidential copy of the intended publication or disclosure at least [**] days prior to the proposed publication or other disclosure date.  If, AMT believes that the publication or intended disclosure contains patentable subject matter or contains Confidential Information of AMT, AMT shall notify ST. JUDE in writing.

 

7.4                               Marking.  AMT shall mark all Licensed Products intended for use under Patent Rights with appropriate information with respect to Patent Rights in accordance with the statutes of the United States relating to the marking of patented articles (see 35 U.S.C. §287(a)) and corresponding foreign rules and regulations.

 

21

 

8.                                      INDEMNIFICATION AND INSURANCE

 

8.1                               Indemnification.

 

(i)                                     Indemnity.

 

(a)                                 Except with respect to third party claims the subject of this Section, neither Party shall be liable to the other in contract, tort, negligence, breach of statutory duty or otherwise for any loss, damage, costs or expenses of any nature whatsoever incurred or suffered by the other or its Affiliates of a direct nature where the same is a loss of turnover, profits, business or goodwill; or an indirect or consequential or punitive nature, including any indirect or consequential economic loss or other indirect or consequential loss of turnover, profits, loss of enterprise value, business or goodwill or otherwise.

 

(b)                                 AMT shall indemnify, defend and hold ST. JUDE, the American Lebanese Syrian Associated Charities, Inc. (ALSAC; a non-profit, 501(c)(3) corporation which supports ST. JUDE), their present and former trustees, directors, governors, officers, agents, faculty, employees and students (“the Indemnitees”) harmless as against any claims, demands, damages, judgments, fees (including reasonable attorneys fees), expenses, or other costs arising from or incidental to any product liability or other lawsuit, claim, demand or other action brought by a third party as a consequence of the use of clinical data provided by ST. JUDE, the practice of the Patent Rights or the sale of Licensed Products by AMT or Sublicensees, whether or not ST. JUDE, either jointly or severally, is named as a party defendant in any such lawsuit and whether or not ST. JUDE is alleged to be negligent or otherwise responsible for any injuries to persons or property.  Such indemnity shall not extend to any claims, demands, damages, judgments, fees (including reasonable attorneys fees), expenses, or other costs to the extent that the same are determined to be the result of the willful misconduct of ST. JUDE, the American Lebanese Syrian Associated 

 

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Charities, Inc., their present and former trustees, directors, governors, officers, agents, faculty, employees or students  Practice of the Patent Rights or sale of Licensed Products by an Affiliate of AMT or an agent or a Sublicensee or a third party on behalf of or for the account of AMT or by a third party who purchases Licensed Product(s) from AMT, shall be considered AMT’s practice of said Patent Rights for purposes of this Section.  The obligation of AMT to defend, indemnify and hold harmless as set out in this Section shall survive the termination of this Agreement, shall continue even after assignment of rights and responsibilities to an Affiliate or Sublicensee, and shall not be limited by any other limitation of liability elsewhere in this Agreement.

 

(c)                                  In the event that it is ultimately determined that AMT is not obligated to indemnify, defend and hold harmless the Indemnitees as against any claims, demands, damages, judgments, fees (including reasonable attorneys fees), expenses, or other costs, the Indemnitees shall reimburse AMT for any and all costs and expenses (including lawyers’ fees) incurred by AMT in its defense with respect to the Indemnitees.

 

(ii)                                  Procedures.  The Indemnitees agree to provide AMT with prompt written notice of any claim, suit, action, demand, or judgment for which indemnification is sought under this Agreement.  In no event shall AMT be liable for any claims, demands, damages, judgments, fees (including reasonable attorney’s fees), expenses, or other costs that result from a delay by the Indemnitees in providing AMT with such notice.  AMT agrees, at its own expense, to provide attorneys reasonably acceptable to Indemnitees to defend against any such claim, unless Indemnitees elect to be separately represented (which shall be at Indemnitee’s discretion), in which event any costs incurred by the Indemnitees in relation to retaining their own attorneys shall be the sole responsibility of the Indemnitees.  The Indemnitees shall 

 

23

 

cooperate fully with AMT in such defense and will permit AMT to conduct and control such defense and the disposition of such claim, suit, or action (including all decisions relative to litigation, appeal, and settlement).  AMT agrees to keep ST. JUDE informed of the progress in the defense and disposition of such claim and to consult with ST. JUDE with regard to any proposed settlement.

