Exhibit 10.35
EXECUTION COPY
RESEARCH AGREEMENT
RESEARCH AGREEMENT (this "AGREEMENT"), dated as of August 9, 2005 (the
"EFFECTIVE DATE"), by and between CombinatoRx, Incorporated, a Delaware
corporation (the "COMPANY"), and CHDI, Inc., a New Jersey corporation (the
"FOUNDATION"). The Company and the Foundation shall hereinafter be referred to
individually as a "PARTY" and collectively as the "PARTIES".
The Foundation supports basic, applied and clinical research aimed at
finding diagnoses, treatments, cures and preventions of Huntington's disease.
The Company is a biopharmaceutical company focused on developing new
medicines built from synergistic combinations of approved drugs.
The Foundation has chosen the Company as a strategic partner to collaborate
with the Foundation on a program to find and develop drugs for Huntington's
disease.
To further the Foundation's objective, the Foundation desires to engage the
Company to conduct certain research and the Company is prepared to conduct that
research.
The Parties have entered into this Agreement for the purpose of, among
other things, ensuring that the results of that collaboration are made readily
available in a timely fashion to accelerate scientific discovery and facilitate
the development of products that diagnose, treat, cure and prevent Huntington's
disease.
In consideration of the mutual representations, warranties and covenants
contained herein and other good and valuable consideration, the receipt and
sufficiency of which are hereby acknowledged, the Parties hereby agree as
follows:
RESEARCH PROJECT
1. RESEARCH PROJECT. The "RESEARCH PROJECT" means the program of scientific
research described in APPENDIX A. The expected time frame for completing
each Phase (as defined in APPENDIX A) of the Research Project together with
the corresponding budget of the number and cost of the full-time employees
of the Company ("FTES") required to complete each such Phase in such time
frame is set forth in APPENDIX B.
2. CONDUCT OF THE RESEARCH PROJECT; CONTINUATION OF THE RESEARCH PROJECT.
(a) CONDUCT OF THE RESEARCH PROJECT. The Company hereby agrees to devote
such resources as set forth in APPENDIX B and effort as is necessary
to (i) conduct the Research Project in accordance with APPENDIX A and
APPENDIX B and (ii) to complete each Phase of the Research Project
within the time frames set forth in APPENDIX B. If at any time the
Company makes a good faith determination that (A) the Research Project
cannot be
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conducted substantially in accordance with APPENDIX A or APPENDIX B,
(B) any Phase of the Research cannot be substantially completed within
the time frame set forth in APPENDIX B for such Phase or (C) the
continued conduct of the Research Project in accordance with APPENDIX
A is unlikely to yield scientifically valid or useful results, the
Company shall promptly give notice (a "CHANGE OF CIRCUMSTANCES
NOTICE") to the Foundation.
(b) CONDITIONS TO THE CONTINUATION OF THE RESEARCH PROJECT. Unless
otherwise agreed to by the Foundation pursuant to a notice delivered
to the Company in accordance with this Agreement, the Company hereby
agrees that the Company shall not proceed to conduct or perform any
Phase of the Research Project if the Company does not first satisfy or
achieve each of the conditions (the "SCIENTIFIC MILESTONES") set forth
in APPENDIX C at the time specified in respect of (i) such Phase or
(ii) any prior Phase of the Research Project which is required or
otherwise necessary to be satisfied or achieved prior to beginning the
conduct or performance of any subsequent Phase of the Research
Project. The determination of whether a Scientific Milestone has been
satisfied or achieved shall be determined by the Research Committee
(as defined below).
(c) ESTABLISHMENT OF A JOINT RESEARCH COMMITTEE; RESPONSIBILITIES OF THE
RESEARCH COMMITTEE.
(i) ESTABLISHMENT OF A JOINT RESEARCH COMMITTEE. The Parties hereby
agree to establish within a reasonable period of time following
the date hereof a Joint Research Committee (the "RESEARCH
COMMITTEE") which shall comprise four members two of which
representatives shall be designated by each Party. The Research
Committee shall establish its own internal operating procedures
and meeting schedule; provided, however, the Research Committee
shall meet at least once every three months during the conduct
and performance of the Research Project.
(ii) RESPONSIBILITIES OF THE RESEARCH COMMITTEE. The Research
Committee shall, among other things, (A) oversee the
implementation and conduct of the Research Project, (B)
determine if changes are needed to the Research Project or the
time frames and budgeted FTE numbers and cost set forth in
APPENDIX B, (C) approve and implement any changes to the
Research Project or the time frames and budgeted FTE numbers
and cost set forth in APPENDIX B and (D) facilitate on-going
communications between the Parties. Any matter which requires a
decision by, or the approval of, the Research Committee under
this Agreement (including any matter described in APPENDIX A)
shall require the affirmative consent of each representative of
the Research Committee. At each meeting of the Research
Committee, one
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representative shall be appointed to record and distribute the
minutes of such meeting.
PAYMENTS
3. OBLIGATION TO MAKE PAYMENTS AND PAYMENT SCHEDULE; QUARTERLY FTE NOTICES;
QUARTERLY PAYMENT ADJUSTMENT.
(a) OBLIGATION TO MAKE PAYMENTS AND PAYMENT SCHEDULE.
(i) OBLIGATION TO MAKE PAYMENTS. The Foundation shall make payments
to the Company for the Research Project as provided in, and
subject to the terms and conditions of, this Agreement. The
Company acknowledges and agrees that the Foundation shall not
be required to make any payment to the Company in respect of
any Phase of the Research Project for which each of the
Scientific Milestones has not been satisfied or achieved.
(ii) PAYMENT SCHEDULE. The amount of each quarterly payment (the
"QUARTERLY PAYMENTS") and milestone payment (the "MILESTONE
PAYMENTS" and, together with the Quarterly Payments, the
"PAYMENTS") are set forth on the payment schedule (the "PAYMENT
SCHEDULE") attached hereto as Appendix D.
(b) QUARTERLY FTE NOTICES.
(i) DELIVERY OF THE QUARTERLY FTE NOTICES. The Company shall
deliver a written notice (each, a "QUARTERLY FTE NOTICE") to
the Foundation promptly following the end of each 90-day period
(each, a "QUARTERLY FTE NOTICE PERIOD") during the period
beginning on the Effective Date and continuing through the
Quarterly FTE Notice Period following the last scheduled
Quarterly Payment made by the Foundation under the terms of
this Agreement.
(ii) REQUIRED INFORMATION IN EACH QUARTERLY FTE NOTICES. Each
Quarterly FTE Notice shall be given in respect of the most
recently ended Quarterly FTE Notice Period and shall:
(A) set forth the Quarterly Payment number and the year and
quarter of the Research Project (in each case, as set
forth in APPENDIX D) covered by such Quarterly FTE Notice
Period;
(B) identify each Phase of the Research Project (each, an
"APPROVED ACTIVE PHASE") for which (1) each of the
Scientific Milestones required to proceed to conduct or
perform such Phase of the Research Project has been
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satisfied or achieved and (2) activities were conducted by
the Company during such Quarterly FTE Notice Period;
(C) set forth the date during such Quarterly FTE Notice Period
that activities actually commenced on each Approved Active
Phase;
(D) set forth the number of FTEs budgeted to devote time to
each Approved Active Phase as set forth in APPENDIX B (the
"BUDGETED FTES") during such Quarterly FTE Notice Period;
(E) set forth (1) the number of FTEs that actually devoted
time to each Approved Active Phase (the "ACTUAL FTES")
during such Quarterly FTE Notice Period up to an amount
not to exceed the number of Budgeted FTEs and (2) the name
and title of each such Actual FTE;
(F) identify each Approved Active Phase that each Actual FTE
actually devoted time to during such Quarterly FTE Notice
Period and set forth the number of days (or prorate
portion thereof) such Actual FTE actually devoted
one-hundred percent of his or her effort to such Approved
Active Phase during such Quarterly FTE Notice Period up to
an amount not to exceed the difference between (1) the
number of days budgeted for such Approved Active Phase as
set forth in Appendix B MINUS (2) the aggregate number of
days an Actual FTE actually devoted one-hundred percent of
his or her effort to such Approved Active Phase as set
forth by the Company in all prior Quarterly FTE Notices;
and
(G) include a certification by the Company that all of the
information provided in such Quarterly FTE Notice is true,
complete and correct.
(c) QUARTERLY PAYMENT ADJUSTMENT.
(i) REVIEW OF QUARTERLY FTE NOTICE. Beginning on the date of the
receipt of a Quarterly FTE Notice, the Foundation shall have a
period (the "QUARTERLY PAYMENT ADJUSTMENT REVIEW PERIOD") of 20
days to request such additional information from the Company as
may be reasonably required by the Foundation to verify the
information set forth in such Quarterly FTE Notice and review
such Quarterly FTE Notice.
(ii) CALCULATION OF QUARTERLY PAYMENT ADJUSTMENT. Within 10 days of
the expiration of the Quarterly Payment Adjustment Review
Period, the Foundation shall calculate the aggregate cost (the
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"ACTUAL QUARTERLY FTE COST") of the Actual FTEs that actually
devoted time to the Approved Active Phases during the Quarterly
FTE Notice Period covered by such Quarterly FTE Notice which
aggregate cost shall include the budgeted management FTE set
forth in APPENDIX B. If the Quarterly Payment made by the
Foundation in respect of such Quarterly FTE Notice Period is
greater than the Actual Quarterly FTE Cost in respect of such
Quarterly FTE Notice Period, (A) the Foundation shall have the
right to credit the amount of such overage against any future
payments required to be made by the Foundation to the Company
under this Agreement or (B) upon the written request of the
Foundation, the Company shall pay the amount of such overage to
the Foundation within 30 days of the receipt of any such
request. For purposes of this Agreement, all calculations shall
be made using a FTE rate of $250,000 per year other than FTEs
allocated to Phase 2 for which a FTE rate of $275,000 shall be
used.
4. CONDITIONS TO THE FOUNDATION'S PAYMENTS.
(a) SPECIFIC CONDITIONS TO PAYMENTS BY THE FOUNDATION. The Foundation may,
but shall not be obligated to, make any specific payment to the
Company for the Research Project required by this Agreement if the
Company does not first satisfy or achieve each of the conditions set
forth in this Agreement (including any attachment to this Agreement)
at the time specified in this Agreement (including any attachment to
this Agreement) relating to the specific payment to be made by the
Foundation to the Company which is required to be satisfied or
achieved prior to the making of such payment by the Foundation.
(b) GENERAL CONDITIONS TO PAYMENTS BY THE FOUNDATION. The Foundation may,
but shall not be obligated to, make any payments to the Company for
the Research Project required by this Agreement upon the occurrence
and continuation of any of the following events:
(i) CHANGE IN RESEARCH PROJECT. The Company gives a Change of
Circumstances Notice to the Foundation;
(ii) BREACH OF THIS AGREEMENT. There is a material breach of any
representation, warranty or covenant of this Agreement by the
Company; or
(iii) BANKRUPTCY EVENT. There is a Bankruptcy Event involving the
Company (as defined in SECTION 20 of this Agreement).
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RESULTS; HIGH Q RESEARCH GROUP AND RESULTS SHARING
5. DEFINITIONS. For the purposes of this Agreement, the following terms have
the meanings set forth below:
(a) "HIGH Q RESEARCH GROUP" means a community of investigators and
organizations funded by the Foundation and its affiliates whose
objective is to find diagnoses, treatments, cures and preventions of
Huntington's disease.
(b) "RESULTS" means any scientifically valid methods, data, outcomes or
other results made in the course of the conduct, or resulting from the
performance, of the Research Project and includes any reagents, cell
lines, compounds, animal models or other materials produced in the
course of the conduct, or resulting from the performance, of the
Research Project. For the avoidance of doubt, Results shall not
include any Company Background Intellectual Property (as defined in
SECTION 7).
(c) "THIRD PARTY RESULTS" means any scientifically valid methods, data,
outcomes or other results (i) made in the course of the conduct, or
resulting from the performance, of research conducted by members of
the High Q Research Group (as defined in SECTION 6(a) of this
Agreement) (other than the Company) and (ii) funded by the Foundation
or one of its affiliates.
6. HIGH Q RESEARCH GROUP; SHARING OF RESULTS WITH OTHERS.
(a) PARTICIPATION IN THE HIGH Q RESEARCH GROUP. Subject to the terms of
this Agreement, the Company hereby acknowledges and agrees that it is
participating in the High Q Research Group.
(b) DELIVERY OF RESULTS TO THE FOUNDATION; WITHDRAWAL OF RESULTS; RESULTS
DEEMED CONFIDENTIAL INFORMATION; EXCLUSION OF COMPANY BACKGROUND
INTELLECTUAL PROPERTY.
(i) DELIVERY OF RESULTS TO THE FOUNDATION; WITHDRAWAL OF RESULTS.
The Company shall inform the Foundation of all Results produced
or discovered within a reasonable period of time following the
production or discovery of each such Result (and, in the case
of any reagents, cell lines, compounds, animal models or other
materials constituting Results, upon the request of the
Foundation, deliver such materials as directed by the
Foundation). If at any time after informing the Foundation of
Results pursuant to this SECTION 6(b), the Company determines
that there is a reasonable scientific basis to conclude that
such Results are not scientifically valid, the Company shall
promptly so notify the Foundation.
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(ii) RESULTS DEEMED CONFIDENTIAL INFORMATION. The Parties hereby
agree that all Results shall be deemed Confidential Information
(as defined in SECTION 14 of this Agreement) and treated as
Confidential Information by each of the Parties in accordance
with the terms of SECTION 14 and SECTION 15 of this Agreement
until, the earlier to occur of (A) the Publication (as defined
in SECTION 16 of this Agreement) of such Results by the Company
and (B) the disclosure of such Results by the Foundation
pursuant to SECTION 6(f) of this Agreement.
(iii) EXCLUSION OF COMPANY BACKGROUND INTELLECTUAL PROPERTY. For the
avoidance of doubt, the Foundation hereby agrees that the
Company shall not be required to share or otherwise disclose or
distribute any Company Background Intellectual Property (as
defined in SECTION 7).
(c) DISCLOSURE OF RESULTS WITHIN THE HIGH Q RESEARCH GROUP; REIMBURSEMENT
OF EXPENSES.
(i) DISCLOSURE OF RESULTS WITHIN THE HIGH Q RESEARCH GROUP. At any
time following the 60-day period beginning on the date that the
Company discloses Results to the Foundation, the Foundation may
disclose such Results to any member of the High Q Research
Group who has agreed to each of the covenants set forth in
SECTION 6(d) of this Agreement with respect to any Results
disclosed to such member. For the avoidance of doubt, such
member shall be bound and obligated to treat any Results
disclosed to such member in the same manner and extent as the
Company is bound and obligated to treat any Third Party Results
disclosed to the Company under SECTION 6(d).
