CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY [**], HAS BEEN OMITTED BECAUSE ARCHERDX, INC. HAS DETERMINED THE INFORMATION (I) IS NOT MATERIAL AND (II) WOULD LIKELY CAUSE COMPETITIVE HARM TO ARCHERDX, INC. IF PUBLICLY DISCLOSED.
THE GENERAL HOSPITAL CORPORATION
EXCLUSIVE PATENT LICENSE AGREEMENT
MGH Agreement No: A217008
MGH Case No: 21678 and 22318
This License Agreement (“Agreement”) is made as of the July 23, 2013 (“Effective Date”), by and between Archer Dx, Inc., a Delaware corporation, having a principal place of business at 16042 W. 59th Ave., Golden, CO 80403 (“Company”) and The General Hospital Corporation, d/b/a Massachusetts General Hospital, a not-for-profit Massachusetts corporation, with a principal place of business at 55 Fruit Street, Boston, Massachusetts 02114 (“Hospital”), each referred to herein individually as a “Party” and collectively as the “Parties”.
Hospital, as a center for patient care, research and education, is the owner of certain Patent Rights (defined below) and desires to grant a license of those Patent Rights to Company in order to benefit the public by disseminating the results of its research via the commercial development, manufacture, distribution and use of Products and Processes (defined below).
Company has the capability to commercially develop, manufacture, distribute and use Products and Processes for public use and benefit and desires to license such Patent Rights.
For good and valuable consideration, the sufficiency of which is hereby acknowledged, the Parties hereby agree as follows:
1. CERTAIN DEFINITIONS
As used in this Agreement, the following terms shall have the following meanings, unless the context requires otherwise.
1.1 “Affiliate” with respect to either Party shall mean any corporation or other legal entity other than that Party in whatever country organized, controlling, controlled by or under common control with that Party. The term “control” shall mean (i) in the case of Company, direct or indirect ownership of fifty percent (50%) or more of the voting securities having the right to elect directors, and (ii) in the case of Hospital, the power, direct or indirect, to elect or appoint fifty percent (50%) or more of the directors or trustees, or to cause direction of management and policies, whether through the ownership of voting securities, by contract or otherwise.
1.2 “ASRs” shall mean analyte specific reagents, which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.
1.3 “Claim” shall mean a claim of an issued and unexpired patent or a claim of a pending patent application within the Patent Rights that has not been (a) admitted to be invalid or unenforceable through reissue, re-examination or disclaimer, or (b) permanently revoked, or (c) held unpatentable, unenforceable or invalid by a decision of a court or other governmental agency of competent jurisdiction that is unappealable, or unappealed in the time allowed for appeal.
1.4 “Distributor” shall mean any third party entity to whom Company, a Company Affiliate or a Sublicensee has granted, express or implied, the right to distribute any Product or Process pursuant to Section 2.1(b)(ii).
1.5 “EMA” shall mean the European Medicines Agency, or any successor agency thereto.
1.6 “FDA” shall mean the U.S. Food and Drug Administration, or any successor agency thereto.
1.7 “First Commercial Sale” shall mean the initial Sale anywhere in the applicable License Territory of a Product or Process.
1.8 “IVD Field” shall mean the collection, preparation, examination and testing of specimens taken from the human body for use in the in vitro diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae.
1.9 “License Field” shall mean the IVD Field and RUO Field and shall not include any use of Products or Processes for entire human genome sequence analysis or any other field not specifically set forth herein.
1.10 “License Territory” shall mean worldwide.
1.11 “Net Sales” shall be calculated as set forth in this Section 1.11.
Subject to the conditions set forth below, “Net Sales” shall mean:
the gross amount billed or invoiced, or if no such bill or invoice is issued the amount received, whichever is greatest, by Company and its Affiliates and Sublicensees for or on account of Sales of Products and Processes;
less the following amounts:
to the extent documented and actually paid or incurred by Company, its Affiliates or Distributors or credited against amounts received by them in effecting such Sale:
amounts repaid or credited by reason of rejection or return of applicable Products or Processes;
reasonable and customary trade, quantity or cash rebates or discounts to the extent allowed and taken;
amounts for outbound transportation, insurance, handling and shipping, but only to the extent separately invoiced in a manner that clearly specifies the charges applicable to the applicable Products; and
taxes, customs duties and other governmental charges levied on or measured by Sales of Products or Processes, to the extent separately invoiced, whether paid by or on behalf of Company so long as Company’s price is reduced thereby, but not franchise or income taxes of any kind whatsoever.
the gross amount billed or invoiced, or if no such bill or invoice is issued the amount received, whichever is greatest, by Company and its Affiliates and Sublicensees for or on account of Sales of Products and Processes to Hospital and Hospital’s Affiliates.
Specifically excluded from the definition of “Net Sales” are amounts attributable to any Sale of any Product or Process between or among Company and any Company Affiliate and/or Sublicensee, unless the transferee is the end purchaser, user or consumer of such Product or Process.
No deductions shall be made for any commissions paid to any individuals or for any costs or expenses of collections.
Net Sales shall be deemed to have occurred and the applicable Product or Process “Sold” on the earliest of the date of billing, invoicing, delivery or payment or the due date for payment.
If any Product or Process is Sold at a discounted price that is lower than the customary price charged, or for non-cash consideration (whether or not at a discount), Net Sales shall be calculated based on the non-discounted cash amount charged to an independent third party for the Product or Process during the same Reporting Period or, in the absence of such transaction, on the fair market value of the Product or Process. Non-cash consideration that could affect any payment due to Hospital hereunder shall not be accepted without the prior written consent of Hospital.
1.12 “Patent Rights” shall mean, inclusively, (a) any patent rights claiming an invention described and enabled in Hospital’s invention disclosure number [**], (b) the U.S. Patent Application number [**], (c) U.S. Patent Application number [**], and/or (d) the equivalent of such applications including any division, continuation (but not including continuation-in-part), and/or any foreign patent application and/or Letters Patent, and/or the equivalent thereof issuing
thereon, and/or reissue, reexamination and/or extension thereof, as may be further described in Appendix A.
1.13 “Process” shall mean any process, method or service the use or performance of which, in whole or in part:
absent the license granted hereunder would infringe, or is covered by, one or more Claims of Patent Rights; or
employs, is based upon or is derived from Technological Information.
1.14 “Product” shall mean any article, device or composition, the manufacture, use, or sale of which, in whole or in part:
absent the license granted hereunder would infringe, or is covered by, one or more Claims of Patent Rights; or
employs, is based upon or is derived from Technological Information.
1.15 “Regulatory Approval” shall mean the clearance, waiver, license, registration, authorization or approval of the applicable Regulatory Authority necessary for the commercial marketing and Sale of a Product or Process.
1.16 “Regulatory Authority” shall mean any national or supranational governmental authority, including without limitation the FDA or EMA, which has responsibility over the marketing and sale of a Product and/or Process.
1.17 “Reporting Period” shall mean each three month period ending March 31, June 30, September 30 and December 31.
1.18 “RUO Field” shall mean non-clinical laboratory research.
1.19 “Sell” (and “Sale” and “Sold” as the case may be) shall mean to sell or have sold, to lease or have leased, to import or have imported or otherwise to transfer or have transferred a Product or Process for valuable consideration (in the form of cash or otherwise), and further in the case of a Process to use or perform such Process for the benefit of a third party.