 

(iii)                               Insurance.  Prior to initial human testing or sale of any Licensed Products and thereafter so long as Licensed Products are being sold in any particular country AMT shall establish and maintain appropriate insurance coverage in the minimum amount of [**] dollars ($[**]) per claim, with an aggregate of [**] dollars ($[**]), to cover any liability arising from AMT’s indemnification obligations under this Section 8 with respect to such human testing or sale of Licensed Product.  Prior to initial human testing or sale of any Licensed Product and thereafter so long as Licensed Products are being sold in any particular country, AMT shall establish and maintain, in each country in which AMT or Sublicensees shall test or sell Licensed Products, product liability or other appropriate insurance coverage in the minimum amount of [**] dollars ($[**]) per claim.  AMT will annually present evidence, in the form of a statement in the annual diligence report to ST. JUDE that such coverage is being maintained.  Upon ST. JUDE’S request, AMT will furnish ST. JUDE with a Certificate of Insurance of each insurance policy obtained.  ST. JUDE and ALSAC shall be listed as additional insured’s in AMT’s said insurance policies.  If such insurance is underwritten on a ‘claims made’ basis, AMT agrees that any change in underwriters during the term of this Agreement and thereafter so long as Licensed Products are being sold will require the purchase of ‘prior acts’ coverage to ensure that coverage will be continuous throughout the term of this Agreement and thereafter so long as Licensed Products are being sold.

 

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9.                                      TERM AND TERMINATION

 

9.1                               Term.  This Agreement shall commence on the Effective Date and, and unless sooner terminated in accordance with any of the provisions herein, expire when no further payment is due from AMT to ST. JUDE hereunder in relation to sales of Licensed Product.

 

9.2                               Voluntary Termination by AMT.  AMT shall have the right to terminate this Agreement, for any reason, upon ninety (90) days, prior written notice to ST. JUDE.  Upon termination, a final report as described in Section 5.2 shall be submitted and any previously arising (before the effective termination date) milestone payments, annual fees, royalty payments, and unreimbursed patent expenses due to ST. JUDE shall become immediately payable.

 

9.3                               Termination for Default.  In the event that either Party commits a material breach of its obligations under this Agreement and fails to cure that breach within [**] days after receiving written notice thereof, the other Party may terminate this Agreement immediately upon written notice to the party in breach unless the Party allegedly in breach disputes that a material breach has occurred and submits notice of such dispute to the other Party, following which the Parties shall first try to resolve the dispute within [**] days of such notice and if such dispute cannot be resolved, the dispute shall be subject to the jurisdiction of the courts pursuant to Section 10.7.  For the avoidance of doubt, there shall be no termination of this Agreement pending the outcome of dispute resolution.

 

If the alleged breach involves non payment of any undisputed amounts due ST. JUDE under this Agreement, AMT shall pay an interest penalty based on the amount owed at a daily accrual rate equal to the lesser of [**] percent ([**]%) per annum or the highest rate permissible by law on the unpaid balance until the undisputed amount is paid in full.

 

9.4                               Termination for Insolvency.  ST. JUDE shall have the right to terminate this Agreement on written notice to AMT in the event of the occurrence of insolvency of AMT.

 

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9.5                               Effect of Termination on Sublicensees.  If termination under Sections 9.3 or 9.4 of this Agreement is no fault of a Sublicensee ST. JUDE agrees to enter into a direct license of Patent Rights with any Sublicensee on substantially the same terms as the sublicense between AMT and the Sublicensee with respect to terms pertaining to the Patent Rights, provided that the terms of the sublicense are at least as favorable to ST. JUDE as the terms of this Agreement and prior to the making of any such sub-license by AMT, ST. JUDE will undertake directly to such Sublicensee that ST. JUDE will do this.

 

9.6                               Effect of Termination.  Upon termination, AMT shall cease to utilize Patent Rights and shall so certify to ST. JUDE in writing that Patent Rights are not being used for any purpose by AMT.  Termination shall not affect any rights or obligations which have accrued prior to termination or which by their nature are intended to survive termination such as Section 1, 5.2 (obligation to provide final report and payment), 7, 8.1, 9.5, 10.1, 10.7 and 10.8.  Upon the early termination of this Agreement, AMT may complete and sell any work-in-progress and inventory of Licensed Products that exists as of the effective date of termination, provided that (i) AMT is current in payment of all amounts due ST. JUDE under this Agreement, (ii) AMT pays ST. JUDE the applicable royalty on such sales of Licensed Products in accordance with the terms and conditions of this Agreement, and (iii) AMT shall complete and sell all work-in-progress and inventory of Licensed Products within [**] months after the effective date of termination.