(ii) REIMBURSEMENT OF EXPENSES. The Foundation hereby agrees to
reimburse the Company for all reasonable direct costs and
expenses incurred by the Company in complying with any request
by the Foundation to provide Results to any member of the High
Q Research Group pursuant to this SECTION 6. The Company shall
submit invoices (including all relevant receipts, if any) to
the Foundation for all such costs and expenses incurred by the
Company on a monthly basis. Each invoice shall be paid by the
Foundation within 30 days of the receipt of such invoice from
the Company for such costs and expenses.
(d) DISCLOSURE OF THIRD PARTY RESULTS TO THE COMPANY. With respect to any
Third Party Results disclosed to the Company, the Company hereby
agrees:
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(i) to hold all Third Party Results in confidence until such Third
Party Results are Published or otherwise made publicly
available (except by breach of this Agreement) so that the
disclosure of the Third Party Results among members of the High
Q Research Group does not constitute a public disclosure and so
that the ability to patent the Third Party Results is
preserved; provided, however, the Company shall not be required
to hold any Third Party Results in confidence if such Third
Party Results (A) were previously known by the Company other
than by reason of disclosure by the Foundation; (B) were
publicly disclosed except by breach of this Agreement either
prior to or subsequent to the receipt of such Third Party
Results by the Company; (C) are rightfully received by the
Company from a third party without an express obligation of
confidence to the Foundation or the member of the High Q
Research Group who discovered such Third Party Results; (D) are
independently developed by the Company without use or reliance
upon Third Party Results provided by the Foundation; (E) are
disclosed pursuant to any applicable federal, state, local or
international law, or any judicial or government request,
requirement or order, provided that the Company takes
reasonable steps to provide the Foundation with sufficient
prior notice in order to allow the Foundation to contest such
request, requirement or order;
(ii) to discuss the Third Party Results only with those employees of
the Company that are advised (A) of the confidential nature of
the Third Party Results and (B) that the Third Party Results
must not be shared with anyone outside of the Company until the
Third Party Results are made publicly available;
(iii) until the Third Party Results are made publicly available, to
not Publish or otherwise publicly disclose methods, data or
other results which are derived using the Third Party Results
without appropriate written permission; and
(iv) to acknowledge other researchers appropriately if the Third
Party Results have contributed to a Publication or presentation
of Results.
(e) DISCLOSURE NOT TO CONSTITUTE PUBLICATION. The Parties acknowledge that
it is the intention of the Foundation, the Company and the other
members of the High Q Research Group that the sharing of Results and
Third Party Results among members of the High Q Research Group is to
be conducted in a manner so that such sharing shall not constitute
"disclosure" for patent purposes.
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(f) DISCLOSURE OF RESULTS OUTSIDE THE HIGH Q RESEARCH GROUP. With respect
to each Result disclosed by the Company to the Foundation, on and
after the later to occur of (i) the fifth anniversary of the date
hereof and (ii) three years after the date of the disclosure of such
Result (such later date hereinafter referred to as the "DISCLOSURE
DATE"), the Foundation shall have the right to disclose (other than
through Publication) such Result to any individual or organization
without any restrictions unless prior to the Disclosure Date the
Company notifies the Foundation that there exists good reasons for
such disclosure to be withheld for an additional six-month period, in
which case the Disclosure Date will be extended for an additional six
months and the provisions of this SECTION 6(f) shall apply to such new
Disclosure Date.
INTELLECTUAL PROPERTY
7. DEFINITIONS. For the purposes of this Agreement, the following terms have
the meanings set forth below:
(a) "COMPANY BACKGROUND INTELLECTUAL PROPERTY" means Intellectual Property
owned or licensed by the Company prior to the date hereof that is
applied to the Research Project at any time together with any
modifications or enhancements to such Intellectual Property Made in
the course of the conduct, or resulting from the performance, of the
Research Project or the term of this Agreement, whichever is longer.
(b) "HD FIELD OF USE" means any activity useful for creating, researching,
developing, manufacturing, distributing or selling a product, process
or service for diagnosing, treating, curing or preventing Huntington's
disease.
(c) "HD INTELLECTUAL PROPERTY" means any Intellectual Property (other than
Company Background Intellectual Property) Made in the course of the
conduct, or resulting from the performance of, the Research Project
that (i) relates to Huntington's disease or (ii) is useful for the
creation, development, manufacture or distribution of a product or
service for the diagnosis, treatment, cure or prevention of
Huntington's disease". For the avoidance of doubt, HD Intellectual
Property shall not include any Company Background Intellectual
Property.
(d) "HD INTELLECTUAL PROPERTY DIAGNOSTIC OR TOOL" means any HD
Intellectual Property which may be used for diagnostic applications or
as a tool for drug discovery in connection with any disease other than
Huntington's disease.
(e) "HD RESEARCH AND DEVELOPMENT" means any activity useful for the
creation, development, manufacture or distribution of a product or
service for the diagnosis, treatment, cure or prevention of
Huntington's disease other than the sale of such product or service.
For the avoidance of doubt, HD Research and Development shall not
include any right to sell a
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product or service (including any transfer of services or products
made using intellectual property rights, whether or not for
consideration, other than a transfer of services or products solely
for research and development purposes without fee or profit).
(f) "INTELLECTUAL PROPERTY" means any discovery, invention, formulation,
know-how, method, technological development, enhancement,
modification, improvement, work of authorship, computer software
(including, but not limited to, source code and executable code) and
documentation thereof, data or collection of data, whether patentable
or not, or susceptible to copyright or any other form of legal
protection.
(g) "MADE" when used in relation to any Intellectual Property means the
conception, discovery, invention or first actual reduction to practice
of such Intellectual Property, as the case may be.
(h) "NON-HD INTELLECTUAL PROPERTY" means any Intellectual Property Made in
the course of the conduct, or resulting from the performance of, the
Research Project that is not HD Intellectual Property ". For the
avoidance of doubt, Non-HD Intellectual Property shall not include any
Company Background Intellectual Property.
(i) "NON-PATENTABLE HD INTELLECTUAL PROPERTY" means any HD Intellectual
Property that is not Patentable HD Intellectual Property.
(j) "PATENTABLE INTELLECTUAL PROPERTY" means all Patentable HD
Intellectual Property and Patentable Non-HD Intellectual Property.
(k) "PATENTABLE HD INTELLECTUAL PROPERTY" means any HD Intellectual
Property which (i) is or may be patentable or otherwise protectable
under Title 35 U.S.C. and corresponding legislation in other
jurisdictions and (ii) is the subject of a patent or pending patent
application, including any continuation, continuation-in-part,
division, extension, substitute, re-examination, reissue and any other
derivative application or patent.
(l) "PATENTABLE NON-HD INTELLECTUAL PROPERTY" means any Non-HD
Intellectual Property which (i) is or may be patentable or otherwise
protectable under Title 35 U.S.C. and corresponding legislation in
other jurisdictions and (ii) is the subject of a patent or pending
patent application, including any continuation, continuation-in-part,
division, extension, substitute, re-examination, reissue and any other
derivative application or patent.
(m) "RESEARCH AND DEVELOPMENT" means any activity useful for the creation,
development, manufacture or distribution of a product or service other
than the sale of such product or service. For the avoidance of doubt,
Research and Development shall not include any right to sell a product
or service (including any transfer of services or products made using
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intellectual property rights, whether or not for consideration, other
than a transfer of services or products solely for research and
development purposes without fee or profit).
8. OWNERSHIP OF INTELLECTUAL PROPERTY.
(a) OWNERSHIP OF HD INTELLECTUAL PROPERTY. The Foundation and the Company
shall jointly own in equal shares all HD Intellectual Property. Each
of the Parties hereby agrees that it will not sell or otherwise
transfer its title to any HD Intellectual Property to any third party
other than an affiliate provided that such affiliate takes title to
such HD Intellectual Property (i) subject to the rights of the
non-transferring Party in such HD Intellectual Property under this
Agreement and (ii) assumes the obligations of the transferring Party
with respect to such HD Intellectual Property under this Agreement.
(b) OWNERSHIP RIGHTS OF NON-HD INTELLECTUAL PROPERTY. The Company shall
own all Company Background Intellectual Property and all Non-HD
Intellectual Property. Except as expressly set forth in this
Agreement, the Foundation shall have no interest in any Non-HD
Intellectual Property resulting from, or conceived during, the
Research Project.
9. INTELLECTUAL PROPERTY; PATENTABLE HD INTELLECTUAL PROPERTY.
(a) NOTICE OF INTELLECTUAL PROPERTY. If either Party believes that any
Intellectual Property has been Made in the course of the conduct, or
resulting from the performance of, the Research Project, such Party
will, within a reasonable period of time thereafter, give notice (an
"INVENTION NOTICE") of such Intellectual Property to the other Party.
Such Intellectual Property Notice shall describe in reasonable detail
the Intellectual Property that such Party believes has been Made and
state whether such Party believes that such Intellectual Property is
Patentable Intellectual Property.
(b) PROSECUTION OF PATENTABLE HD INTELLECTUAL PROPERTY; INVENTORSHIP.
(i) RESPONSIBILITY FOR PROSECUTION OF PATENTABLE HD INTELLECTUAL
PROPERTY. The Company shall prepare, file, prosecute and
maintain the appropriate filings in respect of any Patentable
HD Intellectual Property including filing (A) a provisional
patent application or (B) a patent application (including a
patent application corresponding to a previously filed
provisional patent application) claiming any such Patentable HD
Intellectual Property in the United States and in such other
jurisdictions as the Company determines, acting reasonably,
that are necessary in order to protect the Company's and the
Foundation's rights in such Patentable HD Intellectual
Property. The Company shall ensure that all filings are
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filed in the name of the Company and the Foundation as
co-owners.
(ii) FOUNDATION ELECTION TO HAVE PROSECUTION OF PATENTABLE HD
INTELLECTUAL PROPERTY INITIATED. At any time and from time to
time, the Foundation shall have the right to elect to cause the
Company to prepare, file, prosecute and maintain the
appropriate filings in respect of any Patentable HD
Intellectual Property which is the subject of an Invention
Notice by providing notice (a "FOUNDATION PATENT FILING
NOTICE") of such election to the Company including filing (A) a
provisional patent application or (B) a patent application
(including a patent application corresponding to a previously
filed provisional patent application) claiming any such
Patentable HD Intellectual Property in the United States and in
such other jurisdictions as the Company determines, acting
reasonably, that are necessary in order to protect the
Company's and the Foundation's rights in such Patentable HD
Intellectual Property. The Company shall ensure that all
filings are filed in the name of the Company and the Foundation
as co-owners.
(iii) INVENTORSHIP. The Parties hereby agree that the identity of the
inventor of all Patentable HD Intellectual Property shall be
determined in accordance with United States Patent law (or, if
the jurisdiction in which patent or other protection is being
sought does not permit the application of United States Patent
law to identify the inventor, then in accordance with the
applicable law in that jurisdiction).
(c) COVENANTS OF THE COMPANY. With respect to the prosecution and
maintenance by the Company of any Patentable HD Intellectual Property
pursuant to SECTION 9(b) of this Agreement, the Company hereby agrees
to promptly (i) give all notices required by, and comply with all
other requirements of, applicable law to preserve the Parties' rights
in such Patentable HD Intellectual Property as appropriate; (ii)
prepare, file, prosecute and maintain, as applicable, the appropriate
filings to protect the Parties' rights in such Patentable HD
Intellectual Property; (iii) provide the Foundation with a copy of any
provisional patent application or patent application filed claiming
such Patentable HD Intellectual Property; (iv) provide the Foundation
with copies of all correspondence and other documents relating to the
prosecution and maintenance of such Patentable HD Intellectual
Property that come into the possession or control of the Company; and
(v) such other documents and information related to such Patentable HD
Intellectual Property as the Foundation may reasonably request and the
Company can provide without incurring unreasonable cost and expense.
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(d) PATENT EXPENSES. The Parties hereby agree that all out-of-pocket costs
and expenses (including attorneys' fees and government filing fees)
incurred by the Company to prepare, file, prosecute and maintain the
appropriate filings to protect the Parties' rights in any Patentable
HD Intellectual Property ("PATENT EXPENSES") will be shared equally by
the Parties. The Company shall submit invoices (including all relevant
receipts) for all such Patent Expenses to the Foundation on a monthly
basis or as invoices in respect of Patent Expenses are received from
third parties. Each invoice shall be paid by the Foundation within 30
days of the receipt of such invoice from the Company for such Patent
Expenses.
(e) DISCLAIMER OF INTEREST IN PATENTABLE HD INTELLECTUAL PROPERTY.
(i) DISCLAIMER NOTICE. With respect to any Patentable HD
Intellectual Property, either Party may, at any time, disclaim
its interest in such Patentable HD Intellectual Property and
elect to cease to bear its share of the Patent Expenses in
respect of such Patentable HD Intellectual Property by
providing notice of such election ("PATENTABLE HD INTELLECTUAL
PROPERTY DISCLAIMER NOTICE") to the other Party; provided,
however, the disclaiming Party shall remain liable for is share
of all Patent Expenses incurred or committed to through the
date the non-disclaiming party receives the Patentable HD
Intellectual Property Disclaimer Notice. The Company shall be
deemed to have disclaimed its interest in any Patentable HD
Intellectual Property that is the subject of a Foundation
Patent Filing Notice if the Company fails to comply with the
obligations set forth in SECTION 9(c) of this Agreement with
respect to such Patentable HD Intellectual Property.
(ii) EFFECT OF DISCLAIMER NOTICE. In the event that a Patentable HD
Intellectual Property Disclaimer Notice is delivered by either
Party in respect of Patentable HD Intellectual Property: (A)
the disclaiming Party shall promptly assign its ownership
interest in such Patentable HD Intellectual Property to the
non-disclaiming Party without consideration; (B) except as set
forth in SECTION 9(e)(i) above, as of the date of the receipt
of such Patentable HD Intellectual Property Disclaimer Notice
by the non-disclaiming Party, the disclaiming Party shall no
longer be responsible for its share of the Patent Expenses in
respect of such Patentable HD Intellectual Property; (C) except
as set forth in SECTION 9(e)(i) above, as of the date of the
receipt of such Patentable HD Intellectual Property Disclaimer
Notice by the non-disclaiming Party, the non-disclaiming Party
shall be solely responsible for all Patent Expenses in respect
of such Patentable HD Intellectual Property; (D) except as
expressly set forth in SECTION 10(e) of this Agreement, the
disclaiming Party shall have no further rights to such
Patentable HD Intellectual Property; and (E) the disclaiming
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Party hereby agrees at any time during and after the term of
this Agreement to cooperate with the non-disclaiming Party
without consideration but at the expense of the non-disclaiming
Party in preparing, filing, prosecuting and maintaining, as
applicable, the appropriate filings to protect the
non-disclaiming Party's rights in such Patentable HD
Intellectual Property, including obtaining execution by its
employees of any documents necessary in connection with such
activities. Each of the Parties hereby agrees to use reasonable
efforts to keep the other Party advised of its deliberations
regarding its determinations as to electing to disclaim its
interest in any Patentable HD Intellectual Property.