1.20 “Sublicense Income” shall mean consideration in any form received by Company and/or Company’s Affiliate(s) in connection with or otherwise attributable to a grant of a sublicense or any other right, license, privilege or immunity (regardless of whether such grantee is a “Sublicensee” as defined in this Agreement) to make, have made, use, have used, Sell or have Sold Products or Processes, but excluding consideration included within Net Sales. Sublicense Income shall include without limitation any license signing fee, license maintenance fee, unearned portion of any minimum royalty payment, distribution or joint marketing fee, research and development funding in excess of the cost of performing such research and development, and any consideration received for an equity interest in, extension of credit to or other investment
in Company or Company’s Affiliates to the extent such consideration exceeds the fair market value of the equity or other interest received as determined by agreement of the Parties or by an independent appraiser mutually agreeable to the Parties.
1.21 “Sublicensee” shall mean any sublicensee of rights granted in accordance with Section 2.1(a)(ii). For purpose of this Agreement, a Distributor of a Product or Process shall not be included in the definition of Sublicensee unless such Distributor (i) is granted any right to make, have made, use or have used Products or Processes in accordance with Section 2.1(a)(ii), or (ii) has agreed to pay to Company or its Affiliate(s) royalties on such Distributor’s sales of Products or Processes, in which case such Distributor shall be a Sublicensee for all purposes of this Agreement.
1.22 “Technological Information” shall mean research data, designs, formulae, process information and other information pertaining to the invention(s) claimed in the Patent Rights which is created by Drs. Long Le and John Iafrate and owned by Hospital and is not confidential information of or otherwise obligated to any third party and which Drs. Iafrate and Le know as of the Effective Date and reasonably believes is necessary in order for Company to utilize the licenses granted hereunder, as further described in Appendix B. Company agrees to treat all Technological Information in accordance with the provisions of Appendix E.
2.1 Grant of License.
Subject to the terms of this Agreement and Hospital’s rights in Patent Rights, Hospital hereby grants to Company in the License Field in the License Territory:
an exclusive, royalty-bearing license under its rights in Patent Rights to make, have made, use, have used, Sell and have Sold Products and Processes;
the right to grant sublicenses under the rights granted in Section 2.1(a)(i) to Sublicensees, provided that in each case Company shall be responsible for the performance of any obligations of Sublicensees relevant to this Agreement as if such performance were carried out by Company itself, including, without limitation, the payment of any royalties or other payments provided for hereunder, regardless of whether the terms of any sublicense provide for such amounts to be paid by the Sublicensee directly to Hospital; and
the nonexclusive right to use Technological Information disclosed by Hospital to Company hereunder in accordance with this Agreement.
The license granted in Section 2.1(a) above includes:
the right to grant to the final purchaser, user or consumer of Products the right to use such purchased Products in a method coming within the scope of Patent Rights within the License Field and License Territory; and
the right to grant a Distributor the right to Sell (but not to make, have made, use or have used) such Products and/or Processes for or on behalf of Company, its Affiliates and Sublicensees in a manner consistent with this Agreement.
The foregoing license grant shall include the grant of such license to any Affiliate of Company, provided that such Affiliate shall assume the same obligations as those of Company and be subject to the same terms and conditions hereunder; and further provided that Company shall be responsible for the performance of all of such obligations and for compliance with all of such terms and conditions by Affiliate. Company shall provide to Hospital a fully signed, non-redacted copy of each agreement with each Affiliate that assumes the aforesaid obligations, including all exhibits, attachments and related documents and any amendments, within thirty (30) days of request by Hospital.
2.2 Sublicenses. Each sublicense granted hereunder shall be consistent with and comply with all terms of this Agreement, shall incorporate terms and conditions sufficient to enable Company to comply with this Agreement, shall prohibit any further sublicense or assignment by a Sublicensee without Hospital consent and shall provide that Hospital is a third party beneficiary thereof. Any sublicense granted by Company shall be subject to the prior written approval of Hospital, which approval shall not be unreasonably withheld or delayed. Company shall provide to Hospital a fully signed non-redacted copy of all sublicense agreements and amendments thereto, including all exhibits, attachments and related documents, within thirty (30) days of executing the same, Upon termination of this Agreement or any license granted hereunder for any reason, any sublicenses shall be addressed in accordance with Section 10.8. Any sublicense which is not in accordance with the forgoing provisions shall be null and void.
2.3 Retained Rights; Requirements. Any and all licenses granted hereunder are subject to:
the right of Hospital and Hospital’s Affiliates and not-for-profit academic, government and not-for-profit institutions to make and to use the subject matter described and/or claimed in the Patent Rights; and
for Patent Rights supported by federal funding, the rights, conditions and limitations imposed by U.S. law (see 35 U.S.C. § 202 et seq. and regulations pertaining thereto), including without limitation:
the royalty-free non-exclusive license granted to the U.S. government; and
the requirement that any Products used or sold in the United States shall be manufactured substantially in the United States.
2.4 No Additional Rights. It is understood that nothing in this Agreement shall be construed to grant Company or any of its Affiliates a license, express or implied, under any patent owned solely or jointly by Hospital other than the Patent Rights expressly licensed hereunder. Hospital shall have the right to license any Patent Rights to any other party for any purpose outside of the License Field.
2.5 Disclosure of Technological Information. At Company’s request prior to execution of this Agreement, Hospital (through Drs. Le and Iafrate) shall use reasonable efforts to disclose in confidence within thirty (30) days after execution of this Agreement the Technological Information licensed hereunder.
3. DUE DILIGENCE OBLIGATIONS
3.1 Diligence Requirements. Company shall use, and shall cause its Affiliates and Sublicensees, as applicable, to use, commercially reasonable efforts to develop and make available to the public Products and Processes throughout the License Territory in the License Field. Such efforts shall include achieving the following objectives within the time periods designated below following the Effective Date:
Company shall make a First Commercial Sale of a first Product by December 31, 2013, and shall make continuing Sales of such Product without any elapsed time period of one (1) year or more in which such Sales do not occur.
Company shall make a First Commercial Sale of a second Product by December 31, 2014, and shall make continuing Sales of such Product without any elapsed time period of one (1) year or more in which such Sales do not occur.
Company shall make a First Commercial Sale of a Product in the IVD Field by December 31, 2017, and shall make continuing Sales of such Product without any elapsed time period of one (1) year or more in which such Sales do not occur.
Company shall achieve the following levels of Net Sales for the 12 months immediately preceding each of the following dates:
December 31st, 2014
December 31st, 2015
December 31st, 2016
For each subsequent year after year 3, the level of Net Sales shall increase by ten percent (10%) over the Net Sales in the immediately preceding year. For clarity and by way of example, the
Net Sales in Year 5 following the First Commercial Sale will be $18,700,000 and the Net Sales in Year 6 will be $20,570,000.
Achievement of the foregoing objectives shall be deemed to satisfy Company’s obligations to use commercially reasonable efforts under this Section 3.1.
3.2 Diligence Failures. If Hospital determines that Company has failed to fulfill any of its obligations under Section 3.1, then Hospital may treat such failure as a default and may terminate this Agreement and/or any license granted hereunder in accordance with Section 10.4.
3.3 Diligence Reports. Company shall provide all reports with respect to its obligations under Section 3.1 as set forth in Section 5.
4. PAYMENTS AND ROYALTIES
4.1 License Issue Fee. Company shall pay Hospital a non-refundable license issue fee in the amount of [**] upon execution of this Agreement.