 

10.                               MISCELLANEOUS

 

10.1                        Representation and Warranties of both Parties.

 

(i)                                     Each Party hereby represents and warrants to the other Party, as of the Effective Date, as follows:

 

(a)                                 Such Party has the power and authority and legal right to enter into this Agreement, to perform its obligations and to grant the licenses hereunder,

 

26

 

and has taken all necessary action on its part to authorize the execution and delivery of this Agreement and the performance of its obligations hereunder;

 

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

 

(c)                                  The execution, delivery and performance of this Agreement by such Party do not conflict with any agreement, instrument or understanding, oral or written, to which it is a party or by which it is bound, nor violate any applicable law or regulation of any governmental body or administrative or other agency having jurisdiction over it;

 

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

 

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

 

(ii)                                  Further Representations and Warranties of ST. JUDE:

 

(a)                                 ST. JUDE either legally or beneficially owns or controls the entire right, title and interest in and to the Patent Rights licensed hereunder.

 

(b)                                 there is, to its knowledge as of the Effective Date, no action, suit, claim, proceeding or governmental investigation pending or threatened against ST. JUDE with respect to enforceability of the Patent Rights licensed hereunder, either at law or in equity, before any court or administrative

 

27

 

agency or before any governmental department, commission, board, bureau, agency or instrumentality, whether United States or foreign.

 

(c)                                  ST. JUDE has informed AMT in writing of all intellectual property rights of third parties in the Field of which ST. JUDE is aware to the best of ST. JUDE’s knowledge.

 

ST. JUDE MAKES NO OTHER WARRANTIES CONCERNING THE PATENT RIGHTS, INCLUDING WITHOUT LIMITATION ANY EXPRESS OR IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE.  Specifically, ST. JUDE makes no warranty or representation (i) regarding the validity or scope of the Patent Rights, (ii) that exploitation of the Patent Rights or any Licensed Product will not infringe any patents or other intellectual property rights of a third party, and (iii) that any third party is not currently infringing or will not infringe the Patent Rights.

 

10.2                        Force Majeure.  Neither Party will be responsible for its inability to perform any of its obligations under this Agreement resulting from causes beyond the reasonable control of such Party, including without limitation fires, explosion, flood, war, strike, or riot, provided that the nonperforming Party uses reasonable efforts to avoid or remove such causes of nonperformance and continues performance under this Agreement with reasonable dispatch whenever such causes are removed.

 

10.3                        Headings.  All headings are for convenience only and shall not affect the meaning of any provision of this Agreement.

 

10.4                        Binding Effect.  This Agreement shall be binding upon and inure to the benefit of the parties and their respective permitted successors and assigns.

 

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10.5                        Assignment.  The benefit and/or burden of this Agreement may not be assigned by either Party without the prior written consent of the other Party, such consent not to be unreasonably withheld, except that AMT may, without the consent of ST. JUDE assign this Agreement to an Affiliate or to a successor in connection with a merger, consolidation, or sale of all or substantially all of its assets or that portion of its business to which this Agreement relates, but shall notify ST. JUDE of such an assignment within [**] days of its occurrence.  Any assignment in violation of this provision shall be null and void.

 

10.6                        Amendment and Waiver.  This Agreement may be amended, supplemented, or otherwise modified only by means of a written instrument signed by both Parties.  Any waiver of any rights or failure to act in a specific instance shall relate only to such instance and shall not be construed as an agreement to waive any rights or fail to act in any other instance, whether or not similar.

 

10.7                        Governing Law.  This Agreement shall be governed by and construed in accordance with the laws of the State of New York irrespective of any conflicts of law principles or choice of law rules of any state or country.  Any lawsuit that may be brought with respect to this Agreement shall be brought and tried in a court of competent jurisdiction in New York.  AMT represents that choice of law provisions agreed to by parties to a written contract are generally honored under Dutch law.

 

10.8                        Notice.  Any notices required or permitted under this Agreement shall be in writing, shall specifically refer to this Agreement, and shall be sent by hand, recognized national overnight courier, confirmed facsimile transmission, or registered or certified mail, postage prepaid, return receipt requested, to the following address or facsimile numbers of the parties:

 

	
To ST. JUDE:
    	
Office of Technology Licensing
    
	
 
    	
Mail Stop 0742
    
	
 
    	
St. Jude Children’s Research   Hospital
    

 

29

 

	
 
    	
332 North Lauderdale
    
	
 
    	
Memphis, Tennessee 38105 Attn:   Director
    
	
 
    	
 
    
	
 
    	
Facsimile: (901) 495-3148
    
	
 
    	
 
    
	
To AMT:
    	
Amsterdam Molecular Therapeutics   B.V.
    
	
 
    	
Meibergdreef 611105 BA
    
	
 
    	
Amsterdam, The Netherlands
    
	
 
    	
Attn: Anthony Gringeri
    
	
 
    	
 
    
	
 
    	
Facsimile: +31 20 566 9272
    

 

 

All notices under this Agreement shall be deemed effective upon receipt.  A Party may change its contact information upon written notice to the other Party.