(f) INFRINGEMENT OR MISAPPROPRIATION OF HD INTELLECTUAL PROPERTY.
(i) INFRINGEMENT OR MISAPPROPRIATION OF HD INTELLECTUAL PROPERTY BY
THIRD PARTIES. Each Party hereby agrees to promptly notify the
other Party in writing of any alleged or threatened
infringement or misappropriation of any HD Intellectual
Property by a third party of which it becomes aware. In
connection with any such alleged or threatened infringement or
misappropriation, the Parties hereby agree to confer and take
such action and allocate expenses and recoveries in such manner
as they may mutually agree. Neither Party shall settle a claim
brought against a third party in respect of such infringement
or misappropriation without the consent of the other Party.
(ii) INFRINGEMENT OR MISAPPROPRIATION CLAIMS BY THIRD PARTIES
RELATED TO HD INTELLECTUAL PROPERTY. Each Party hereby agrees
to notify the other party in writing if any third party alleges
that any HD Intellectual Property infringes or misappropriate
such third party's Intellectual Property rights. In connection
with any such alleged infringement or misappropriation, the
Parties hereby agree to confer and take such action and
allocate expenses in such manner as they may mutually agree.
Neither Party shall settle a claim brought by a third party in
respect of such infringement or misappropriation without the
consent of the other Party.
10. LICENSES.
(a) COMMERCIALIZATION OF HD INTELLECTUAL PROPERTY; RESERVATION OF RIGHTS
REGARDING HD INTELLECTUAL PROPERTY.
(i) COMMERCIALIZATION OF HD INTELLECTUAL PROPERTY. The Parties
hereby agree that neither Party shall (A) except as expressly
permitted by SECTION 10(a)(ii)(A), SECTION 10(a)(ii)(C) or
SECTION 10(a)(ii)(D) of this Agreement, use or otherwise
exploit any HD Intellectual Property for any use or purpose or
(B) except as expressly
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permitted by SECTION 10(a)(ii)(B), SECTION 10(a)(ii)(C) or
SECTION 10(a)(ii)(E) of this Agreement, grant any license of
any HD Intellectual Property for any use or purpose. The
Parties hereby further agree that, except as expressly
permitted by SECTION 10(a)(ii) of this Agreement, the use or
other exploitation of any HD Intellectual Property (other than
any HD Intellectual Property Diagnostic or Tool outside the HD
Field of Use) by either of the Parties or a third party for
uses other than Research and Development shall only be done
pursuant the grant of a commercial license (any such license
shall hereinafter be referred to as a "COMMERCIAL LICENSE")
pursuant to a license agreement executed by each of the
Parties.
(ii) RESERVATION OF RIGHTS BY THE PARTIES TO GRANT CERTAIN LICENSES.
(A) COMPANY'S RIGHT TO USE HD INTELLECTUAL PROPERTY. The
Company hereby reserves the right to use any HD
Intellectual Property for all uses and purposes relating
to Research and Development.
(B) COMPANY'S RIGHT TO GRANT RESEARCH AND DEVELOPMENT
LICENSES. The Company hereby reserves the right to grant
non-exclusive licenses throughout the world in respect of
any HD Intellectual Property for all uses and purposes
relating to Research and Development.
(C) COMPANY'S RIGHT TO USE AND GRANT COMMERCIAL LICENSES IN
RESPECT OF HD INTELLECTUAL PROPERTY DIAGNOSTICS OR TOOLS.
The Company hereby reserves the right to (1) use any HD
Intellectual Property Diagnostic or Tool for all uses and
purposes outside the HD Field of Use and (2) grant
commercial licenses throughout the world in respect of any
HD Intellectual Property Diagnostic or Tool for all uses
and purposes outside of the HD Field of Use.
(D) FOUNDATION'S RIGHT TO USE HD INTELLECTUAL PROPERTY. The
Foundation hereby reserves the right to use any HD
Intellectual Property for all uses and purposes relating
to HD Research and Development.
(E) FOUNDATION'S RIGHT TO GRANT HD RESEARCH AND DEVELOPMENT
LICENSES. The Foundation hereby reserves the right to
grant non-exclusive licenses throughout the world in
respect of any HD Intellectual Property for all uses and
purposes relating to HD Research and Development.
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(b) CONSULTATIONS BETWEEN THE COMPANY AND THE FOUNDATION REGARDING
COMMERCIAL LICENSES; EXCLUSIVE RIGHT TO NEGOTIATE; THIRD PARTY
PROPOSALS.
(i) GOOD FAITH CONSULTATIONS. The Parties hereby agree to consult,
and work in partnership, with each other in accordance with the
provisions of this SECTION 10 concerning the grant of any
Commercial License. With respect to any decision regarding the
granting of any Commercial License, the Parties hereby further
agree to (A) act in good faith and on a responsive basis and
(B) make such decision on a reasonable basis using the
principles and guidelines set forth in SECTION 10(c) of this
Agreement.
(ii) EXCLUSIVE RIGHT TO NEGOTIATE A COMMERCIAL LICENSE. The Parties
hereby agree that the Company shall have an exclusive first
right to negotiate with the Foundation to obtain for itself
each Commercial License. Such exclusive right to negotiate
shall extend for a period of 90 days beginning on the date
either Party notifies the other Party in writing of its desire
to initiate the process for the granting of a Commercial
License; provided, however, no such notice may be given in
respect of such Commercial License prior to the earlier to
occur of (A) the mutual agreement of the Parties, (B) with
respect to any compound combination, the date on which all data
reasonably necessary to permit the filing of investigational
new drug application ("IND") with the United States Food and
Drug Administration (the "FDA") is available and (C) the fourth
anniversary of the Effective Date. During such 90-day period,
the Parties hereby agree to negotiate with each other under the
principles and guidelines set forth in SECTION 10(b) and
SECTION 10(c). If, upon the expiration of such 90-day period,
the Parties have not reached an agreement to grant such
Commercial License to the Company, the Parties may submit
alternative proposals for such Commercial License for
consideration in accordance with this SECTION 10.
(iii) RIGHT TO MAKE PROPOSAL REGARDING THE GRANTING OF A COMMERCIAL
LICENSE.
(A) Subject to SECTION 10(b)(ii), the Parties hereby agree (1)
that either Party may submit to the Parties for their
consideration under this SECTION 10 a proposal for the
granting of a Commercial License and (2) to consult and
make a determination regarding the granting of a
Commercial License in respect of such proposal in
accordance with the provisions of this SECTION 10.
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(B) if (1) the Parties are evaluating multiple proposals
(including one submitted by the Company pursuant to which
the Company would be granted a Commercial License (the
"COMPANY PROPOSAL")) to determine whether or not the
principles and guidelines set forth in this SECTION 10 for
the granting of a Commercial License have been satisfied
and (2) more than one of such proposals (including the
Company Proposal) satisfies the principles and guidelines
set forth in this SECTION 10 on an equivalent basis, the
Foundation hereby agrees to accept the Company Proposal
and agrees to grant a Commercial License to the Company in
accordance with this SECTION 10.
(c) PRINCIPLES AND GUIDELINES FOR GRANTING COMMERCIAL LICENSES.
(i) FUNDAMENTAL PRINCIPLES AND GUIDELINES. The Parties hereby agree
that a Commercial License shall be granted if and only if the
Parties mutually agree that the granting of such Commercial
License is reasonably likely to:
(A) maximize the impact on the health and well-being of
Huntington's disease patients;
(B) maximize the availability of diagnostic or therapeutic
products to Huntington's disease patients; and
(C) maximize the speed of which diagnostic or therapeutic
products are available to Huntington's disease patients.
(ii) AVAILABILITY OF PRODUCTS AS PRIMARY FACTOR FOR GRANTING
COMMERCIAL LICENSES. Subject to SECTION 10(c)(iii), if (A) the
Parties are evaluating multiple proposals (including a Company
Proposal) for the granting of a Commercial License, (B) more
than one of the proposals satisfies the principles and
guidelines set forth in this SECTION 10 (other than (1) the
proposed economic terms and (2) the proposed time frame for
making the diagnostic or therapeutic product which is to be the
subject of such Commercial License available to Huntington's
disease patients) on an equivalent basis; and (C) one of the
proposals sets forth a time frame for making the diagnostic or
therapeutic product which is to be the subject of such
Commercial License available to Huntington's disease patients
that is substantially shorter than those set forth in the other
proposals being considered by the Parties, the Parties hereby
agree that the proposal setting forth such substantially
shorter time frame shall be accepted by the Parties and a
Commercial License granted to the entity making such proposal
even if the economic terms of such proposal are
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substantially less than those set forth in the other proposals
being considered by the Parties.
(iii) COMMERCIAL LICENSE AGREEMENT TERMS AND CONDITIONS. In addition
to the principles and guidelines set forth in SECTION 10(c)(i)
and SECTION 10(c)(ii) of this Agreement, the Parties hereby
further agree that a Commercial License shall be granted if and
only if the Parties mutually agree that the terms and
conditions of the license agreement in respect of such
Commercial License incorporates the following terms, principles
and guidelines:
(A) reasonable performance milestones and a demonstrated
capacity of the licensee to be able to meet those
milestones; and
(B) reasonable business and other terms and conditions that
are in keeping with the then existing market standards for
agreements of such type and nature in respect of similar
technology and in similar disease indications.
(d) RESOLUTION OF DISPUTES REGARDING THE GRANTING OF COMMERCIAL LICENSES.
If the Parties do not reach a mutual agreement regarding the granting
of a Commercial License in respect of a proposal for the granting of a
Commercial License submitted by either of the Parties for their
consideration in accordance with the provisions of this SECTION 10,
the Parties hereby agree that the resolution of such disagreement
shall be determined in accordance with the dispute resolution
procedures set forth in SECTION 26 of this Agreement.
(e) RESERVATION OF NON-EXCLUSIVE LICENSES OF DISCLAIMED PATENTABLE HD
INTELLECTUAL PROPERTY.
(i) RESERVATION OF NON-EXCLUSIVE LICENSE BY THE FOUNDATION. With
respect to each patent (including (A) any patent application,
divisional, continuation, continuation-in-part, substitute,
renewal, reexamination, extension or reissue in respect of such
patent or (B) any intellectual property rights claimed in
respect of such patent) claiming Patentable HD Intellectual
Property which the Foundation has disclaimed its interest
pursuant to SECTION 9(e) of this Agreement, the Foundation
hereby reserves a non-exclusive, paid-up, irrevocable,
perpetual license throughout the world for all purposes
relating to HD Research and Development including a license to
(1) make, have made, use and have used products or processes
resulting from such Patentable HD Intellectual Property, (2)
practice and have practiced such Patentable HD Intellectual
Property and (3) use and have used the Confidential Information
relating to such Patentable HD Intellectual Property. The
foregoing
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license (a) shall be for all purposes and activities relating
to HD Research and Development only, (b) shall not include any
right to sell (including any transfer of services or products
made using intellectual property rights, whether or not for
consideration, other than a transfer of services or products
solely for research and development purposes without fee or
profit), (c) shall not be subject to royalties or other fees
and (d) shall include the right to grant sublicenses on the
same terms; provided, that, such sublicense (i) is granted
without payment of royalties, other fees or profit and (ii)
prohibits the sublicensee from granting sublicenses.
(ii) RESERVATION OF NON-EXCLUSIVE LICENSE BY THE COMPANY. With
respect to each patent (including (A) any patent application,
divisional, continuation, continuation-in-part, substitute,
renewal, reexamination, extension or reissue in respect of such
patent or (B) any intellectual property rights claimed in
respect of such patent) claiming Patentable HD Intellectual
Property which the Company has disclaimed its interest pursuant
to SECTION 9(e) of this Agreement, the Company hereby reserves
a non-exclusive, paid-up, irrevocable, perpetual license
throughout the world for all purposes relating to Research and
Development including a license to (1) make, have made, use and
have used products or processes resulting from such Patentable
HD Intellectual Property, (2) practice and have practiced such
Patentable HD Intellectual Property and (3) use and have used
the Confidential Information relating to such Patentable HD
Intellectual Property. The foregoing license (a) shall be for
all purposes and activities relating to Research and
Development only, (b) shall not include any right to sell
(including any transfer of services or products made using
intellectual property rights, whether or not for consideration,
other than a transfer of services or products solely for
research and development purposes without fee or profit), (c)
shall not be subject to royalties or other fees and (d) shall
include the right to grant sublicenses on the same terms;
provided, that, such sublicense (i) is granted without payment
of royalties, other fees or profit and (ii) prohibits the
sublicensee from granting sublicenses.
11. NON-ASSERT COVENANT. So long as the Parties are in compliance with the
terms and conditions of this Agreement, each of the Parties hereby
undertakes not to bring any action or assist others in bringing any action,
and undertakes to ensure, by contract or otherwise, that its licensees and
assignees of any HD Intellectual Property or Non-HD Intellectual Property
will not bring any action or assist others in bringing any action, against
the Foundation, its licensees or assignees of any HD Intellectual Property
or any other person on the ground that the practice or use, as the case may
be, of any HD Intellectual Property for any purpose or activity relating to
HD Research and Development infringes or misapropriates the
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proprietary rights of such Party, its licensees or assignees in any HD
Intellectual Property or Non-HD Intellectual Property.
12. LICENSES TO COMPANY BACKGROUND INTELLECTUAL PROPERTY; SCOPE OF LICENSE TO
USE COMPANY BACKGROUND INTELLECTUAL PROPERTY.
(a) LICENSES TO COMPANY BACKGROUND INTELLECTUAL PROPERTY. To the extent it
has the legal right to do so, the Company hereby agrees, upon the
request of the Foundation and subject to the provisions of this
SECTION 12, SECTION 14 and SECTION 26, to grant to the Foundation (or
a third party designated by the Foundation) a non-exclusive, paid-up,
license throughout the world to use the Company Background
Intellectual Property to the extent necessary to enable the Parties to
commercially exploit the HD Intellectual Property in accordance with
the terms of this Agreement. In clarification of the foregoing, the
Foundation acknowledges and understands (i) the sensitive nature of
the Company Background Intellectual Property and (ii) the extent to
which the Company seeks to protect Company Background Intellectual
Property and confidential information. Therefore, the Foundation
hereby agrees that the Company shall not be required to grant a
license pursuant to this SECTION 12 in connection with the commercial
exploitation of any HD Intellectual Property if a commercially
reasonable alternative method is available for a third party to
commercially exploit such HD Intellectual Property.