4.2 Patent Cost Reimbursement. Company shall reimburse Hospital for all costs associated with the preparation, filing, prosecution and maintenance of all Patent Rights (“Patent Costs”). As of the Effective Date, Hospital has incurred approximately Eight Thousand Two Hundred dollars ($8,200) in Patent Costs, which amount Company shall pay to Hospital upon execution of this Agreement. Company shall pay to Hospital, or at Hospital’s request directly to patent counsel, all other Patent Costs within thirty (30) days of Company’s receipt of an invoice for such Patent Costs either from Hospital or Hospital’s patent counsel. Company agrees to indemnify, defend and hold Hospital harmless from and against any and all liabilities, damages, costs and expenses arising from the failure of Company to timely pay such invoices and Patent Costs. Hospital shall instruct patent counsel to provide copies to Hospital for Hospital’s administrative files of all invoices detailing Patent Costs which are sent directly to Company. If Company pays any Patent Costs directly, Company shall advise patent counsel that Hospital is and shall remain patent counsel’s client.
4.3 Annual License Fee. Company shall pay to Hospital the following non-refundable amounts as an annual license fee within thirty (30) days after each of the following anniversaries of the Effective Date:
the first anniversary of the Effective Date: [**];
the second anniversary of the Effective Date: [**]; and
the third anniversary and each subsequent anniversary of the Effective Date: [**].
Such annual license fees shall be credited against royalties subsequently due on Net Sales made during the same calendar year, if any, but shall not be credited against royalties due on Net Sales made in any other year.
4.4 Milestone Payments. In addition to the payments set forth in Sections 4.1 through 4.3 above, Company shall pay Hospital the following milestone payments:
[**] within sixty (60) days of the First Commercial Sale of a Product in the RUO Field;
[**] within sixty (60) days of the First Commercial Sale of a first Product and for each subsequent Product that are ASRs;
[**] within sixty (60) days of the First Commercial Sale of a first Product that has received Regulatory Approval; and,
[**] within sixty (60) days of the First Commercial Sale of a second Product that has received Regulatory Approval.
The aggregate payments made by Company under this Section 4.4 shall not exceed [**].
4.5 Royalties and Sublicense Income.
Beginning with the First Commercial Sale in any country in the License Territory, Company shall pay Hospital during the term of any license granted under Section 2.1(a)(i), a royalty of [**] of the Net Sales of all Products and Processes. The royalty rates contained in this Section 4.5(a) shall be reduced by fifty percent (50%) on a country-by-country basis for any Product or Process, the manufacture, use, sale, importation or performance of which in or into a specific country is not covered by Patent Rights in such country.
If Company is required to obtain one or more licenses under patents owned by a third party to avoid infringement by any Product or Process of such third party patent, Company may deduct fifty percent (50%) of the amounts owing to such third party from the royalty and other payments owing to Hospital under Section 4.5(a) for such Product. However, the amount to be paid to Hospital under Section 4.5(a) shall not be reduced to less than fifty percent (50%) of the amount that would otherwise be due to Hospital.
Company shall pay Hospital a percentage of all Sublicense Income as follows:
[**] of any Sublicense Income received by Company within five (5) years of the Effective Date; and
[**] of any Sublicense Income received by Company after five (5) years following the Effective Date.
All payments due to Hospital under this Section 4.5 shall be due and payable by Company within thirty (30) days after the end of each Reporting Period, and shall be accompanied by a report as set forth in Sections 5.3 and 5.4.
4.6 Equity Rights. Within 30 days of the Effective Date, Company shall issue to Hospital shares of Company’s common stock (the “Hospital Shares”) in the manner, and with the rights, benefits and preferences, set forth in this Section 4.6.
Equity. The Hospital Shares shall equal [**] of Common Stock of the Company, which represent approximately [**] of the total issued and outstanding capital stock of Company calculated on the date of this Agreement and will represent this same percentage as of the closing date of the sale of substantially all of the Company’s assets related to this Agreement whether by sale, merger, operation of law or otherwise, if such closing date occurs within [three (3) months] after the Effective Date. If such sale does not occur within such three (3) month period, then, if necessary, additional Hospital Shares shall be issued such that the Hospital Shares shall represent at least [**] of the total issued and outstanding capital stock of the Company calculated on a Fully-Diluted Basis (as defined below) until such time as Company has received cash equity in one or more equity financings of at least two million dollars ($2,000,000) (the “Funding Threshold”).
The term “Fully-Diluted Basis” means all of Company’s capital stock either outstanding or reserved for issuance, assuming the exercise of all options, warrants and other convertible securities and the conversion of all preferred stock and convertible debt instruments and assuming the grant of all shares reserved under any equity incentive or similar plans.
Investor Rights Agreements. Hospital and the Hospital Shares will have co-sale and tag-along rights, piggyback registration rights, and information rights with respect to Company’s audited and unaudited financial statements. In addition, if and when Company becomes a party to any investor rights agreement, shareholder agreement or similar agreement (collectively, “Investor Rights Agreements”), Hospital shall also become a party to such agreement with the same rights and obligations as other investors, except that (i) Hospital will not have any demand registration rights, and (ii) such agreements may not limit Hospital’s rights under Section 4.6(d) below. Company will provide Hospital with drafts of all Investor Rights Agreements prior to execution thereof. Hospital’s rights under any Investor Rights Agreement may be amended or waived by a vote of a majority of the shares held by Company’s investors, provided, however, that no waiver or amendment shall adversely affect Hospital’s rights without Hospital’s written consent, such consent not to be unreasonably withheld or delayed except for consents with respect to Section 4.6(d) which shall be in Hospital’s discretion. The Hospital Shares, and Hospital’s rights under all Investor Rights Agreements, shall be transferable to any Affiliate free of any transfer restrictions and to any transferee pursuant to Section 4.6(d) below.
Observer Rights. Hospital shall have the right to send an observer to all Board of Director meetings of Company provided he or she agrees (i) to any confidentiality provisions generally applicable to Company’s directors, and (ii) at the request of
the Board of Directors to recuse himself or herself from any portion of a meeting of the Board of Directors which poses a conflict of interest. Such board observer rights shall terminate upon the first to occur of (i) the third anniversary of the First Commercial Sale of a Product or Process, (ii) such time as Company has Five Million Dollars ($5,000,000) in Net Sales; or (iii) the assignment of this Agreement to a purchaser of substantially all of the Company’s assets related to this Agreement whether by sale, merger, operation of law or otherwise.
Freedom to Transfer Shares if Conflict of Interest. If Hospital’s ownership of the Hospital Shares shall at any time create a conflict of interest affecting Hospital’s ability to conduct clinical trials, clinical studies, clinical research or clinical validation or if Hospital shall otherwise be required to divest itself of the Hospital Shares due to law or Hospital’s conflict of interest policies, then Hospital shall have the right to elect to (i) put the Hospital Shares to Company at a purchase price equal to the Hospital Share Price, which Company may pay by delivery of a promissory note, or (ii) sell the Hospital Shares to any third party free of any restriction and free of any co-sale rights, tag along rights, rights of first offer or first refusal, and free of any other encumbrances or restrictions of Company or its stockholders or investors, provided, however, that Hospital shall use its commercially reasonable good faith efforts to sell the Hospital Shares to a purchaser that is not a direct competitor of Company. Hospital’s rights under this Section 4.6(d) shall terminate on the date on which all of the Hospital Shares are freely saleable on the public markets pursuant to Rule 144 promulgated under the Securities Act of 1933, as amended.