 

10.9                        Severability.  In the event that any provision of this Agreement shall be held invalid or unenforceable for any reason, such invalidity or unenforceability shall not affect any other  provision of this Agreement, and the Parties shall negotiate in good faith to modify the Agreement to preserve (to the extent possible) their original intent.  During such negotiation, this Agreement shall be construed as if such provision were deleted by agreement of the Parties.

 

10.10                 Entire Agreement.  This Agreement, together with the Sponsored Research Agreement and the AMT Technology License Agreement between the Parties executed concurrently herewith, constitutes the entire agreement between the Parties with respect to the subject matter and supersedes all prior agreements or understandings between the Parties relating to its subject matter.

 

IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed by their duly authorized representatives.

 

30

 

	
Amsterdam Molecular Therapeutics   B.V.
    	
 
    	
St. Jude Children’s Research   Hospital, Inc.
    
	
 
    	
 
    	
 
    
	
By:
    	
/s/ A.J. Gringeri
    	
 
    	
By:
    	
/s/ J. Scott Elmer
    
	
 
    	
Anthony Gringeri
    	
 
    	
 
    	
J. Scott Elmer
    
	
 
    	
Chief Operating Officer
    	
 
    	
 
    	
Director, Technology Licensing
    
	
 
    	
 
    	
 
    
	
Date:
    	
4   July 2008
    	
 
    	
Date:
    	
07/07/08
    
							

 

31

 

 

 

ST. JUDE CHILDREN’S RESEARCH HOSPITAL, INC.   (1)

 

and

 

UNIQURE BIOPHARMA BV   (2)

 

 

AMENDMENT N°1 TO THE

EXCLUSIVE LICENSE AGREEMENT

 

 

 

THIS AMENDMENT N°1 TO THE EXCLUSIVE LICENSE AGREEMENT (this “Amendment”), with the effective date of July 12, 2012 (“Effective Date”),

 

BY AND BETWEEN

 

(1)                                 ST. JUDE CHILDREN’S RESEARCH HOSPITAL, INC., a Tennessee not-for-profit corporation located at 262 Danny Thomas Place, Memphis, Tennessee 38105 (“St. Jude”); and

 

(2)                                 UNIQURE BIOPHARMA BV (formerly: Amsterdam Molecular Therapeutics (AMT) B.V.), a company incorporated under the laws of the Netherlands, with offices at Meibergdreef 61, 1105 BA Amsterdam, The Netherlands (“uniQure”).

 

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

 

BACKGROUND:

 

(A)                               The Parties have signed an Exclusive License Agreement dated July 7th, 2008 (hereinafter the “Agreement”).

 

(B)                               The Parties desire that the Agreement be amended as set forth below in order to:

 

I.                                        change the name of the licensee from Amsterdam Molecular Therapeutics B.V. (“AMT”) to uniQure biopharma B.V. This name change is the result of a transaction that took place on 30 March 2012, whereby Amsterdam Molecular Therapeutics N.V., a public company, was liquidated and all its operations and stocks were transferred to UniQure B.V., a privately held company;

 

II.                                   add language related to financial terms associated with sublicensing, so as to clarifyfinancial obligations due to St.Jude from sublicensing of the patent rights granted in the Agreement by uniQure in order to expedite the development of therapeutics for rare diseases.

 

IT IS NOW AGREED AS FOLLOWS:

 

1.             Modifications

 

I.                                        In the Agreement, all references to “Amsterdam Molecular Therapeutics B.V.” are changed to “uniQure biopharma B.V.”.

 

II.                                   In the Agreement, all references to “AMT” are changed to “uniQure”.

 

III.                              Section 4.5 (i)* is amended to read as follows:

 

* 2nd subsection (f) of Section 4.5.

 

 

(i)                                     Support for research, Development and/or manufacturing activities corresponding directly to the Development and commercial manufacture of Licensed Products, which do not exceed the fully-burdened cost for undertaking such research, Development, and/or manufacturing performed by or for AMT (including third parties on AMT’s behalf), each pursuant to a specific agreement including a performance plan and commensurate budget;

 

IV.                               The following Section 4.7 is added to the Agreement:

 

4.7                               Sublicense consideration apportionment. The percentages referred to under subsections (i), (ii) and (iii) immediately below the first paragraph of Section 4.5 shall apply only to that portion of sublicense consideration attributable to sublicensing of the Patent Rights.  In any agreement which includes the grant of a sublicense to Patent Rights along with other rights and assets held by uniQure that are necessary or desirable for the development, manufacture and sale of Licensed Products, the Parties shall agree on the portion of income from such an agreement that should be attributable to sublicensing of the Patent Rights, taking into account the value of the Patent Rights in comparison to the value of the other rights and assets transferred by uniQure to the sublicensee that are necessary or desirable for the development, manufacture and sale of Licensed Products.