(b) SCOPE OF LICENSE TO USE COMPANY BACKGROUND INTELLECTUAL PROPERTY. To
the extent the Company is required to grant a non-exclusive license
pursuant to this SECTION 12, the Parties hereby agree that such a
license shall only be granted to the limited extent actually necessary
to commercially exploit the HD Intellectual Property and for no other
purpose, including, but not limited to, (i) discover or identify other
drug candidates or (ii) explore other materials or compounds in an
effort to discover a competitive therapeutic to treat Huntington's
disease. The Parties further agree that any such license shall (A)
contain appropriate and reasonable restrictions under the
circumstances designed to safeguard the integrity and proprietary
nature of the Company Background Intellectual Property and (B) be for
a term no longer than is necessary to commercially exploit the HD
Intellectual Property.
(c) RESOLUTION OF DISPUTES RELATING TO LICENSES OF COMPANY BACKGROUND
INTELLECTUAL PROPERTY. In the event a dispute arises under this
SECTION 12, and the matter is referred to an arbitrator pursuant to
the terms of this Agreement, the arbitrator shall be given mutual
instructions by the Parties that the provisions of this SECTION 12 are
to be strictly construed and limited in order to adequately and
appropriately protect the Company Background Intellectual Property.
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13. REVENUE SHARING.
(a) AGREEMENT TO SHARE REVENUE. The Parties hereby agree that all revenue
("REVENUE") received by either of the Parties from the grant of any
Commercial License of any HD Intellectual Property (other than HD
Intellectual Property which has been disclaimed by one of the Parties
pursuant to SECTION 9(e) of this Agreement) to a third party shall be
distributed as follows:
(i) First, to the Foundation until an amount equal to the aggregate
amount of payments required to be made by the Foundation to the
Company (including any milestone payments actually paid to the
Company by the Foundation), under this Agreement has been
distributed to the Foundation;
(ii) Second, provided that the initial regulatory approval to sell a
therapeutic product which provides a benefit to Huntington's
disease patients has been granted by the appropriate regulatory
authority, to the Company until an amount equal to the amount
distributed to the Foundation pursuant to SECTION 13(a)(i) has
been distributed to the Company; and
(iii) Thereafter, equally to the Foundation and the Company.
(b) REVENUE SHARING NOT APPLICABLE TO REVENUE FROM COMMERCIAL LICENSING
WHERE THE COMPANY IS THE LICENSEE. The Parties hereby agree that this
SECTION 13 shall not apply to any Revenue received by either of the
Parties in respect of a Commercial License of any HD Intellectual
Property where the Company is the licensee of the interests of the
Foundation in such HD Intellectual Property.
CONFIDENTIAL INFORMATION; PUBLICITY; PUBLICATION
14. CONFIDENTIAL INFORMATION. For the purposes of this Agreement, the term
"CONFIDENTIAL INFORMATION" shall mean (a) this Agreement, (b) the Results
and (c) all information provided by one Party (the "DISCLOSING PARTY") to
another Party (the "RECEIVING PARTY") that is clearly identified as
"Confidential" by the Disclosing Party at the time of disclosure. If such
transmittal occurs orally, the Disclosing Party will promptly reduce such
transmittal to writing, xxxx and identify it as confidential, and provide
such record to the Receiving Party. Specifically excepted from Confidential
Information is all information that: (i) was previously known by the
Receiving Party other than by reason of disclosure by the Disclosing Party;
(ii) is publicly disclosed except by breach of this Agreement either prior
to or subsequent to the Receiving Party's receipt of such information;
(iii) is rightfully received by the Receiving Party from a third party
without an express obligation of confidence to the Disclosing Party; (iv)
is independently developed by the Receiving Party without use or reliance
upon Confidential Information provided by the Disclosing Party; (v) is
disclosed
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pursuant to any applicable federal, state, local, or international law, or
any judicial or government request, requirement or order, provided that the
Receiving Party takes reasonable steps to provide the Disclosing Party with
sufficient prior notice in order to allow the Disclosing Party to contest
such request, requirement or order; or (vi) was provided by the Disclosing
Party more than five years prior to disclosure by the Receiving Party.
15. CONFIDENTIALITY. The Receiving Party shall not disclose any Confidential
Information without written authorization from the Disclosing Party, except
(a) the Foundation may disclose Confidential Information to the extent
expressly permitted by the terms and conditions of SECTION 6 of this
Agreement; (b) the Foundation may disclose Confidential Information in
furtherance of the any license contemplated in SECTION 10 of this
Agreement, provided that the Foundation imposes a corresponding obligation
of confidentiality on the third party receiving such Confidential
Information; (c) the Company may disclose Confidential Information to the
extent expressly permitted by the terms and conditions of SECTION 16 of
this Agreement; and (d) either Party may disclose Confidential Information
to the extent expressly permitted by the terms and conditions of SECTION 17
of this Agreement.
16. PUBLICATION.
(a) DEFINITIONS. For the purposes of this Agreement, the term "PUBLISH"
means (i) to publish in a peer reviewed scientific journal of general
circulation; (ii) present at a scientific meeting and "PUBLICATION"
has a corresponding meaning; or (iii) to disseminate, discuss or
otherwise make publicly available outside of the High Q Research Group
the Results or details regarding the Research Project.
(b) EXCLUSIVE RIGHT TO PUBLISH. The Company shall have (i) the sole and
exclusive right to Publish Results and (ii) the sole and final
authority over any and all decisions related to Publication of
Results. The Company hereby agrees to provide appropriate
acknowledgement of the Foundation's support of, and contribution to,
the Research Project in any Publication of the Results.
(c) NOTICE OF PLANNED PUBLICATION OR OTHER PUBLIC DISCLOSURE BY THE
RESEARCHER; FOUNDATION'S RIGHT OF REVIEW PRIOR TO PUBLICATION OR OTHER
PUBLIC DISCLOSURE BY THE COMPANY. The Company shall provide the
Foundation with a copy of any manuscript, abstract or presentation
containing or based upon any Results for the Foundation's review and
comment pursuant to this SECTION 16(c) prior to the submission to a
journal for review for Publication or other public disclosure of such
manuscript, abstract or presentation. The Foundation shall have a
period (the "PUBLICATION REVIEW PERIOD") of 60 days (unless a shorter
period is required by any regulatory or governmental entity but in no
event less than 20 days), following the receipt of a proposed
manuscript or an abstract or
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presentation in which to review and comment on the proposed
manuscript, abstract or presentation, as the case may be. In the event
the Foundation identifies in writing information in any such
manuscript, abstract or presentation which could reasonably be
expected to adversely affect potential intellectual property rights
associated with the Results, the Company shall either remove such
information from such manuscript, abstract or presentation or delay
the Publication or other public disclosure until appropriate steps,
reasonably satisfactory to the Foundation, have been taken by the
Company to protect the intellectual property rights. If there are any
changes made to any proposed manuscript, abstract or presentation that
has previously been provided to the Foundation which could reasonably
be expected to adversely affect potential intellectual property rights
associated with the Results, (1) the Company shall provide the
Foundation with a copy of such revised manuscript, abstract or
presentation and (2) the review and comment rights provided to the
Foundation under this SECTION 16(c) shall apply to such revised
manuscript, abstract or presentation.
17. PUBLICITY. No Party shall use the name, trademarks, logos, physical
likeness or other symbol of another Party (or their employees) for any
marketing, advertising, public relations or other purposes without the
prior written consent of an authorized representative of the affected
Party, except that (a) either Party may make reference to the Foundation's
support of the Research Project, provided that, in any such reference, the
relationship of the Parties shall be accurately and appropriately described
and (b) either Party may disclose, without the other Party's approval, (i)
the existence of this Agreement; (ii) a general summary of the subject
matter of the Research Project; (iii) the aggregate dollar amount of
financial support to be provided under this Agreement; and (iv) any
specific terms of this Agreement that are a matter of public record except
by breach of this Agreement. All press releases shall be jointly issued.
COVENANTS
18. COVENANTS. Each of the Company, and where expressly applicable, the
Foundation, hereby agrees to each of the following:
(a) COMPLIANCE WITH LAW. The Research Project will be conducted in
compliance with all applicable federal, state, local, international,
health authority and institutional laws, rules, regulations, orders
and guidelines.
(b) USE OF FUNDS. All funds provided to the Company by the Foundation
under this Agreement shall be used for the Research Project in
accordance with this Agreement and for no other purposes.
(c) REPORTS; DISCLOSURE OF INFORMATION. The Company will provide the
Foundation with interim written reports at least every six months and
a final written report on the status and progress of the Research
Project,
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including an analysis of milestones achieved. Each such report shall
include a copy of all Results and underlying data and each such report
shall be treated as Confidential Information. Each Party agrees to
provide to the other Party all information which may at any time come
into the possession of such Party which relates to any compound
combination evaluated in the course of the conduct or performance of
the Research Project.
(d) AUDIT; ACCESS. At reasonably convenient times and dates, (i) the
Foundation and its representatives shall have the right to audit the
Company's compliance with this Agreement and (ii) the Company will
provide the Foundation and its representatives with reasonable access
to the Research Project facilities, data and personnel in order to
assess the progress of the Research Project.
(e) RESEARCH TEAM. The Research Project shall only be conducted by
individuals who have agreed to assign any rights they may acquire in
any resulting Intellectual Property to the Company so that the Company
may perform its obligations under this Agreement. The Company shall
cause any such individual to assign any such Intellectual Property to
the Company so that the Company may perform its obligations under this
Agreement. Any person participating in the Research Project at the
request of the Foundation shall assign any rights they may acquire in
any resulting Intellectual Property to the Foundation.
(f) LICENSES AND APPROVALS. The Company has obtained all, and will obtain
all, future, licenses, permits, consents and other approvals necessary
for the Company to perform its obligations and convey the rights
granted under this Agreement.
(g) CONFLICTING OBLIGATIONS. The Company has not granted any right or
entered into any agreement or understanding that conflicts with the
Company's obligations or the Foundation's rights under this Agreement.
The Company will not grant any right and will not enter into any
agreement or understanding that conflicts with the Company's
obligations or the Foundation's rights under this Agreement. The
Foundation has not granted any right or entered into any agreement or
understanding that conflicts with the Foundation's obligations or the
Company's rights under this Agreement. The Foundation will not grant
any right and will not enter into any agreement or understanding that
conflicts with the Foundation's obligations or the Company's rights
under this Agreement.
(h) REQUIRED THIRD PARTY INTELLECTUAL PROPERTY RIGHTS. The Company and the
Foundation shall consult with each other in order to facilitate the
licensing by the Company of any intellectual property rights of any
third party (the "REQUIRED THIRD PARTY INTELLECTUAL PROPERTY RIGHTS")
that must be licensed by the Company to use a reagent, cell line,
compound or other materials
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necessary for the Company to conduct or perform the Research Project.
The Foundation shall reimburse the Company for the out-of-pocket costs
of licensing any Required Third Party Intellectual Property Rights
provided the terms and conditions upon which such Required Third Party
Intellectual Property Rights are to be licensed are approved in
writing by the Foundation. The Foundation hereby acknowledges and
agrees that the Company is not obligated to conduct or perform the
Research Project using any reagent, cell line, compound or other
material if, in the Company's reasonable determination, the Company
does not have a valid license or other right to use such reagent, cell
line, compound or other material to conduct or perform the Research
Project.
(i) INTELLECTUAL PROPERTY. The Company owns or has the right to use
pursuant to a valid and enforceable, written license, sublicense,
agreement, or other permission, all Company Background Intellectual
Property existing as of the date hereof. Except for the Required Third
Party Intellectual Property Rights, the Company Background
Intellectual Property existing as of the date hereof constitutes all
Intellectual Property necessary or useful to conduct and perform the
Research Project and the other obligations of the Company under this
Agreement. The Company will not interfere with, infringe upon,
violate, misappropriate or otherwise come into conflict with any
Intellectual Property rights of any third party in the conduct and
performance of the Research Project.
(j) FURTHER ASSURANCES. Each Party shall execute such further documents,
instruments, licenses and assurances and take such further actions as
the other Party may reasonably request from time to time to better
enable the other Party to exercise its rights under this Agreement
and/or to confirm the terms and conditions of this Agreement.
PAYMENTS
19. PAYMENTS. Subject to the terms and conditions of this Agreement, payments
will be remitted to the Company at the address set forth in SECTION 24 of
this Agreement.
TERM; TERMINATION; EFFECT OF TERMINATION
20. DEFINITION. For the purposes of this Agreement, the term "BANKRUPTCY EVENT"
shall mean the (a) making of a general assignment for the benefit of
creditors by the an entity; (b) filing of any petition by an entity or the
commencement of any proceeding voluntarily by an entity for any relief
under any bankruptcy or insolvency laws or any law relating to the relief
of debtors; (c) consent by an entity to the entry of an order in an
involuntary bankruptcy or insolvency case; (d) entry of an order or decree
for relief against an entity by a court of competent jurisdiction in an
involuntary case under any bankruptcy or insolvency laws or any law
relating to the relief of debtors, which order or decree is unstayed and in
effect for a period of sixty (60) consecutive days; (e) appointment, with
or without
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the consent of an entity, of any receiver, liquidator, custodian, assignee,
trustee, sequestrator or other similar official of an entity or any
substantial part of its property; or (f) admission by an entity in writing
of its inability to pay its debts generally as they become due.
21. TERM; TERMINATION OF CERTAIN PROVISIONS; EFFECT OF TERMINATION OF CERTAIN
PROVISIONS.
(a) TERM. The term of this Agreement shall commence on the date hereof and
shall continue in effect until terminated (in whole or in part) in
accordance with the terms hereof or by the mutual written agreement of
the Parties.
(b) TERMINATION OF CERTAIN PROVISIONS BY THE FOUNDATION. The Foundation
may, by giving notice to the Company, elect to terminate each of the
provisions specified in SECTION 21(e)(i) of this Agreement and
discontinue the Research Project upon the occurrence and continuation
of any of the following events:
(i) CHANGE IN RESEARCH PROJECT. The Company gives a Change of
Circumstances Notice to the Foundation.
(ii) INTERRUPTION. The Research Project is interrupted for more than
90 consecutive days at any time or for more than 120 days in
any 12 month period.
(iii) SATISFACTION OR ACHIEVEMENT OF SCIENTIFIC MILESTONES. If (A)
the Company does not satisfy or achieve each of the Scientific
Milestones on or before the date such Scientific Milestone was
to be satisfied or achieved or (B) the Company does not
complete the screening required by Phase 2B of the Research
Project within 39 months of the Effective Date; provided,
however, the date of termination in respect of the termination
of this Agreement by the Foundation due to the occurrence of
the circumstances described in this SECTION 21(b)(iii) shall be
30 days following the receipt by the Company of a notice of
termination from the Foundation delivered in accordance with
this Agreement.
(iv) BREACH OF THIS AGREEMENT. If the Company (A) materially
breaches any representation or warranty given by it under this
Agreement or (B) defaults in the performance of any of its
obligations under this Agreement and such breach or default is
not remedied within 45 days of the receipt by the Company of
notice of such breach or default from the Foundation.