4.7 Form of Payment. All payments due under this Agreement shall be drawn on a United States bank and shall be payable in United States dollars. Each payment shall reference this Agreement and its Agreement Number and identify the obligation under this Agreement that the payment satisfies. Conversion of foreign currency to U.S. dollars shall be made at the conversion rate existing in the United States, as reported in The Wall Street Journal, on the last working day of the applicable Reporting Period. Such payments shall be without deduction of exchange, collection or other charges, and, specifically, without deduction of withholding or similar taxes or other government imposed fees or taxes, except as permitted in the definition of Net Sales.
Checks for all payments due to the Hospital under this Agreement shall be made payable to the Hospital and addressed as set forth below:
Massachusetts General Hospital
Payments via wire transfer should be made as follows:
4.8 Overdue Payments. The payments due under this Agreement shall, if overdue, bear interest beginning on the first day following the Reporting Period to which such payment was incurred and until payment thereof at a per annum rate equal to two percent (2%) above the prime rate in effect on the due date as reported by The Wall Street Journal, such interest rate being compounded on the last day of each Reporting Period, not to exceed the maximum permitted by law. Any such overdue payments when made shall be accompanied by all interest so accrued. Said interest and the payment and acceptance thereof shall not preclude Hospital from exercising any other rights it may have as a consequence of the lateness of any payment.
5. REPORTS AND RECORDS
5.1 Diligence Reports. Within sixty (60) days after the end of each calendar year, Company shall report in writing to Hospital on progress made toward the objectives set forth in Section 3.1 during such preceding 12 month period, including, without limitation, progress on research and development, status of applications for regulatory approvals, manufacturing, sublicensing and the number of sublicenses entered into and marketing. All diligence reports shall be considered the Confidential Information of Company.
5.2 Milestone Achievement Notification. Company shall report to Hospital the dates on which it achieves the milestones set forth in Section 4.4 within sixty (60) days of each such occurrence.
5.3 Sales Reports. Company shall report to Hospital the date of the First Commercial Sale in each country of the License Territory within thirty (30) days of each such occurrence. Following the First Commercial Sale, Company shall deliver reports to Hospital within thirty (30) days after the end of each Reporting Period. Each report under this Section 5.4 shall have substantially the format outlined in Appendix C, shall be certified as correct by an officer of Company and shall contain at least the following information as may be pertinent to a royalty accounting hereunder for the immediately preceding Reporting Period:
the number of Products and Processes Sold by Company, its Affiliates and Sublicensees in each country;
the amounts billed, invoiced and received by Company, its Affiliates and Sublicensees for each Product and Process, in each country, and total billings or payments due or made for all Products and Processes;
calculation of Net Sales for the applicable Reporting Period in each country, including an itemized listing of permitted offsets and deductions;
total royalties payable on Net Sales in U.S. dollars, together with the exchange rates used for conversion; and
any other payments due to Hospital under this Agreement.
If no amounts are due to Hospital for any Reporting Period, the report shall so state. All sales reports shall be considered the Confidential Information of Company.
5.4 Sublicense Income Reports. Company shall, along with delivering payment as set forth in Section 4.6, report to Hospital within thirty (30) days of receipt the amount of all Sublicense Income received by Company, and Company’s calculation of the amount due and paid to Hospital from such income, including an itemized listing of the source of income comprising such consideration, and the name and address of each entity making such payments in substantially the format outlined in Appendix D. All sublicense income reports shall be considered the Confidential Information of Company.
5.5 Audit Rights. Company shall maintain, and shall cause each of its Affiliates and Sublicensees to maintain, complete and accurate records relating to the rights and obligations under this Agreement and any amounts payable to Hospital in relation to this Agreement, which records shall contain sufficient information to permit Hospital and its representatives to confirm the accuracy of any payments and reports delivered to Hospital and compliance in all other respects with this Agreement. Company shall retain and make available, and shall cause each of its Affiliates and Sublicensees to retain and make available, such records for at least three (3) years following the end of the calendar year to which they pertain, to an independent certified public account selected by Hospital and reasonably acceptable to Company and upon at least fifteen (15) days’ advance written notice, for inspection during normal business hours, to verify any reports and payments made and/or compliance in other respects under this Agreement. If any examination conducted by Hospital’s representatives pursuant to the provisions of this Section show an underreporting or underpayment of five percent (5%) or more in any payment due to Hospital hereunder, Company shall bear the full cost of such audit and shall remit any amounts due to Hospital (including interest due in accordance with Section 4.7) within thirty (30) days of receiving notice thereof from Hospital.
6. PATENT PROSECUTION AND MAINTENANCE
6.1 Prosecution. Hospital shall be responsible for the preparation, filing, prosecution and maintenance of all patent applications and patents included in Patent Rights using patent counsel reasonably acceptable to Company. Company shall reimburse Hospital for Patent Costs incurred by Hospital relating thereto in accordance with Section 4.2.
6.2 Copies of Documents. With respect to any Patent Right licensed hereunder, Hospital shall instruct the patent counsel prosecuting such Patent Right to (i) copy Company on patent prosecution documents that are received from or filed with the United States Patent and Trademark Office and any foreign equivalent, as applicable; (ii) if requested by Company,
provide Company with copies of draft submissions to the USPTO prior to filing; and (iii) give reasonable consideration to the comments and requests of Company or its patent counsel.
6.3 Company’s Election Not to Proceed. Company may elect to surrender any patent or patent application in the Patent Rights in any country upon sixty (60) days’ advance written notice to Hospital. Such notice shall relieve Company from the obligation to pay for future Patent Costs but shall not relieve Company from responsibility to pay Patent Costs incurred prior to the expiration of the sixty (60) day notice period. Upon expiration of such notice period: such U.S. or foreign patent application or patent shall thereupon cease to be a Patent Right hereunder and Company shall have no further rights therein; and Hospital shall be free to license its rights to that particular U.S. or foreign patent application or patent to any other party on any terms.
6.4 Confidentiality of Prosecution and Maintenance Information. Company agrees to treat all information related to prosecution and maintenance of Patent Rights as Confidential Information in accordance with the provisions of Appendix E.
7. THIRD PARTY INFRINGEMENT AND LEGAL ACTIONS
7.1 Hospital Right to Prosecute. Hospital will protect its Patent Rights from infringement and prosecute infringers when, in its sole judgment, such action may be reasonably necessary, proper and justified. If Company shall have supplied Hospital with written evidence demonstrating to Hospital’s reasonable satisfaction prima facie infringement of a claim of a Patent Right in the License Field in the License Territory by a third party which poses a material threat to Company’s rights under this Agreement, Company may by notice request Hospital to take steps to enforce such Patent Right against such alleged third party infringer. Hospital shall notify Company within three (3) months of the receipt of such notice whether Hospital intends to prosecute the alleged infringement. If Hospital notifies Company that it intends to so prosecute, Hospital shall, within three (3) months of its notice to Company either (i) cause such infringement to terminate, or (ii) initiate legal proceedings against the infringer.
7.2 Company Right to Prosecute. In the event Hospital notifies Company that Hospital does not intend to prosecute infringement identified under Section 7.1, Company may, upon notice to Hospital, initiate legal proceedings against the infringer at Company’s expense with respect to a claim of a Patent Right in the License Field in the License Territory. Before commencing such action, Company and, as applicable, any Affiliate, shall consult with Hospital, concerning, among other things, Company’s standing to bring suit, the advisability of bringing suit, the selection of counsel and the jurisdiction for such action and shall use reasonable efforts to accommodate the views of Hospital regarding the proposed action, including without limitation with respect to potential effects on the public interest. Company shall be responsible for all costs, expenses and liabilities in connection with any such action and shall indemnify and hold Hospital harmless therefrom, regardless of whether Hospital is a party-plaintiff, except for the expense of any independent counsel retained by Hospital in accordance with Section 7.5 below.