 

2.                                      Miscellaneous: All the other provisions of the Agreement remain unchanged and fully applicable between the Parties, and the terms and definitions used in the Agreement shall, so far as possible, apply to this Amendment.

 

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

 

 

	
St.   Jude Children’s Research Hospital, Inc.
    	
UniQure   biopharma B.V.
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
By:
    	
 
    	
 
    	
By:
    	
/s/   PJ Morgan
    
	
Name:
    	
 
    	
 
    	
Name:
    	
PJ   Morgan
    
	
Title:
    	
 
    	
 
    	
Title:
    	
CFO
    
	
Date:
    	
 
    	
 
    	
Date:
    	
12   July 2012Exhibit 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.

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

(g)                                  Detailed production instructions, including the:

 

(i)            Sequences to be followed; and

 

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

 

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

 

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

 

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

 

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

 

(ii)           Release Testing methods; and

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

2                                         Development and Manufacture; Purchase; Property Decisions

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

3                                         Project Plan; Project Management

 

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

 

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

 

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

 

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

 

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

 

3.6                               Project Changes.

 

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

 

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

 

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

 

4                                         Manufacturing and Processing Activities

 

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

 

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

 

4.3                               Raw Materials and Consumables.

 

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

 

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

 

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

 

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

 

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

 

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

 

5                                         Development Runs.

 

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

 

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6                                         Clinical Batches

 

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

 

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

 

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

 

7                                         Deliveries

 

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

 

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

 

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

 

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

 

8                                         Payments

 

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

 

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

 

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

 

9                                         Documentation

 

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

 

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

 

17

 

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.

 

30

 

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

 

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

 

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

 

18                                  Use of Names

 

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

 

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

 

19                                  Term; Termination

 

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

 

31

 

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

 

19.2                        Termination.  This Agreement may be terminated as follows:

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

32

 

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

 

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

 

19.3                        Consequences of Termination.

 

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

 

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

 

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

 

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

 

33

 

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

 

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

 

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

 

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

 

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

 

34

 

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

 

20                                  Force Majeure

 

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

 

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

 

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

 

35

 

21                                  Miscellaneous

 

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

 

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

 

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

 

And

 

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

 

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

 

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

 

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

 

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

 

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

 

36

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

37

 

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

 

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

 

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

 

[the remainder of this page intentionally blank]

 

38

 

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

 

 

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

 

39

 

Exhibit A 
 Project Plan

 

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

 

Responsibilities

 

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

 

	
 
    	
 
    	
Task
    	
 
    	
AMT responsibility
    	
 
    	
Institut Pasteur
   responsibility
    
	
1
    	
 
    	
Process   Development
    	
 
    	
process   development
    	
 
    	
potency   testing of the batches
    
	
2
    	
 
    	
Assay   Development
    	
 
    	
AW   assays
    	
 
    	
transgene   specific assays, such as activity assays.
    
	
3
    	
 
    	
In   vivo tests in mice
    	
 
    	
—
    	
 
    	
In   vivo testing
    
	
 
    	
 
    	
Tox   in rats and dogs
    	
 
    	
 
    	
 
    	
In   vivo testing
    
	
4
    	
 
    	
MSV/WSV   for cGMP batches
    	
 
    	
MSV/WSV
    	
 
    	
—
    
	
5
    	
 
    	
cGMP   batch production
    	
 
    	
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
    	
 
    	
process   development
    	
 
    	
potency   testing of the batches
    
	
2
    	
 
    	
Assay   Development
    	
 
    	
AW   assays
    	
 
    	
transgene   specific assays, such as activity assays.
    
	
3
    	
 
    	
In   vivo tests in mice
    	
 
    	
—
    	
 
    	
In   vivo testing
    
	
 
    	
 
    	
Tox   in rats and dogs
    	
 
    	
 
    	
 
    	
In   vivo testing
    
	
4
    	
 
    	
MSV/WSV   for cGMP batches
    	
 
    	
MSV/WSV
    	
 
    	
—
    
	
5
    	
 
    	
cGMP   batch production
    	
 
    	
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
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
[**]
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
[**]
    	
 
    	
[**]
    	
 
    	
[**]
    

 

10

 

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

 

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

 

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.

 

13

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00225-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00225-of-00352.parquet"}]]