(v) BANKRUPTCY EVENT. The Company becomes subject to a Bankruptcy
Event.
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(c) TERMINATION OF CERTAIN PROVISIONS BY THE COMPANY. The Company may, by
giving notice to the Foundation, elect to terminate each of the
provisions specified in SECTION 21(e)(i) of this Agreement and
discontinue the Research Project upon the occurrence and continuation
of any of the following events:
(i) BREACH OF THIS AGREEMENT. If the Foundation (A) materially
breaches any representation or warranty given by it under this
Agreement or (B) defaults in the performance of any of its
obligations under this Agreement and such breach or default is
not remedied within 45 days of the receipt by the Foundation of
notice of such breach or default from the Company.
(ii) BANKRUPTCY EVENT. The Foundation becomes subject to a
Bankruptcy Event.
(d) FACILITATION OF CONTINUED RESEARCH. Upon any termination of this
Agreement, if requested by the Foundation, the Company will use its
commercially reasonable efforts to facilitate the continuance of the
Research Project elsewhere. For clarification purposes, for purposes
of this SECTION 21(d), "commercially reasonable efforts" shall mean
that the Company will (i) take the actions necessary to transfer the
research information and data, inventory, copies of notebooks,
compound libraries and the like to the Foundation (or such third party
as directed by the Foundation) and (ii) participate in telephone and
in-person discussions at mutually convenient and agreed upon times and
places.
(e) EFFECT OF TERMINATION OF CERTAIN PROVISIONS.
(i) TERMINATION OF SPECIFIED PROVISIONS; SURVIVAL OF REMAINING
PROVISIONS. Immediately upon an election by the Foundation
pursuant to SECTION 21(b) of this Agreement or by the Company
pursuant to SECTION 21(c) of this Agreement, each of any
termination of this Agreement, SECTION 2, SECTION 3(a), SECTION
4 and SECTION 19 shall immediately terminate and have no
further force or effect. The Parties hereby acknowledge and
agree that in the event of the termination of the provisions
specified in this SECTION 21(e)(i), all other sections and
provisions of this Agreement shall survive indefinitely and
remain in full force and effect.
(ii) EFFECT OF TERMINATION. The Parties hereby acknowledge and agree
that in the event of the termination of the provisions
specified in this SECTION 21(e)(i) of this Agreement shall not
(A) relieve any Party then in breach of this Agreement for any
liabilities to the other Party in respect of such breach or (B)
relieve either Party from any of the obligations such Party may
have under any of the
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sections or provisions of this Agreement that expressly survive
any termination of this Agreement.
MISCELLANEOUS
22. INDEPENDENT CONTRACTOR. The Company is acting as an independent contractor
and not an agent, joint venturer or partner of the Foundation.
23. INDEPENDENT RESEARCH. Nothing in this Agreement shall be construed to limit
the freedom of the Company to engage in similar inquiries made
independently under other contracts or agreements with parties other than
the Foundation.
24. NOTICES. Any notice required or permitted to be given by this Agreement
shall be in writing and shall be delivered by personal delivery, facsimile
(provided the sender has evidence of successful transmission) or next day
courier service. Any notice so delivered shall be deemed to be given,
delivered and received, if delivered by personal delivery, on the day of
delivery and if delivered by facsimile or courier service, on the day
following dispatch. All such notices are to be given or made to the Parties
at the following addresses (or to such other address as any Party may
designate by a notice given in accordance with the provisions of this
section):
If to the Foundation to:
CHDI, Inc.
c/o MRSSI, Inc.
000 Xxxxxxx Xxxxxx, Xxxxx 000
Xxx Xxxx, XX 00000
Attention: Xxxx Xxxx
Telephone: 000-000-0000 x000
Fax: 000-000-0000
If to Company to:
CombinatoRx, Incorporated
000 Xxxxxx Xxxxxx
Xxxxxx, XX 00000
Attention: Xxxxxx Xxxx, Vice-President
Telephone: 000-000-0000
Fax: 000-000-0000
25. INDEMNITY.
(a) The Foundation shall indemnify the Company, including, as applicable,
its directors, officers, employees and agents, against any and all
losses, costs and damages (including reasonable legal fees) suffered
by the Company (and/or such other related persons) as a result of the
Foundation's negligence, willful misconduct or breach of this
Agreement.
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(b) The Company shall indemnify the Foundation, including, as applicable,
its members, directors, officers, employees and agents, against any
and all losses, costs and damages (including reasonable legal fees)
suffered by the Foundation (and/or such other related persons) as a
result of the Company's negligence, willful misconduct or breach of
this Agreement.
26. ALTERNATIVE DISPUTE RESOLUTION. If a dispute arises out of or relates to
this Agreement (including any notice delivered in accordance with this
Agreement), or breach thereof, the Parties agree first to try in good faith
to settle such dispute, failing which such dispute shall be settled by a
single arbitrator in an arbitration in New York, NY administered by JAMS
under its Comprehensive Arbitration Rules and Procedures. The Parties
hereby agree that the arbitrator shall be instructed by each of the Parties
that (a) that this Agreement is to be narrowly construed and interpreted
and (b) the arbitrator shall not be entitled to award speculative or
consequential damage or lost profits. The arbitrator's fees and expenses
shall be shared equally by the Parties. Each Party shall be responsible for
its own costs and expenses, including fees of witnesses, consultants,
travel and attorneys' fees and disbursements. The award rendered by the
arbitrator shall be final and binding on the Parties, and judgment on the
award may be entered in any court having jurisdiction thereof if reasonably
necessary for enforcement. The Parties agree that, notwithstanding anything
to the contrary in such rules, any and all such proceedings shall be
confidential. During the pendency of any arbitration proceeding hereunder,
the Parties further agree that this Agreement shall remain in full force
and effect and the Parties shall continue to fulfill and satisfy their
respective obligations hereunder other than to the extent such obligation
is the subject of such arbitration proceeding.
27. ASSIGNMENT. The Company may not assign this Agreement without the written
consent of the Foundation, except to an entity (a) that acquires all or
substantially all of the business of the Company (whether by sale of assets
or stock or by merger) and (b) who agrees, in writing, to assume Company's
obligations under this Agreement. The Company hereby agrees that any entity
that acquires all or substantially all of the business of the Company
(whether by sale of assets or stock or by merger) shall (i) acquire the
Company's interest in the HD Intellectual Property and (ii) agree, in
writing, to assume Company's obligations under this Agreement. The
Foundation may assign this Agreement so long as the assignee expressly
assumes in writing the Foundation's obligations in this Agreement.
28. INCORPORATION OF APPENDICES AND EXHIBITS; ENTIRE AGREEMENT; AMENDMENT. The
appendices and exhibits identified in this Agreement are incorporated
herein by reference and made a part hereof. If anything in any appendix or
exhibit attached to this Agreement conflicts with any terms or conditions
set forth in the body of this Agreement, the terms and conditions set forth
in the body of this Agreement shall control. This Agreement constitutes the
entire agreement among the Parties relating to the Research Project and all
prior understandings and agreements relating to the Research Project are
superseded hereby. This Agreement may not be amended except by a document
signed by the Company and the Foundation.
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29. NO WAIVER. Any failure of a Party to enforce any provision of this
Agreement shall not be deemed a waiver of its right to enforce such
provision on any subsequent occasion. No waiver of any provision of this
Agreement shall be valid unless it is in writing and is executed by the
Party against whom such waiver is sought to be enforced. A waiver by any of
the Parties of any provision of this Agreement will not be construed to be
a waiver of any succeeding breach thereof or of any other provision of this
Agreement.
30. SEVERABILITY. Whenever possible, each provision of this Agreement shall be
interpreted in such manner as to be effective and valid under applicable
law. In the event a court of competent jurisdiction holds any provision of
this Agreement to be invalid, such holding shall have no effect on the
remaining provisions of this Agreement, and they shall continue in full
force and effect.
31. INTERPRETATION; HEADINGS. The word "including" shall mean "including
without limitation". All pronouns and any variations thereof refer to the
masculine, feminine or neuter, singular or plural, as the context may
require. All terms defined in this Agreement in their singular or plural
forms have correlative meanings when used herein in their plural or
singular forms, respectively. Headings used in this Agreement are for
convenience of reference only and are not intended to influence the
interpretation hereof.
32. GOVERNING LAW. This Agreement shall be governed by and construed in
accordance with the domestic laws of the State of Delaware without giving
effect to any choice or conflict of law provision or rule (whether of the
State of Delaware or any other jurisdiction) that would cause the
application of the laws of any jurisdiction other than the State of
Delaware.
33. NO STRICT CONSTRUCTION. The Parties have participated jointly in the
negotiation and drafting of this Agreement. In the event of an ambiguity or
question of intent or interpretation arises, this Agreement shall be
construed as if drafted jointly by the Parties, and no presumption or
burden of proof shall arise favoring or disfavoring any of the Parties by
virtue of the authorship of any of the provisions of this Agreement,
however, the Agreement is to be strictly and narrowly construed.
34. COUNTERPARTS. This Agreement may be signed, including by facsimile
signature, in two or more counterparts and each such counterpart will
constitute an original document and such counterparts, taken together, will
constitute the same instrument.
* * * * *
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In witness to the foregoing, the Parties have executed this Research
Agreement as of the date first written above.
FOUNDATION:
CHDI, Inc.
By: /s/ Xxxxxxx X. Xxxxxxx
-----------------------------------
Name: Xxxxxxx X. Xxxxxxx
Title: President
Hereunto Duly Authorized
COMPANY:
CombinatoRx, Incorporated
By: /s/ Xxxxxx Xxxxxx
-----------------------------------
Name: Xxxxxx Xxxxxx
Title: President and Chief Executive Officer
Hereunto Duly Authorized
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APPENDIX A TO RESEARCH AGREEMENT
(DESCRIPTION OF RESEARCH PROJECT)
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INTRODUCTION
GENERAL.
The goal of the Research Project is to rapidly discover novel combinations of
therapeutics that will enter clinical trials for the prevention or slowing of
the progression of Huntington disease. This Research Project description sets
forth two different mechanistic approaches towards this goal: (a) the prevention
of cytotoxicity in a cell-based model system and (b) the regulation of expanded
huntingtin (htt) protein levels in cells from Huntington disease patients.
The Research Project shall be conducted in five distinct phases (each, a
"PHASE") each of which shall be conducted over the specified period of time
beginning once all Scientific Milestones have been satisfied and all Required
Third Party Intellectual Property Rights necessary to conduct each such Phase
have been acquired by, or on behalf of, the Company. The Phases of the Research
Project are:
- Phase 1 - Assay Development and Optimization
- Phase 1A - Optimization of Assay 1
- Phase 1B - Development and Optimization of Assay 2
- Phase 1C - Development and Optimization of Assay 0
- Xxxxx 0 - Xxxxxxx Xxxxxxxxx
- Xxxxx 0X - Determination of Single Agent Activities of Selected
Compounds
- Phase 2B - Combination Screening and Nomination of Compound
Combinations for Secondary Screening
- Phase 3 - Secondary Screening
- Phase 4 - Pharmacokinetic, Pharmacodynamic and Toxicological Evaluation
- Phase 5 - Demonstration of Efficacy of Active Combinations in an
Huntington disease mouse model
Each Phase of the Research Project shall be conducted in accordance with the
estimated time frames set forth in APPENDIX B. A detailed description of the
specific research activities to be conducted during each Phase is set forth
below.
The Company's Huntington disease Therapeutic Area Team comprising PhD and
BS-level scientists will be responsible for assay development and optimization
during Phase 1 of the Research Project and then interface with the screening and
technology groups during Phases 2, 3 and 4 of the Research Project. The Research
Project will be managed by a PhD level scientist and assisted by the Company's
project management group. The broader Research Project team will include members
of the Company's computational biology, informatics and new products groups, and
later stages of the Research Project will involve the Company's IN VIVO
pharmacology, bioanalytical and clinical development groups. The Research
Project and the activities of the Research Project team shall be managed by the
Research Committee.
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The Foundation will provide funding to the Company to support the Research
Project team consisting of the number of FTE's set forth in APPENDIX B
representing all functions and expertise required to complete the Research
Project (except IN VIVO efficacy studies which will be performed at
Psychogenics, Inc. ("PSYCHOGENICS") or such other entity selected by the
Foundation). During the Phase 1 of the Research Project, the Company will staff
the research team with (a) at least one PhD scientist FTE, (b) at least one
associate scientist FTE per mechanistic approach or assay type (1. cytotoxicity
and 2. htt protein levels) and (c) one-half senior scientific management FTE.
The transition to Phase 2 of the Research Project will require the addition of
at least one screening technician FTE as well as one FTE from the screening
core.
DEFINITIONS.
For the purposes of this Agreement, the following terms have the meanings set
forth below:
- "HIT" shall mean an entity that (a) displays a concentration-response
relationship in the primary screen but not the counter assay, (b) has a
purity of greater than 90% by LC/Mass Spec and (c) is a suitable
candidate for further analysis.
- "LEAD" shall mean a Hit that (a) displays a concentration-response
relationship in selected secondary assays, (b) is blood brain barrier
penetrable and (c) is deemed of high enough quality to be tractable for
IN VIVO testing in animal models of Huntington disease.
- "CANDIDATE" shall mean a Lead that (a) exhibits sufficient efficacy in
predictive animal models of Huntington disease and (b) is suitable for
first-in-man studies.
PHASE 1 - ASSAY DEVELOPMENT AND OPTIMIZATION
GENERAL.
Two expanded huntingtin-induced cell toxicity assays will be developed and
optimized using different cell lines. The first cell toxicity assay ("ASSAY 1")
will be optimized for high-throughput screening on the Company's platform
("HTS") using a cell line that is readily available. The second cell toxicity
assay ("ASSAY 2") will be developed and optimized using a cell line which must
be engineered and validated. A third assay ("ASSAY 3" and, together with Assay 1
and Assay 2, the "ASSAYS") will be developed and optimized using a high-content
imaging system to measure htt protein levels.
The optimization of Assay 1 shall begin on the date upon which an immediately
available cell line approved by the Research Committee is acquired by, or on
behalf of, the Company. Subject to the successful optimization of Assay 1 by the
Company and the approval of Assay 1 by the Research Committee, the Company will
begin Phase 2 of the Research Project using Assay 1 while additional assays are
being developed and optimized. pilot experiments in respect of Assay 2 shall
begin on the date upon which cell lines and cDNA constructs approved by the
Research Committee are acquired by, or on behalf of, the Company. The
development and optimization of Assay 2 shall begin on the date human neuronal
cell lines (E.G., TRex Flp-In neuroblastomas) approved by the Research Committee
are acquired by, or on behalf of, the Company in order to create an inducible
expression system with constructs for wild-type and expanded htt protein
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with variable glutamine repeat lengths. Assay 3, a high contect imaging assay to
monitor expanded htt protein levels and/or the presence of htt-aggregates in
Huntington disease patient derived cell lines, shall be developed and optimized
in parallel to Assay 1 and 2 and shall begin on the date cell lines and htt
specific antibodies approved by the Research Committee are acquired by, or on
behalf of, the Company.