7.3 Hospital Joined as Party-Plaintiff. If Company elects to commence an action as described in Section 7.2 above, Hospital shall have, in its sole discretion, the option to join such
action as a party-plaintiff. If Hospital is required by law to join such action as a party-plaintiff, Hospital may either, in its sole discretion, permit itself to be joined as a party-plaintiff at the sole expense of Company, or assign to Company all of Hospital’s right, title and interest in and to the Patent Right which is the subject of such action (subject to all of Hospital’s obligations to the government under law and any other rights that others may have in such Patent Right). If Hospital makes such an assignment, such action by Company shall thereafter be brought or continued without Hospital as a party; provided, however, that Hospital shall continue to have all rights of prosecution and maintenance with respect to Patent Rights and Company shall continue to meet all of its obligations under this Agreement as if the assigned Patent Right were still licensed to Company hereunder. For clarity, Hospital’s right to assign to Sponsor all of Hospital’s right, title and interest in and to the Patent Right(s) which are the subject of an enforcement action is predicated upon such assignment being sufficient to resolve all issues surrounding Sponsor’s standing to enforce such Patent Right(s). To the extent such assignment would not resolve such issues, Hospital agrees to permit itself to be joined as a party-plaintiff at the sole expense of Sponsor.
7.4 Notice of Actions; Settlement. Company shall promptly inform Hospital of any action or suit relating to Patent Rights and shall not enter into any settlement, consent judgment or other voluntary final disposition of any action relating to Patent Rights, including but not limited to appeals, without the prior written consent of Hospital.
7.5 Cooperation. Each Party agrees to cooperate reasonably in any action under Section 7 which is controlled by the other Party, provided that the controlling party reimburses the cooperating party for any costs and expenses incurred by the cooperating party in connection with providing such assistance, except for the expense of any independent counsel retained by the cooperating party in accordance with this Section 7.5. Such controlling party shall keep the cooperating party informed of the progress of such proceedings and shall make its counsel available to the cooperating party. The cooperating party shall also be entitled to independent counsel in such proceedings but at its own expense, said expense to be offset against any damages received by the Party bringing suit in accordance with Section 7.6.
7.6 Recovery. Any award paid by third parties as the result of such proceedings (whether by way of settlement or otherwise) shall first be applied to reimbursement of any legal fees and expenses incurred by either Party and then the remainder shall be divided between the Parties as follows:
(a) for any amounts other than punitive damages, any remainder after expenses shall be treated as Net Sales, and Company shall pay royalties on such Net Sales to Hospital as provided in Section 4.5(a); and
for any punitive damages received, remaining after Company and Hospital have been compensated under Section 7.6(a) shall be shall be shared equally by the Parties.
8. INDEMNIFICATION AND INSURANCE
Company shall indemnify, defend and hold harmless Hospital and its Affiliates and their respective trustees, directors, officers, medical and professional staff, employees, and agents and their respective successors, heirs and assigns (the “Indemnitees”), against any liability, damage, loss or expense (including reasonable attorney’s fees and expenses of litigation) incurred by or imposed upon the Indemnitees or any one of them in connection with any claims, suits, actions, demands or judgments arising out of any theory of product liability (including, but not limited to, actions in the form of contract, tort, warranty, or strict liability) concerning any product, process or service made, used, or sold or performed pursuant to any right or license granted under this Agreement.
Company agrees, at its own expense, to provide attorneys reasonably acceptable to the Hospital to defend against any actions brought or filed against any party indemnified hereunder with respect to the subject of indemnity contained herein, whether or not such actions are rightfully brought; provided, however, that any Indemnitee shall have the right to retain its own counsel, at the expense of Company, if representation of such Indemnitee by counsel retained by Company would be inappropriate because of conflict of interests of such Indemnitee and any other party represented by such counsel. Company agrees to keep Hospital informed of the progress in the defense and disposition of such claim and to consult with Hospital prior to any proposed settlement.
This section 8.1 shall survive expiration or termination of this Agreement.
Beginning at such time as any such product, process or service is being commercially distributed, sold, leased or otherwise transferred, or performed or used (other than for the purpose of obtaining regulatory approvals), by Company, an Affiliate or Sublicensee, Company shall, at its sole cost and expense, procure and maintain commercial general liability insurance in amounts not less than [**] per incident and [**] annual aggregate and naming the Indemnitees as additional insureds. Such commercial general liability insurance shall provide (i) product liability coverage and (ii) broad form contractual liability coverage for Company’s indemnification under Section 8.1 of this Agreement. If Company elects to self-insure all or part of the limits described above (including deductibles or retentions which are in excess of [**] annual aggregate) such self-insurance program must be acceptable to the Hospital and the Risk Management Foundation. The minimum amounts of insurance coverage required under this Section 8.2 shall not be construed to create a limit of Company’s liability with respect to its indemnification under Section 8.1 of this Agreement.
Company shall provide Hospital with written evidence of such insurance upon request of Hospital. Company shall provide Hospital with written notice at least fifteen (15) days prior to the cancellation, non-renewal or material change in such insurance; if Company does not obtain replacement insurance providing comparable coverage prior to the expiration of such fifteen (15) day period, Hospital shall have the right to terminate this Agreement effective at the end of such fifteen (15) day period without notice or any additional waiting periods.
Company shall maintain such commercial general liability insurance beyond the expiration or termination of this Agreement during (i) the period that any such product, process, or service is being commercially distributed, sold, leased or otherwise transferred, or performed or used (other than for the purpose of obtaining regulatory approvals), by Company or by a licensee, affiliate or agent of Company and (ii) a reasonable period after the period referred to in (c) (i) above which in no event shall be less than fifteen (15) years.
This section 8.2 shall survive expiration or termination of this Agreement.
9. DISCLAIMER OF WARRANTIES; LIMITATION OF LIABILITY
9.1 Title to Patent Rights. To the best knowledge of Hospital’s Office of Research, Ventures and Licensing, Hospital is the owner by assignment from Dr. John Iafrate, Dr. Long Le and Dr. Zongli Zheng of the Patent Rights and has the authority to enter into this Agreement and license the Patent Rights to Company hereunder.
9.2 No Warranties. HOSPITAL MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED, CONCERNING THE PATENT RIGHTS AND THE RIGHTS GRANTED HEREUNDER, INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NONINFRINGEMENT, VALIDITY OF PATENT RIGHTS CLAIMS, WHETHER ISSUED OR PENDING, AND THE ABSENCE OF LATENT OR OTHER DEFECTS, WHETHER OR NOT DISCOVERABLE, AND HEREBY DISCLAIMS THE SAME. SPECIFICALLY, AND NOT TO LIMIT THE FOREGOING, HOSPITAL MAKES NO WARRANTY OR REPRESENTATION (i) REGARDING THE VALIDITY OR SCOPE OF ANY OF THE CLAIM(S), WHETHER ISSUED OR PENDING, OF ANY OF THE PATENT RIGHTS, AND (ii) THAT THE EXPLOITATION OF THE PATENT RIGHTS OR ANY PRODUCT WILL NOT INFRINGE ANY PATENTS OR OTHER INTELLECTUAL PROPERTY RIGHTS OF HOSPITAL OR OF ANY THIRD PARTY.
9.3 Limitation of Liability. IN NO EVENT SHALL HOSPITAL OR ANY OF ITS AFFILIATES OR ANY OF THEIR RESPECTIVE TRUSTEES, DIRECTORS, OFFICERS, MEDICAL OR PROFESSIONAL STAFF, EMPLOYEES AND AGENTS BE LIABLE TO LICENSEE OR ANY OF ITS AFFILIATES, SUBLICENSEES OR DISTRIBUTORS FOR INDIRECT, SPECIAL, INCIDENTAL OR CONSEQUENTIAL DAMAGES OF ANY KIND ARISING IN ANY WAY OUT OF THIS AGREEMENT OR THE LICENSE OR RIGHTS
GRANTED HEREUNDER, HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, INCLUDING WITHOUT LIMITATION ECONOMIC DAMAGES OR INJURY TO PROPERTY OR LOST PROFITS, REGARDLESS OF WHETHER HOSPITAL SHALL BE ADVISED, SHALL HAVE OTHER REASON TO KNOW, OR IN FACT SHALL KNOW OF THE POSSIBILITY OF THE FOREGOING.
10. TERM AND TERMINATION
10.1 Term. The term of this Agreement shall commence on the Effective Date and shall remain in effect until the later of the date on which all issued patents and filed patent applications within the Patent Rights have expired or been abandoned, unless this Agreement is terminated earlier in accordance with any of the other provisions of Section 10.
10.2 Termination for Failure to Pay. If Company fails to make any payment due hereunder, Hospital shall have the right to terminate this Agreement upon ten (10) business days written notice, unless Company makes such payments plus any interest due, as set forth in Section 4.7, within said ten (10) day notice period. If payments are not made, Hospital may immediately terminate this Agreement at the end of said ten (10) day period. Company shall be entitled to only one such cure period in a calendar year; for a second failure to make payment on time, Hospital shall have the right to terminate this Agreement immediately upon written notice.
10.3 Termination for Insurance and Insolvency.
Insurance. Hospital shall have the right to terminate this Agreement in accordance with Section 8.2(b) if Company fails to maintain the insurance required by Section 8.2.
Insolvency and other Bankruptcy Related Events. Hospital shall have the right to terminate this Agreement immediately upon written notice to Company with no further notice obligation or opportunity to cure if Company: (i) shall become insolvent; (ii) shall make an assignment for the benefit of creditors; or (iii) or shall have a petition in bankruptcy filed for or against it.
10.4 Termination for Non-Financial Default. If Company, any of its Affiliates or any Sublicensee shall default in the performance of any of its other obligations under this Agreement not otherwise covered by the provisions of Section 10.2 and 10.3, and if such default has not been cured within sixty (60) days after notice by Hospital in writing of such default, Hospital may immediately terminate this Agreement, and/or any license granted hereunder with respect to the country or countries in which such default has occurred, at the end of said sixty (60) day cure period. Hospital shall also have the right to terminate this Agreement and/or any such license immediately, upon written notice, in the event of repeated defaults even if cured within such sixty (60) day periods.
10.5 Challenging Validity. During the term of this Agreement, Company shall not challenge, and shall restrict Company Affiliates and Sublicensees from challenging, the validity of the
Patent Rights and in the event of any breach of this provision Hospital shall have the right to terminate this Agreement and any license granted hereunder immediately. In addition, if the Patent Rights are upheld Company shall reimburse Hospital for its legal costs and expenses incurred in defending any such challenge.
10.6 Termination by Company. Company shall have the right to terminate this Agreement by giving ninety (90) days advance written notice to Hospital and upon such termination shall immediately cease all use and Sales of Products and Processes, subject to Section 10.9.
10.7 Effect of Termination on Sublicenses. Any sublicenses granted by Company under this Agreement shall provide for termination or assignment to Hospital of Company’s interest therein, at the option of Hospital, upon termination of this Agreement or upon termination of any license hereunder under which such sublicense has been granted.
10.8 Effects of Termination of Agreement. Upon termination of this Agreement or any of the licenses hereunder for any reason, final reports in accordance with Section 5 shall be submitted to Hospital and all royalties and other payments, including without limitation any unreimbursed Patent Costs, accrued or due to Hospital as of the termination date shall become immediately payable. Company shall cease, and shall cause its Affiliates and Sublicensees to cease under any sublicense granted by Company, all Sales and uses of Products and Processes upon such termination, subject to Section 10.9. The termination or expiration of this Agreement or any license granted hereunder shall not relieve Company, its Affiliates or Sublicensees of obligations arising before such termination or expiration.
10.9 Inventory. Upon early termination of this Agreement other than for Company default, Company, Company Affiliates and Sublicensees may complete and sell any work-in-progress and inventory of Products that exist as of the effective date of termination provided that (i) Company pays Hospital the applicable running royalty or other amounts due on such Net Sales in accordance with the terms and conditions of this Agreement, and (ii) Company, Company Affiliates and Sublicensees shall complete and sell all work-in-progress and inventory of Products within six (6) months after the effective date of termination. Upon expiration of this Agreement, Company shall pay to Hospital the royalties set forth in Section 4.5(a) for Sales of any Product that was in inventory or was a work-in-progress on the date of expiration of the Agreement.
11. COMPLIANCE WITH LAW
11.1 Compliance. Company shall have the sole obligation for compliance with, and shall ensure that any Affiliates and Sublicensees comply with, all government statutes and regulations that relate to Products and Processes, including, but not limited to, those of the Food and Drug Administration and the Export Administration, as amended, and any applicable laws and regulations of any other country in the License Territory. Company agrees that it shall be solely responsible for obtaining any necessary licenses to export, re-export, or import Products or Processes covered by Patent Rights and/or Technological Information. Company shall
indemnify and hold harmless Hospital for any breach of Company’s obligations under this Section 11.1.
11.2 Patent Numbers. Company shall cause all Products sold in the United States to be marked with all applicable U.S. Patent Numbers, to the full extent required by United States law. Company shall similarly cause all Products shipped to or sold in any other country to be marked in such a manner as to conform with the patent laws and practices of such country.
12.1 Entire Agreement. This Agreement constitutes the entire understanding between the Parties with respect to the subject matter hereof.
12.2 Notices. Any notices, reports, waivers, correspondences or other communications required under or pertaining to this Agreement shall be in writing and shall be delivered by hand, or sent by a reputable overnight mail service (e.g., Federal Express), or by first class mail (certified or registered), or by facsimile confirmed by one of the foregoing methods, to the other party. Notices will be deemed effective (a) three (3) working days after deposit, postage prepaid, if mailed, (b) the next day if sent by overnight mail, or (c) the same day if sent by facsimile and confirmed as set forth above or delivered by hand. Unless changed in writing in accordance with this Section, the notice address for Hospital shall be as follows:
Executive Director, Research Ventures and Licensing
Massachusetts General Hospital
101 Huntington Avenue, 4th Floor
Boston, MA 02199
Fax No. (617) 954-9361
Unless changed in writing in accordance with this Section, the notice address for Company shall be as follows:
16042 W. 59th Ave.
Golden, CO 80403
Attn: Jason Myers
12.3 Amendment; Waiver. This Agreement may be amended and any of its terms or conditions may be waived only by a written instrument executed by an authorized signatory of the Parties or, in the case of a waiver, by the Party waiving compliance. The failure of either Party at any time or times to require performance of any provision hereof shall in no manner affect its rights at a later time to enforce the same. No waiver by either Party of any condition or term shall be deemed as a further or continuing waiver of such condition or term or of any other condition or term.