PHASE 1A - OPTIMIZATION OF ASSAY 1
GENERAL.
Assay 1 will be optimized using a readily available htt or expanded htt
expressing cell line. Several htt and expanded htt expressing cell lines are
available from the Huntington disease research community. These include full
length wild type and expanded htt, and exon 1 wild type and expanded htt
expressing cell lines, each with variable glutamine (Q) repeat lengths. These
cell lines have existing protocols for htt-induced cytotoxicity. Examples of
possible cell lines and protocols include:
- Humanized N-terminal Exon 1, Q111, full length htt striatal cell lines
derived from knock-in mice, chemical induced susceptibility assay
(protocol: Macdonald, Harvard/MGH).
- Tebufenozide-induced HttN90-Q103-GFP (exon1) in PC12 cells, viability
measured by release of lactate dehydrogenase (protocol: Xxxx Xxxxxxxxxx,
UCLA)
- Tebufenozide-induced HttN90-Q103-GFP (exon1) in PC12 cells, rescue from
reduction of cell viability is measured with a cell viability dye,
Alamar Blue (protocol: Xxxxx Xxxxxxxxx, Columbia Univ).
- ST14A cells (rat embryonic striatal precursor made by Xxxxx Xxxxxxxx)
induced to differentiate into striatal-like neurons with 39C and serum
W/D and express HttN548-Q120 (HEAT domain 1 plus 157 AAs), rescue from
reduction in cell viability is measured with a cell viability dye,
calcein AM (protocol: Xxxxx Xxxxxxxxx, Columbia Univ).
- HEK293 tet-induced HttN90-Q51 (exon1), rescue from cell toxicity
measured by quantifying protein content of lysates (protocol: Xxxxx
Xxxxxx, Xxx Xxxxxxxx Inst).
- Muristerine A-induced expression of Htt-Q103-EGFP in PC12 cells, GFP
cell count for fraction of cells with aggregates (protocol: Xxxx
Xxxxxxxxx, Harvard/MGH).
- HeLa cell with htt Q79, measurement of ATP depletion (protocol: Xxxxxxx,
Boston Univ).
- Among others with varying Q lengths and host cell backgrounds.
The Research Committee shall evaluate various cell lines and select up to four
cell lines for preliminary evaluation by the Company for use in Phase 1A of the
Research Project. The cell lines selected by the Research Committee shall be
acquired by, or on behalf of, the Company and conduct a preliminary evaluation
of each such cell line for its viability for optimization into Assay 1. Based
upon this preliminary evaluation by the Company, the Research Committee shall
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select one cell line to be used for optimization into Assay 1. Using the
approved cell line, the Company shall optimize such cell line into Assay 1 in
accordance with the development/optimization and validation procedures described
below. Furthermore, Assay 1 shall (a) be amenable to HTS and (b) consider each
of the following parameters as approved by the Research Committee:
- Uses a cell line that displays inducible cell death or cytotoxic
measurments dependent on the induction of expanded htt and that is
specific for the expanded form of htt and not wild type htt (I.E., the
response to expanded htt GREATER THAN wildtype htt).
- Uses a viability readout that tracks inducible cell death with an
acceptable signal to noise ratio (~3:1) and a Z' value acceptable to the
Research Committee.
- Uses an assay format amenable to a 384-well plate using one of several
viability readouts.
- Uses an inducible cytotoxic measurement that occurs on a time course
appropriate for HTS (LESS THAN 36 hours).
- Observation of dose-dependent htt induction, and parallel dose-dependent
cytotoxicity.
- Identification of one or more positive controls that inhibit the
htt-induced cytotoxicity.
- Is characterized by response to induction that is reversible upon wash
out of inducer (ability to track this will depend on protein stability
and kinetics of cell death).
- Is characterized by cell lines that will recapitulate disease relevant
features, such as sensitivity to stimulation with dopamine, glutamate or
neuronal toxin.
Upon selection of the cell line by the Research Committee, the Company will
expand and characterize the selected cell line and complete the optimization of
Assay 1 in accordance with the development/optimization and validation
procedures described below. Furthermore, Assay 1 shall (a) be amenable to HTS
and (b) meets each of the specifications set forth above.
PHASE 1B - DEVELOPMENT AND OPTIMIZATION OF ASSAY 2
GENERAL.
Assay 2 will be developed and optimized using human neuronal cell lines (E.G.,
neuroblastomas) in order to create an inducible expression system with
constructs for wild-type and expanded htt protein with variable glutamine repeat
lengths. Assay 2 will be developed and optimized by the Company using a novel
TRex Flp-In neuroblastoma cell line made by Invitrogen Corporation
("INVITROGEN"). The TRex Flp-In neuroblastoma cell line shall be transferred to
the Company for introduction by the Company of the desired htt constructs and
the creation of stably transfected human neuronal cell lines capable of inducing
htt protein expression. The Foundation shall use reasonable efforts to acquire
such TRex Flp-In neuroblastoma cell line by entering into an agreement (the
"INVITROGEN AGREEEMENT") with Invitrogen upon terms and conditions acceptable to
the Foundation in its sole discretion to develop and deliver to the Company a
TRex Flp-In neuroblastoma cell line. The Invitrogen Agreement shall require
Invitrogen to produce the TRex
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Flp-In neuroblastoma cell line substantially in accordance with the
specifications described below.
PHASE 1B - PART 1: PILOT EXPERIMENTS BY THE COMPANY.
In order to select the neuronal cell line background that will yield the desired
phenotype, a series of pilot transient transfections described below will be
performed by the Company to determine the best candidate cell lines for TRex
Flp-In stable line generation. Criteria for the selection include cell death (or
an earlier cytotoxicity measurement) after transient expression of expanded htt,
but not wild type htt, as well as attributes amenable for HTS (cell growth rate
and ease of handling).
Candidate cell lines will be transiently transfected by the Company with
wildtype and expanded htt expression constructs, both exon 1 and full length.
The expression constructs used will depend on availability in the Huntington
disease research community, but will include varying htt Q-lengths, E.G., ~20
(normal) as well as ~50 and ~100 (expanded). The cDNAs approved by the Research
Committee for use in the pilot experiments to be conducted by the Company will
be transferred from Huntington disease research community to the Company and
their sequence confirmed by the Company. Upon such confirmation, the Company
shall conduct the pilot experiments. The relative transfection efficiencies of
the wild type and expanded expression constructs will be compared to determine
which lines appear to be differentially sensitive to the expression of wild type
versus expanded htt. Cell lines for comparison include XX0X, XXX0x, and IMR32,
among other human neuronal cell lines, as well as the rodent lines N1a. and
PC-12 (a line known to display cytotoxicity upon expanded htt expression).
The expected amount of time to conduct the pilot transient transfections
described above is three months following the date upon which cell lines and
cDNA constructs approved by the Research Committee are acquired by, or on behalf
of, the Company.
PHASE 1B - PART 2: PRODUCTION OF TREX FLP-IN NEUROBLASTOMA CELL LINE BY
INVITROGEN.
Based on the transient transfection pilot experiment results, the Research
Committee shall evaluate the cell lines and, if warranted, approve up to two
cell lines for use as the parental cell lines for the generation of TRex Flp-In
stable cell lines. Upon the production of stable TRex Flp-In cell lines by
Invitrogen, which is estimated to take between eight to 12 months, the cell
lines will be transfered to the Company. The cell lines are to be produced to
ensure that the created single integration site does not negatively affect the
cell line.
PHASE 1B - PART 3: DEVELOPMENT AND OPTIMIZATION OF ASSAY 2 FROM THE TREX FLP-IN
NEUROBLASTOMA CELL LINE.
Upon receipt of the TRex Flp-In stable cell lines from Invitrogen, the Company
shall develop and optimize such cell line into Assay 2 in accordance with the
development/optimization and validation procedures described below. Furthermore,
Assay 2 shall (a) be amenable to HTS and (b) consider each of the following
parameters as approved by the Research Committee:
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- Uses a cell line that displays inducible cell death or cytotoxic
measurments dependent on the induction of expanded htt and that is
specific for the expanded form of htt and not wild type htt (I.E., the
response to expanded htt GREATER THAN wildtype htt).
- Uses a viability readout that tracks inducible cell death with an
acceptable signal to noise ratio (~3:1) and a Z' value acceptable to the
Research Committee.
- Uses an assay format amenable to a 384-well plate using one of several
viability readouts.
- Uses an inducible cytotoxic measurement that occurs on a time course
appropriate for HTS (LESS THAN 36 hours).
- Observation of dose-dependent htt induction, and parallel dose-dependent
cytotoxicity.
- Identification of one or more positive controls that inhibit the
htt-induced cytotoxicity.
- Is characterized by response to induction that is reversible upon wash
out of inducer (ability to track this will depend on protein stability
and kinetics of cell death).
- Is characterized by cell lines that will recapitulate disease relevant
features, such as sensitivity to stimulation with dopamine, glutamate or
neuronal toxin.
To develop and optimize Assay 2, the Company will transfect the TRex Flp-In cell
lines with (a) normal exon 1 of htt, (b) expanded exon 1 of htt, (c) normal full
length htt and (d) expanded full length htt, each in the appropriate vector and
epitope tagged in order to facilitate the detection of exogenous protein. The
transfected cells will then be selected to generate homogenous pools of
inducible cell lines for sceening. Upon selection of the transfected cells, the
Company will generate homogenous pools of inducible cell lines for sceening.
After the Company has generated these cell lines, the Company will prepare
frozen early passage aliquots of this cell line in sufficient quantity to ensure
that the Assay 2 is reproducible and that the Company does not have to culture
the line for extended periods. Additionally, primary neuronal cultures may be
used by the Company to establish possible neuronal characteristics of the
generated cell lines.
PHASE 1A AND 1B - ASSAY DEVELOPMENT, OPTIMIZATION AND VALIDATION PROCEDURES FOR
ASSAY 1 AND ASSAY 2
VIABILITY READOUTS.
In order to determine the optimal induction conditions for the use of each of
Assay 1 and Assay 2 in Phase 2 of the Research Project, the Company will
evaluate the stable lines for expanded htt-specific inducible cell death. The
Company will test multiple clones and pools for each of the construct/cell line
combinations. The Company will evaluate at least five viability readouts each of
which monitors some aspect of cell viability: (a) Alamar Blue reduction which
detects the presence of cellular reductases, (b) lactate dehydrogenase ("LDH")
release which is an enzyme released by dying cells, (c) cellular ATP levels
which can be detected by the use of luciferase, (d) calcein AM cleavage which
detect the presence of cellular esterases and (e) mitochondrial inner membrane
potential which is often disrupted in dying cells. For each of these viability
readouts, the Company shall optimize the variable parameters. Moreover, the
Company will test at least four concentrations of inducer (E.G., tetracycline)
in each of these assay conditions. Throughout this process, the Company will
note any morphological features specific to
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expression of expanded htt since such features may become useful in subsequent
assay design and optimization.
The Company will be able to interrogate this multiparameter space using 384-well
plates. For example, if the Company looks at five clones or pools per construct,
induces with five doses of inducer, and samples each viability assay at four
time points and five doses of assay substrate, this will require 30,000 data
points, or 100 plates. The Company can also interrogate the multiparameter space
at higher resolution by increasing the number of plates or by employing "Design
of Experiment" statistics (using JMP software). From these data, the Company
will select the cell line with the optimal Z' score (i.e. the best inducible
toxicity of expanded htt) in which wild-type htt does not cause toxicity.
DETERMINING THE KINETICS OF CELL DEATH.
In the optimal cell line selected for each of Assay 1 and Assay 2, the Company
will test a range of inducer concentrations versus length of induction time to
determine the kinetics of cytotoxicity and recovery. That is, the Company will
induce expanded htt expression, and then withdraw inducer after various lengths
of time (12 hours, 24 hours, 36 hours, etc.). In each case, the Company will
allow the cells to recover for a total incubation time of three days, at which
point the Company will select among the several previously described
cytotoxic/viability endpoints and look at the readout that is potentially
reversible (E.G., mitochondria membrane potential). This experiment will help
the Company assess the extent to which induction of expanded htt is reversible
upon removal of inducer. In parallel with these experiments, the Company will
measure the half-life of induced expanded and wild-type htt proteins using
35S pulse-chase labeling. The Company will select assay conditions based on
these experiments that allow the Company to identify both enhancers and
suppressors of htt toxicity (I.E., a concentration and length of inducer
treatment such that increases and decreases in toxicity are both detectable).
VALIDATION WITH POSITIVE CONTROLS.
The Company will validate each of Assay 1 and Assay 2 using all relevant
positive controls, with an attempt to control for a variety of cell death
mechanisms. The Company will solicit suggestions for positive control compounds
from the htt research community and will utilize those compounds approved by the
Research Committee. Potential positive control compounds include HDAC
inhibitors, neurotrophic factors, RNAi, and caspase inhibitors. For the latter,
two different pan-caspase inhibitors (Z-VAD-fmk and BOC-D-fmk) will be tested.
In addition, if the Company selects the mitochondrial membrane potential
readout, the Company will attempt to use cyclosporine A as a positive control.
The Company will test the dose-response curves for the compounds approved by the
Research Committee and the time-dependence of their ability to rescue death in
order to help determine whether timing of compound addition relative to htt
induction is an important variable and how this can be optimized for the conduct
of Phase 2 of the Research Project.
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PHASE 1C - DEVELOPMENT OF ASSAY 3
GENERAL.
Assay 3 shall be developed to monitor expanded htt protein levels and/or the
presence of htt-aggregates in Huntington disease patient derived cell lines
using high-content imaging assay. The Company shall develop Assay 3 as described
below, which assay shall consider each of the following parameters as approved
by the Research Committee:
- Use of a primary cell line that originates from Huntington disease
patient samples.
- Use of a readout that tracks htt protein levels (both wild-type and/or
expanded) relative to an internal control, such as actin.
- Use of a readout that is able to differentiate the Huntington disease
patient cell line versus control lines.
- Use of a readout that is relevant to Huntington disease disease
pathology (increased htt aggregation).
- The abnormal phenotype exhibited by the patient line will be able to be
reversed by treatment with putative control compounds, and/or RNAi.
- The high content readout will allow the identification of
intracellular/subcellular localizations, aggregates for Htt protein and
other morphological characteristics.
- A significant signal to noise ratio and Z' value acceptable to the
Research Committee.