12.4 Binding Effect. This Agreement shall be binding upon and inure to the benefit of and be enforceable by the Parties hereto and their respective permitted successors and assigns.
12.5 Assignment. Company shall not assign this Agreement or any of its rights or obligations under this Agreement without the prior written consent of Hospital; provided, however, that if Company has fulfilled its diligence obligations as set forth in Section 3, no such consent will be required to assign this Agreement to a successor of the Company’s business to which this Agreement pertains or to a purchaser of substantially all of the Company’s assets related to this Agreement whether by sale, merger, operation of law or otherwise; provided that such successor or purchaser shall agree in writing to be bound by all of the terms and conditions of this Agreement. Company shall notify Hospital in writing of any such assignment and provide a copy of all assignment documents and related agreements to Hospital within thirty (30) days after such assignment. Failure of an assignee to agree to be bound by the terms hereof or failure of Company to notify hospital and provide copies of assignment documentation shall be grounds for termination of this Agreement for default. Further, neither any rights granted under this Agreement nor any sublicense may be assigned by any Sublicensee without the prior written consent of Hospital.
12.6 Force Majeure. Neither Party shall be responsible for delays resulting from causes beyond the reasonable control of such Party, including without limitation fire, explosion, flood, war, sabotage, strike or riot, provided that the nonperforming Party uses commercially reasonable efforts to avoid or remove such causes of nonperformance and continues performance under this Agreement with reasonable dispatch whenever such causes are removed.
12.7 Use of Name. Neither Party shall .use the name of the other Party or of any trustee, director, officer, staff member, employee, student or agent of the other Party or any adaptation thereof in any advertising, promotional or sales literature, publicity or in any document employed to obtain funds or financing without the prior written approval of the Party or individual whose name is to be used. For Hospital, such approval shall be obtained from Hospital’s VP of Public Affairs.
12.8 Governing Law. This Agreement shall be governed by and construed and interpreted in accordance with the laws of the Commonwealth of Massachusetts, excluding with respect to conflict of laws , except that questions affecting the construction and effect of any patent shall be determined by the law of the country in which the patent shall have been granted. Each Party agrees to submit to the exclusive jurisdiction of the Superior Court for Suffolk County, Massachusetts, and the United States District Court for the District of Massachusetts with respect to any claim, suit or action in law or equity arising in any way out of this Agreement or the subject matter hereof.
12.9 Hospital Policies. Company acknowledges that Hospital’s employees and medical and professional staff members and the employees and staff members of Hospital’s Affiliates are subject to the applicable policies of Hospital and such Affiliates, including, without limitation, policies regarding conflicts of interest, intellectual property and other matters. Company shall
provide Hospital with any agreement it proposes to enter into with any employee or staff member of Hospital or any of Hospital’s Affiliates for Hospital’s prior review and shall not enter
into any oral or written agreement with such employee or staff member which conflicts with any such policy. Hospital shall provide Company, at Company’s request, with copies of any such policies applicable to any such employee or staff member.
12.10 Severability. If any provision(s) of this Agreement are or become invalid, are ruled illegal by any court of competent jurisdiction or are deemed unenforceable under then current applicable law from time to time in effect during the term hereof, it is the intention of the parties that the remainder of this Agreement shall not be effected thereby. It is further the intention of the parties that in lieu of each such provision which is invalid, illegal or unenforceable, there be substituted or added as part of this Agreement a provision which shall be as similar as possible in economic and business objectives as intended by the parties to such invalid, illegal or enforceable provision, but shall be valid, legal and enforceable.
12.11 Survival. In addition to any specific survival references in this Agreement, Sections 1, 2.4, 4.2 (solely with respect to costs incurred prior to termination), 4.6, 4.7, 4.8, 5.3, 5.4, 5.5, 6.4, 8.1, 8.2, 9.2, 9.3, 10.8, 10.9, 10.10, 12.1, 12.2, 12.3, 12.4, 12.7, 12.8, 12.9, 12.10, 12.11, 12.12 and 12.13 shall survive termination or expiration of this Agreement. Any other rights, responsibilities, obligations, covenants and warranties which by their nature should survive this Agreement shall similarly survive and remain in effect.
12.12 Interpretation. The parties hereto are sophisticated, have had the opportunity to consult legal counsel with respect to this transaction and hereby waive any presumptions of any statutory or common law rule relating to the interpretation of contracts against the drafter.
12.13 Headings. All headings are for convenience only and shall not affect the meaning of any provision of this Agreement.
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IN WITNESS WHEREOF, the Parties have caused this Agreement to be executed by their duly authorized representatives as of the Effective Date first written above.
ARCHER DX, INC.
The General Hospital Corporation
/s/ Jason Meyers
/s/ Irene Abrams
Director, Partners HealthCare Research
Ventures & Licensing
July 31, 2013
July 23, 2013
DESCRIPTION OF PATENT RIGHTS
DESCRIPTION OF TECHNOLOGICAL INFORMATION
Molecular profiling of patient tumor specimens for gene fusions is critical in determining clinical response to a growing number of kinase inhibitors (e.g. ABL, ALK, ROS1, RET). With limited laboratory resources and limited tumor tissue as a challenge, simultaneously detecting multiple actionable genetic mutations will become more important in the era of targeted therapy in cancer. Next-generation sequencing (NGS) is a promising tool in translating rapidly-advancing cancer genomic data into the clinic. However, sequencing whole genomes routinely or for a large number of samples is still impractical in the clinic. Deep sequencing of a subset of the genome is currently a time- and cost-effective approach to detect variants in regions of interest. In particular, low-level somatic variants could be missed by whole genome sequencing with limited coverage depth, but can be efficiently identified by targeted sequencing to a high coverage.
Current clinic assays for the detection of gene rearrangements include fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RT-PCR, each associated with its own challenges. FISH has limited scalability for increasing volumes of diagnosis requests due to its low throughput, high cost and expertise, and IHC is often limited by high-performance rearrangement-specific antibodies. FISH and IHC do not provide information on fusion breakpoints, which are important to know as they may underlie the heterogeneity in treatment responses observed in the clinics, as suggested by in vitro observation that different variants of ALK-EML4 fusion proteins showed different sensitivities to ALK inhibitors. RT-PCR requires knowing both fusion partners, limiting its utility when there are numerous partners and numerous breakpoint variants for each partner.
The technology developed by Drs. Le, Zheng and Iafrate represents a PCR-based library preparation method for Next Generation Sequencing using highly-multiplexed amplification of gene targets, a method termed “Anchored Multiplex PCR” or “AMP” that addresses many of the limitations of current targeted approaches. AMP was designed to profile known actionable genetic alterations, including gene rearrangements (needing only to know one partner in the fusion event), point mutations, small or large insertions and deletions (indels) and copy number changes. The assay is designed for low starting amounts (-50 ng DNA) and low quality FFPE specimens, allowing for robust performance across various clinical sample types with a rapid turnaround time. AMP is a method to construct targeted sequencing libraries for next generation sequencing (NGS) in which a single type of double-stranded DNA adapter (containing one sequencing primer) is ligated to the double-stranded DNA (gDNA or cDNA) template. Two rounds of PCR nested on both sides are performed with pools of gene specific primers (GSP1s and GSP2s). GSP2 contains the second sequencing primer sequence, thus allowing a fully-competent sequencing library to be completed. Since one side of each and any of multiple fragments has a specific gene specific sequence (the anchor) and the other side has a randomly ligated adaptor, it is termed anchored multiplex PCR.