To develop Assay 3, the Company will use a high-content screen (E.G. a Cellomics
Arrayscan automated imaging station) to capture fluorescent images of human
Huntington disease patient fibroblasts stained with Hoechst 33342 (a nuclear
dye) and antibodies available both commercially and from the Huntington disease
research community. Antibodies to expanded huntingtin, wild type huntingtin,
oligomeric expanded huntingtin and actin will be evaluated by the Company.
The Company will develop Assay 3 into a 96- or 384-well plate format compatible
for HTS, in which the Company can rapidly assess the effects of compounds on the
level of wild-type huntingtin, expanded huntingtin, and a control protein
(actin). In addition, changes in protein localization or aggregation will be
quantified.
Assay 3 will be validated using, among other controls selected by the Research
Committee, (a) HDAC inhibitors, which should up-regulate both expanded and
wild-type forms of huntingtin, (b) proteasome inhibitors, which should act
similarly to HDAC inhibitors, (c) transcription and translation inhibitors,
which should decrease the levels of both expanded and wild-type huntingtin
proteins, (d) an aldehyde-based peptidic deubiquitinating enzyme inhibitor,
which should increase the degradation of both wild-type and expanded proteins by
preventing removal of ubiquitin chains, and (e) RNAi.
EVALUATION OF CELL LINES.
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The Company will evaluate six human Huntington disease fibroblast lines and four
age/gender control fibroblasts approved by the Research Committee from the
Xxxxxxx cell repository and/or academic collaborators. Cell lines will be
evaluated for the following characteristics:
- Doubling time: this feature will be an important factor in deciding
whether or not aggregates or nuclear inclusions will be a viable
endpoint.
- Cellular localization of wild-type and expanded htt protein.
- Aggregates: determine whether aggregates are visible, and if so, the
Company will study in real-time the kinetics of aggregate formation,
reversibility with positive controls such as Congo Red.
- General morphology both at cellular level (cell membrane, cell size and
shape) and at the subcellular level (nuclei, ER, mitochondria): this
will allow thorough comparison between the Huntington disease patient
lines and the control lines, to determine all possible morphological
endpoints that can be tracked. Any such characteristic will be evaluated
as to its possible relevance to disease pathology as well as its
reversibility.
After obtaining the cell lines, the Company will cryopreserve aliquots of each
cell line. After the Company has identified and selected an optimal cell line,
the Company will prepare additional frozen early passage aliquots of this cell
line in order to allow the Company to thaw a fresh aliquot on a regular basis,
if necessary. This will ensure that Assay 3 will be reproducible without the
Company being required to culture this cell line for more than a week at a time.
EVALUATION OF ANTIBODIES.
In the development and optimization of Assay 3, the Company will test a panel of
antibodies to the antigens of interest (wild-type htt, expanded htt, oligomeric
htt and actin) for their ability to efficiently and specifically test its target
antigen. For collection and prioritization of antibodies, the Company will
collect input and suggestions about available antibodies from the Foundation and
from researchers in the Huntington disease research community. Antibodies will
be evaluated for their specificity to htt, using immuno-blotting and
immunocytochemistry. Cell lines that express tagged versions of htt will be
used, if possible, and siRNA experiments may also prove useful for distinction
of oligomeric versus monomeric htt. Test specificity/quality of antibodies that
distinguish the oligomeric versus monomeric Htt protein via dot
blot/ELISA/imaging analysis as described in the reference (see Xxxxx, et al.
2003).
ASSAY OPTIMIZATION.
The Company will test the candidate antibody/cell line combinations that meet
the above qualifications, varying primary/secondary antibody concentrations, and
the time of incubation (testing five time points) to optimize the assay staining
conditions. For instance, the Company could test 5 time points x 10
concentrations x 400 antibody/cell line combinations = 20,000 data points. Using
384-the well plates, this will require ~100 plates, which is feasible, given an
assumed plate processing capacity of 100 plates per day in high-content mode.
From these data, the Company will select the cell line with the optimal Z' score
for all signals being detected. The Company will then iterate several additional
cycles of optimizing the assay conditions (plate
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type, medium composition, secondary antibody, length of incubation, etc.) to
prepare the Assay 3 for cHTS. In the development of Assay 3, the Company will
use "Design of Experiment" statistics (using JMP software) to sample this
multiparameter space.
VALIDATION WITH CONTROLS.
The Company will seek a broad panel of potential positive controls for testing
in Assay 3 to validate the selected cell line using two different pan-caspase
inhibitors (Z-VAD-fmk and BOC-D-fmk), which may affect processing or
localization of htt. Assay 3 will also be validated using (a) HDAC inhibitors,
which should up-regulate both expanded and wild-type forms of huntingtin, (b)
proteasome inhibitors, which should act similarly to HDAC inhibitors, (c)
transcription and translation inhibitors, which should decrease the levels of
both expanded and wild-type huntingtin proteins, (d) an aldehyde-based peptidic
deubiquitinating enzyme inhibitor, which should increase the degradation of both
wild-type and expanded proteins by preventing removal of ubiquitin chains and
(e) known anti-aggregation compounds derived from the Foundation secondary
screening collection. The Company will test the dose-response curves for these
compounds and the time-dependence of their effects. This will help determine
whether length of compound treatment is an important variable and how this can
be optimized for Phase 2 of the Research Project.
PHASE 2 - PRIMARY SCREENING
GENERAL.
Upon the completion of the development of each Assay by the Company, the
Research Committee shall evaluate each such Assay for use in Phase 2 of the
Research Project. Each Assay approved by the Research Committee for use in Phase
2 of the Research Project (each, an "APPROVED PRIMARY SCREENING ASSAY") shall be
utilized by the Company in Phase 2 of the Research Project.
Phase 2 of the Research Project shall be conducted in two sub-phases: Phase 2A
and Phase 2B of the Research Project. In Phase 2A of the Research Project, the
Company will screen at least ~1,600 in each Approved Primary Screening Assay to
determine the "single agent" activities of such compounds. And, in Phase 2B of
the Research Project, the Company shall use the results from Phase 2A of the
Research Project to determine a recommended combination screening strategy and,
subject to the approval of such combination screening strategy by the Research
Committee, the Company shall screen between 100,000 and 1,000,000 binary
combinations of compounds in each Approved Primary Screening Assay.
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PHASE 2A - DETERMINATION OF SINGLE AGENT ACTIVITIES OF SELECTED COMPOUNDS
GENERAL.
Utilizing each Approved Primary Screening Assay, the Company shall determine the
"single agent" activities of at least 1,300 compounds utilizing a dose-response
of concentrations. The Company will select at least 1,300 from the Company's
library of approved compounds ("COMPANY LIBRARY COMPOUNDS") with a focus on
selecting compounds with highest probability of crossing the blood-brain barrier
(the "BBB"). In addition, the Foundation shall have the right to identify and
select up to 300 compounds ("FOUNDATION SELECTED COMPOUNDS") that are of
particular interest to research currently being conducted in the broader
Huntington disease research community, including those previously identified IN
VITRO and/or studied IN VIVO. The Company shall screen all of the Company
Library Compounds and the Foundation Selected Compounds to determine the "single
agent" activity of such compounds.
COMPOUND SELECTION.
The Company will select at least 1,300 Company Library Compounds which fully
represent the mechanistic and structural diversity of approved compounds. Upon
the request of the Foundation, the Company Library Compounds can be prioritized
by their likelihood of crossing the BBB, based on the Company's internal BBB
ranking. The Company's internal analysis takes the factors into consideration:
(a) known CNS effect in humans, as demonstrated by therapeutic class or
documented side-effect in the literature, (b) the ability to cross BBB in
experimental system, as demonstrated by published experiments and (c) in silico
prediction of BBB partitioning, based on chemical structure. The up to 300
Foundation Selected Compounds to be screened will be selected from the following
categories: 50-100 compounds from the Foundation's secondary screening
consortium, 208 compounds that the Foundation has identified from the literature
as potentially being of interest for Huntington disease, and approximately 100
biological agents that have been reported to be of interest to Huntington
disease. These lists will be cross referenced with the Company collection to
identify compounds that are already available at the Company, and up to 300 of
those that are not will be acquired by the Company. The precise number of
Foundation Selected Compounds acquired will depend on their availability. The
Company will discuss the possibility of formatting the biological agents for
screening with EMD Biosciences. If the Company does not reach an acceptable
arrangement with this or another supplier, the Company will purchase these
proteins individually, then format them in 384-well plates, heeding the
manufacturers' instructions regarding storage conditions.
SCREENING.
The Company's screening method begins with a "ranking" phase where the single
agent activity of compounds in our libraries is determined. Ranking of single
agents is generally performed in a 2 x 12 format as described below, although
this may be tailored to the specific needs of a particular assay. Based on this
ranking, compounds are classified as "active," possessing activity in the
subject assay, or "inactive," possessing no activity the subject assay.
Separating the testing
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of active and inactive compounds makes an efficient and complete search of all
pair-wise combinations tractable.
2 x 12 RANKING FORMAT.
Each 384-well ranking plate contains nine different compounds, numbered 1-9,
that are plated in two adjacent columns and are diluted from top to bottom in 12
steps. Positive controls are located in columns two and 23. DMSO treated
negative controls are located in columns nine and 16.
COUNTER SCREENING.
Putative Hits from the Phase 2A screening will be tested in variants of each
Approved Screening Assay to eliminate false positive results. These counter
screens will identify compounds that (a) suppress expression of expanded htt,
(b) alter the concentration or metabolism of inducer, or (c) directly activate
the assay readout (I.E., are fluorescent or react with luciferase) by using cell
lines that express wild type htt; or by running the assay without cells or
primary antibodies. Testing in the approved counter screens is requisite for
proceeding onto Phase 2B.
PHASE 2B - COMBINATION SCREENING AND NOMINATION OF COMPOUND COMBINATIONS FOR
SECONDARY ASSAY(S)
GENERAL
The Research Committee shall use the actual throughput achieved during Phase 2A
of the Research Project, together with the compound activity results of the
single agent ranking, to determine a recommended combination screening strategy.
The determination of a recommended combination screening strategy will be
influenced by the number of actives that emerge from the single agent ranking
and the throughput of the screening using each Approved Primary Screening Assay.
The recommended combination screening strategy shall be approved by the Research
Committee prior to the initiation of Phase 2B of the Research Project. The
combination screening strategy approved by the Research Committee will be used
to survey between 100,000 and 1,000,000 pairwise combinations, as described
below.
Using the combination screening strategy approved by the Research Committee, the
Company shall screen between 100,000 and 1,000,000 binary combinations of
compounds in each Approved Primary Screening Assay. The most active combinations
will be retested at high resolution and confirmed hits will be subjected to IN
SILICO prioritization based on achievable plasma concentrations, known
toxicities, known drug-drug incompatibilities and other literature information
in the Company's chalice knowledgebase. Due to the size and diversity of
combination space, a library of 1,600 compounds contains over 1,000,000 unique
pair-wise combinations. Thus, a relatively small number of known compounds
generates a very large number of possible compound combinations. Such a large
and diverse group of potential compound combinations greatly increases the
likelihood of the identification of a novel Huntington disease therapeutic. If
any of the Approved Primary Screening Assays is a high
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throughput assay that can be processed at the Company's standard throughput, the
Company will be able to screen more than 1,000,000 binary compound combinations
in each such Approved Primary Screening Assay.
Based on information from the ranking phase, there are several types of
combination screens the Company performs:
(a) "active + active" - all active compounds are crossed with each
other;
(b) "active + inactive" - all active compounds are crossed with all
inactive compounds; and
(c) "inactive + inactive" - all inactive compounds are crossed with each
other.
In brief, active compounds are tested in combination against the other actives
using a dose-ratio matrix format and inactive compounds are tested using a
pooling strategy to maximize the number of combinations that can be surveyed on
a single plate.
In dose matrix screening, a focus compound is serially diluted from
top-to-bottom using a fixed dilution factor. The EC50 value determined is used
to target the appropriate concentration range. Cross compounds are serially
diluted from left-to-right on a separate plate. Aliquots from each master plate
are transferred to a third plate to create the dose matrix. Cells and other
components of the assay are then added prior to incubation to allow induction of
the combination effect. Assay plates are processed and data collected are
associated with the specific compound combination. This experimental design
allows efficient automation of the compound distribution process to generate all
possible pairwise combinations after preparation of a small set of master
plates.
The screening will be conducted using optimized plate formats to efficiently
take advantage of the single-agent activity information. Active compounds (peak
inhibition GREATER THAN 20% at 95% confidence from replicates) require complete
coverage of the transitional concentrations of the single-agent response curves
(between the EC10 and EC90 concentrations), while this range cannot be specified
in the case of inactive compounds. For example, the Company has designed
sparse-matrix plate formats which permit 54 blocks to be compressed on to a
plate, which can be reconstructed to produce sparsely sampled 6x6 dose matrix
blocks. For inactive compounds, the Company uses a single-concentration
combination format which represents 208 combinations per plate, along with the
corresponding single agent responses. For combinations involving one active and
one inactive agent, the master plates are compatible, producing combination
blocks with two six point dose-response curves, one with the inactive compound
at a single high concentration.
High-resolution "9x9" combination plates are run to confirm detection of
synergistic combinations and to allow quantitation of combination activity. A
smaller dilution factor (E.G., two) and a nine-step dilution curve are used for
each compound in the combination to provide greater precision in describing the
synergy surface. This is important because observed effects are next compared to
expected response surfaces derived from the single-agent response curves using
established reference models for compound interactions.
In addition to the above-described cHTS screen, the Company has the ability to
perform "enhancer" screens on select compounds of interest. In this screening
mode, the Company tests a specific compound of interest against each of the
compounds in our collection to identify drugs
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that enhance the potency or intrinsic activity of a compound of interest. Such
enhancer screening can be performed using compounds discovered by the Huntington
disease Research Project community and will be added at the request and approval
of the Research Committee.
If assay throughput is a limiting factor, the Company will consider alternative
combination screening strategies that will allow the Company to optimally
explore the combination space within the time allotted. At a minimal, this
screen would examine 100,000 combinations. For instance, the Company could focus
on 35 single agent actives from the primary screen and perform both a 35 x 35
screen, as the well as an enhancer screen that would pair each of the 35 actives
with each of the ~1600 compounds in the ranking library as described above.
COUNTER SCREENING.
Putative Hit combinations from the Phase 2B screening will be tested in variants
of each Approved Screening Assay to eliminate false positive results. These
counter screens will identify compound combinations that (a) suppress expression
of expanded htt, (b) alter the concentration or metabolism of inducer, or (c)
directly activate the assay readout (I.E., are fluorescent or react with
luciferase) by using cell lines that express wild type htt; or by running the
assay without cells or primary antibodies. Testing in the approved counter
screens is requisite for proceeding onto Phase 3.
PHASE 3 - SECONDARY SCREENING
GENERAL.