The method is easily customizable with standard molecular biology reagents, and allows multiplexing of over 600 amplicons, with high on-target rate (average 88%) and uniform coverage. Nearly 100% of targeted bases had >100X coverage and 95% had >500X. Different targeted RNA-seq and gDNA-seq panels have been designed and detected various genetic variants including large insertion and deletions, and known gene rearrangements (including ALK, RET and ROS1 fusions in lung cancer) and also previously unknown fusion partners. The assay performed as well as gold-standard fusion detection methods (i.e. FISH) in a panel of over 150 FFPE samples, and novel MSN–ROS1 gene fusion was detected in lung cancer as evidence of the utility of the technique.
Also included in this license is a method modification termed AMP2, which simplifies the method and improves its ability to use poor quality archived nucleic acid which is critical to certain applications (e.g. clinical tumor genotyping). A new synthetic oligonucleotide design for incorporating the first sequencing primer into the library consists of a primer with a 5’ sequencing primer sequence (can be Illumina, Roche, Life Technologies, Ion Torrent or any other NGS method-compatible primer) and a 3’ sequence containing at least 6 random nucleotides (can be up to 12 nucleotides). Step one involves incubation of this oligonucleotide primer with the template DNA (gDNA or cDNA is acceptable), annealing of the oligonucleotide primer randomly with the template, and extension of the primer using a DNA polymerase. Following removal of the unincorporated primers, the new extension products can be used in the original AMP protocol starting at the GSP1 PCR step. This new methods allows one to avoid mechanical or enzymatic shearing, end-repair, A-tailing, ligation of adapters, and multiple clean‑
up steps. The AMP2 method will also have the advantage of utilizing a random 6 to 12mer sequencing that will be sequenced and could serve as a unique molecular barcode, allowing bioinformatic algorithms to improve variant calling accuracy for both single nucleotide, indel, and copy number variants. Thus AMP2 provides a simplified targeted library construction method with improved performance for nucleic acid from archived material regardless if they are in double-stranded or single-stranded form (see below), and allows for higher-quality variant/mutation assessment.
Both AMP and AMP2 will allow for targeted sequencing libraries to be generated from a variety of samples for a variety of sequencing techniques. While the methods were developed with cancer genotyping in mind, the assay can be used for germline human, and any non-human enriched sequencing approaches. The method should be compatible with sequencing genomic DNA as starting material, but also RNA (once converted to cDNA) for mutation analysis of RNA and RNA expression.
[Information included in this Schedule has been omitted in accordance with Item 601(a)(5) of Regulation S-K]
[Information included in this Schedule has been omitted in accordance with Item 601(a)(5) of Regulation S-K]
CONFIDENTIALITY TERMS AND CONDITIONS
1. Definition of Confidential Information. “Confidential Information” shall mean any information, including but not limited to data, techniques, protocols or results, or business, financial, commercial or technical information, disclosed by one Party (each a “Discloser” as applicable) to the other Party (each a “Recipient” as applicable) in connection with the terms of that certain Exclusive License Agreement dated July 23, 2013 (the “License Agreement”) and identified as confidential at the time of disclosure (the “Purpose”). Hospital’s Confidential Information shall also include all information disclosed by Hospital to Company in connection with the Patent Rights. Capitalized terms used in this Appendix that are not otherwise defined herein have the meanings ascribed in the License Agreement to which this Appendix is attached and made a part thereof.
2. Exclusions. “Confidential Information” under this Agreement shall not include any information that (i) is or becomes publicly available through no wrongful act of Recipient; (ii) was known by Recipient prior to disclosure by Discloser, as evidenced by tangible records; (iii) becomes known to Recipient after disclosure from a third party having an apparent bona fide right to disclose it; (iv) is independently developed or discovered by Recipient without use of Discloser’s Confidential Information, as evidenced by tangible records; or (v) is disclosed to another party by Discloser without restriction on further disclosure. The obligations of confidentiality and non-use set forth in this Agreement shall not apply with respect to any information that Recipient is required to disclose or produce pursuant to applicable law, court order or other valid legal process provided that Recipient promptly notifies Discloser prior to such required disclosure, discloses such information only to the extent so required and cooperates reasonably with Discloser’s efforts to contest or limit the scope of such disclosure.
3. Permitted Purpose. Recipient shall have the right to, and agrees that it will, use Discloser’s Confidential Information solely for the Purpose as described in the License Agreement, except as may be otherwise specified in a separate definitive written agreement negotiated and executed between the parties.
4. Restrictions. For the term of the License Agreement and a period of three (3) years thereafter (and indefinitely with respect to any individually identifiable health information disclosed by Hospital to Company, if any), each Recipient agrees that: (i) it will not use such Confidential Information for any purpose other than as specified herein, including without limitation for its own benefit or the benefit of any other person or entity; and (ii) it will use reasonable efforts (but no less than the efforts used to protect its own confidential and/or proprietary information of a similar nature) not to disclose such Confidential Information to any other person or entity except as expressly permitted hereunder. Recipient may, however, disclose Discloser’s Confidential Information only on a need-to-know basis to its and its Affiliates employees, staff members and agents (“Receiving
Individuals”) who are directly participating in the Purpose and who are informed of the confidential nature of such information, provided Recipient shall be responsible for compliance by Receiving Individuals with the terms of this Agreement and any breach thereof. Each party further agrees not to use the name of the other party or any of its Affiliates or any of their respective trustees, directors, officers, staff members, employees, students or agents in any advertising, promotional or sales literature, publicity or in any document employed to obtain funds or financing without the prior written approval of the party or individual whose name is to be used, in the case of Hospital such approval to be given by the Public Affairs Department. This Section 4 shall survive termination or expiration of this Agreement.
5. Right to Disclose. Discloser represents that to the best of its knowledge it has the right to disclose to each Recipient all of Discloser’s Confidential Information that will be disclosed hereunder.
6. Ownership. All Confidential Information disclosed pursuant to this Agreement, including without limitation all written and tangible forms thereof, shall be and remain the property of the Discloser. Upon termination of this Agreement, if requested by Discloser, Recipient shall return or destroy at Discloser’s discretion all of Discloser’s Confidential Information, provided that Recipient shall be entitled to keep one copy of such Confidential Information in a secure location solely for the purpose of determining Recipient’s legal obligations hereunder.
7. No License. Nothing in this Agreement shall be construed as granting or conferring, expressly or impliedly, any rights by license or otherwise, under any patent, copyright, or other intellectual property rights owned or controlled by Discloser relating to Confidential Information, except as specifically set forth in the License Agreement.
8. Remedies. Each party acknowledges that any breach of this Agreement by it may cause irreparable harm to the other party and that each party is entitled to seek injunctive relief and any other remedy available at law or in equity.
9. General. These Confidentiality Terms and Conditions, along with the License Agreement, contain the entire understanding of the parties with respect to the subject matter hereof, and supersede any prior oral or written understandings between the parties relating to confidential treatment of information. Sections 1, 2, 4, 6, 8 and 9 of these Confidentiality Terms and Conditions shall survive any expiration or termination of the License Agreement.