At any time and from time to time during the conduct of Phase 2B of the Research
Project, the Research Committee may evaluate compound combinations for which the
screening is completed for utilization in Phase 3 of the Research Project. Each
compound combination approved by the Research Committee for utilization in Phase
3 of the Research Project (each, a "PHASE 3 APPROVED COMPOUND COMBINATION")
shall be utilized by the Company in Phase 3 of the Research Project for
secondary screening.
In Phase 3 of the Research Project, Phase 3 Approved Compound Combinations will
be prioritized using a panel of secondary assays selected and approved by the
Research Committee (each, an "APPROVED SECONDARY SCREENING ASSAY") including (a)
each of the Approved Primary Screening Assays and (b) the additional assays
described below (such as those that may be available from the Huntington disease
research community) that would further characterize and validate the Phase 3
Approved Compound Combinations being developed. Phase 3 Approved Compound
Combinations will be prioritized and tested to validate the observed activities
and to determine the selectivity of the mechanism of action.
EFFECT IN ALTERNATE COMPANY DEVELOPED AND OPTIMIZED ASSAYS.
Each Approved Primary Screening Assay will serve as a secondary assay for the
other. The Company will test Hit combinations from each Approved Primary
Screening Assay in each of the other Approved Primary Screening Assays that have
been developed and optimized. This will
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serve to determine if suppressors of cytotoxicity affect disposition of expanded
or wild type htt, and if modulators of htt disposition can affect cytotoxicity
of htt.
IMMUNO-BLOT OF HTT LEVELS.
The Company will measure expanded and wild type htt levels (induced for Assay 1
and Assay 2, and endogenous for Assay 3) to determine whether compounds are
affecting the overall levels of htt. For Assay 1 and Assay 2, this will serve as
a counter screen for false positives. For Assay 3, this will serve to confirm
one type of hit class: modulators of htt levels. Also, if an ELISA is available,
the Company will also use it to conduct such testing.
ACTIVITY IN ADDITIONAL CELL LINES.
The Company will test Hit combinations in additional cell lines that were
identified in Phase 1 of the Research Project. Thus, the Company will test
suppressors of cytotoxicity in additional cell backgrounds for their ability to
suppress htt cytotoxicity and the Company will test modulators of htt
disposition for their ability to act in additional Huntington disease patient
fibroblasts. These Approved Secondary Screening Assays will ensure any compound
effects are not idiosyncratic to the one cell line used in the primary screen.
STRIATAL BRAIN SLICE ASSAY.
Subject to the approval of the Research Committee, the Company will collaborate
with Don Lo (Duke University) and colleagues to test active combinations in the
striatal brain slice assay that is currently being run in Dr. Lo's laboratory.
Other assays being developed in Dr. Lo's lab, including those with co-culture of
striatal and cortical neurons, may also prove useful as secondary assays.
TRANSFECTED PRIMARY STRIATAL NEURON ASSAY.
Subject to the approval of the Research Committee, the Company will collaborate
with Trophos S.A. (Marseille, France) to test Hit combinations in the
transiently transfected striatal neuron cytotoxicity assay.
OTHER SECONDARY ASSAYS.
The Company welcomes the input from the Foundation to facilitate the evaluation
of candidate combinations with the most disease-relevant secondary assays
available. Subject to the approval of the Research Committee, the Company will
bring such assays in-house if the identified laboratories are unable to test the
Phase 3 Approved Compound Combinations in such assays.
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PHASE 4 - PHARMACOKINETIC, PHARMACODYNAMIC AND TOXICOLOGICAL EVALUATION
GENERAL.
At any time and from time to time during the conduct of Phase 3 of the Research
Project, the Research Committee may evaluate compound combinations for which the
screening is completed for utilization in Phase 4 of the Research Project. Each
Phase 3 Approved Compound Combinations approved by the Research Committee for
utilization in Phase 4 of the Research Project (each, a "PHASE 4 APPROVED
COMPOUND COMBINATION") shall be utilized by the Company in Phase 4 of the
Research Project for evaluation in rodents to determine whether such Phase 4
Approved Compound Combination exhibits desired pharmaceutical properties
expected from the profiles of the single agents, including matched half-lives,
if necessary, BBB penetration to sufficient concentrations and minimal toxicity.
PHARMACOKINETIC / PHARMACODYNAMIC ANALYSIS OF PRE-CLINICAL CANDIDATES.
The Company will evaluate each Phase 4 Approved Compound Combination in rodents
to determine whether the each such Phase 4 Approved Compound Combination
exhibits the desired pharmaceutical properties in combination. The Research
Committee will select and approve a up to six Phase 4 Approved Compound
Combination which the Company will be assess IN VIVO, in mouse-based
pharmacokinetic, pharmacodynamic studies and blood-brain barrier penetration
studies. The Company will assess the concentration found in blood and brain for
the individual compounds in each Phase 4 Approved Compound Combination after
oral gavage, IP, IM and IV injection in adult mice. The route of administration
that provides an achievable brain concentration above the concentration required
will be explored further using a variety of doses and time points. These latter
experiments will aim to determine the half-life of each Approved Phase 4
Compound Combination and such compound combination's constituent compounds in
blood and brain after a specific method of administration. These studies will
allow the Company to select Phase 4 Compound Combinations for further study that
cross the blood-brain barrier and that have reasonable half-lives and achieve
concentrations IN VIVO such that the Company expects them to act in the central
nervous system ("CNS"). Animals will be perfused with 0.9% saline prior to
removal of brain tissue to provide a more accurate estimate of the final drug
concentration in the tissue. Phase 4 Compound Combinations selected by the
Research Committee will then be given using the selected route of administration
to adult mice for one week (or longer if recommended by the Research Committee),
and toxicity measured using body weight and behavioral monitoring. Phase 4
Approved Compound Combinations that are non-toxic at the required dose will be
further studied in newborn mice. The Company will administer these Phase 4
Approved Compound Combinations to mice using the selected route of
administration and the achievable concentration in blood and brain will be
measured. These studies will confirm that such Phase 4 Approved Compound
Combinations can be administered to newborn mice, cross the blood-brain barrier
and accumulate to a sufficient concentration in the nervous system that the
Company expects protection from expanded htt pathology to occur.
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PHASE 5 - DEMONSTRATION OF EFFICACY OF ACTIVE COMBINATIONS IN A HUNTINGTON
DISEASE MOUSE MODEL
GENERAL.
Upon the completion the pharmacokinetic, pharmacodynamic and toxicological
evaluation of each Phase 4 Approved Compound Combination in Phase 4 of the
Research Project, the Foundation may evaluate and select Phase 4 Approved
Compound Combinations for utilization in Phase 5 of the Research Project. Each
Phase 4 Approved Compound Combination selected by the Foundation for utilization
in Phase 5 of the Research Project for evaluation a mouse Huntington disease
efficacy model shall be referred to herein a "PHASE 5 APPROVED COMPOUND
COMBINATION".
MOUSE MODEL TESTING.
Each Phase 5 Approved Compound Combination will be tested using the most disease
relevant animal model that is available at the time such Phase 5 Approved
Compound Combination is available to be as determined by the Foundation. As of
the date hereof, the most relevant animal model available is the R6/2 Huntington
disease mouse model. The Foundation shall solicit input from the Company in
respect of the nature and extent of the mouse model testing program to be
utilized under Phase 5 of the Research Project. However, the specific timing,
nature and extent of all mouse model testing under the Phase 5 Approved Compound
Combinations under Phase 5 of the Research Project shall be determined by the
Foundation in its sole discretion and all such testing shall be carried out at
the sole direction of the Foundation.
All mouse model testing of the Phase 5 Approved Compound Combinations under
Phase 5 of the Research Project shall be conducted by Psychogenics or such other
entity as the Foundation shall elect in its sole discretion. The costs of any
mouse model testing of the Phase 5 Approved Compound Combinations under Phase 5
of the Research Project conducted at the direction of the Foundation shall be
paid by the Foundation.
IN VIVO pharmacological testing of Huntington disease model animals will be done
using multiple dose levels and a subset will receive single agents alone as a
control. These animal studies will include both short term (LESS THAN 2 months)
and long term (6 month survival) endpoints. Critical information regarding the
efficacy and potential safety of administering the Phase 5 Approved Compound
Combinations will also be collected.
The results of mouse model testing of the Phase 5 Approved Compound Combinations
shall be used by the Parties to determine whether any of the Phase 5 Approved
Compound Combinations constitutes a Candidate for which the Parties should seek
the filing of an IND with the FDA either by the Company or a third party. Any
such determination shall be made subject to, and in accordance with, the terms
of this Agreement (including SECTION 9, SECTION 10 and SECTION 12).
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APPENDIX B TO RESEARCH AGREEMENT
(RESEARCH PROJECT TIME FRAMES AND FTE BUDGET)
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APPENDIX C TO RESEARCH AGREEMENT
(SCIENTIFIC MILESTONES)
Research Project Phase Condition(s) to Begin Conduct of Phase
---------------------- --------------------------------------
RESEARCH PROJECT - SCIENTIFIC MILESTONES
Phase 1 through Phase 5 Execution of this Agreement by the Parties.
The Research Committee has made each decision and granted
each approval expressly set forth in this Agreement that is
specifically required or otherwise necessary to begin the
conduct of any specific Phase of the Research Project.
Xxxxx 0X Xx least four cell lines approved by the Research Committee
for Phase 1A (a) have been acquired by, or on behalf of the
Company (including any related Required Third Party
Intellectual Property Rights) and (b) the Company has taken
delivery of such cell lines within three months of the
Effective Date.
Phase 1B - Part 1 The cell lines and cDNA constructs approved by the Research
Committee for Phase 1B - Part 1 (a) have been acquired by, or
on behalf of the Company (including any related Required
Third Party Intellectual Property Rights) and (b) the Company
has taken delivery of such cell lines and cDNA constructs
within three months of the Effective Date.
Phase 1B - Part 2 The Research Committee has approved at least one cell line
for use as the parental cell line for the generation of the
TRex Flp-In neuroblastoma cell line by Invitrogen within six
months of the Effective Date.
The Foundation and Invitrogen have executed the Invitrogen
Agreement within six months of the Effective Date.
Phase 1B - Part 3 Invitrogen has delivered the TRex Flp-In neuroblastoma cell
line to the Company within 12 months of the execution of the
Invitrogen Xxxxxxxxx.
Xxxxx 0X The cell lines and htt specific antibodies approved by the
Research Committee for Xxxxx 0X (x) have been acquired by, or
on behalf of the Company (including any related Required
Third Party Intellectual Property Rights) and (b) the Company
has taken delivery of such cell lines and cDNA constructs
within three months of the Effective Date.
Phase 2 and 3 - Use of Assay 1 for Screening Complete optimization of Assay 1 within four months following
the date the Company has taken delivery of the cell
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line approved by the Research Committee for use in the
optimization of Assay 1.
Assay 1 meets each of the specifications set forth in
APPENDIX A and is approved by the Research Committee for use
in Phase 2 and 3.
Phase 2 and 3 - Use of Assay 2 for Screening Complete development and optimization of Assay 2 within five
months following the delivery of the TRex Flp-In
neuroblastoma cell line to the Company.
Assay 2 meets each of the specifications set forth in
APPENDIX A and is approved by the Research Committee for use
in Phase 2 and 3.
Phase 2 and 3 - Use of Assay 3 for Screening Complete development and optimization of Assay 3 within nine
months following the date cell lines and htt specific
antibodies approved by the Research Committee for use in the
development and optimization of Assay 3 are acquired by, or
on behalf of, the Company.
Assay 3 meets each of the specifications set forth in
APPENDIX A and is approved by the Research Committee for use
in Phase 2 and 3.
Phase 2A The Company has (a) selected at least 1,300 Company Library
Compounds within one month of the approval by the Research
Committee of any of the Assays for use in Phase 2 and 3 and
(b) acquired each Foundation Selected Compound within one
month of the selection of such compounds by the Foundation.
Phase 2B The screening required by Phase 2A has been completed within
26 months of the Effective Date.
The combination screening strategy for Phase 2B is approved
by the Research Committee.
Phase 3 The Research Committee approves at least one Phase 3 Approved
Compound Combination.
Phase 4 The Research Committee approves at least one Phase 4 Approved
Compound Combination.
Phase 5 The Foundation approves at least one Phase 5 Approved
Compound Combination.
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APPENDIX D TO
RESEARCH AGREEMENT
(PAYMENT SCHEDULE)
Payment Number Payment Amount Date(s) and/or Condition(s) of Payment
-------------- -------------- --------------------------------------
QUARTERLY PAYMENTS
Payment 1 $ 343,750 Execution of this Agreement by the Parties.
Year 1 - Quarter 1
Payment 2 $ 368,750 Achievement or satisfaction of each condition set forth in
Year 1 - Quarter 2 this APPENDIX D in respect Payment 1.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 1.
Payment 3 $ 425,000 Achievement or satisfaction of each condition set forth in
Year 1 - Quarter 3 this APPENDIX D in respect Payment 1 through Payment 2.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 2.
Payment 4 $ 525,000 Achievement or satisfaction of each condition set forth in
Year 1 - Quarter 4 this APPENDIX D in respect Payment 1 through Payment 3.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 3.
Payment 5 $ 471,875 Achievement or satisfaction of each condition set forth in
Year 2 - Quarter 1 this APPENDIX D in respect Payment 1 through Payment 4.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 4.
Payment 6 $ 531,250 Achievement or satisfaction of each condition set forth in
Year 2 - Quarter 2 this APPENDIX D in respect Payment 1 through Payment 5.
EXECUTION COPY
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 5.
Payment 7 $ 512,500 Achievement or satisfaction of each condition set forth in
Year 2 - Quarter 3 this APPENDIX D in respect Payment 1 through Payment 6.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 6.
Payment 8 $ 540,625 Achievement or satisfaction of each condition set forth in
Year 2 - Quarter 4 this APPENDIX D in respect Payment 1 through Payment 7.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 7.
Payment 9 $ 537,500 Achievement or satisfaction of each condition set forth in
Year 3 - Quarter 1 this APPENDIX D in respect Payment 1 through Payment 8.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 8.
Payment 10 $ 400,000 Achievement or satisfaction of each condition set forth in
Year 3 - Quarter 2 this APPENDIX D in respect Payment 1 through Payment 9.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 9.
Payment 11 $ 365,625 Achievement or satisfaction of each condition set forth in
Year 3 - Quarter 3 this APPENDIX D in respect Payment 1 through Payment 10.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 10.
Payment 12 $ 365,625 Achievement or satisfaction of each condition set forth in
Year 3 - Quarter 4 this APPENDIX D in respect Payment 1 through Payment 11.
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EXECUTION COPY
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 11.
Payment 13 $ 331,250 Achievement or satisfaction of each condition set forth in
Year 4 - Quarter 1 this APPENDIX D in respect Payment 1 through Payment 12.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 12.
Payment 14 $ 193,750 Achievement or satisfaction of each condition set forth in
Year 4 - Quarter 2 this APPENDIX D in respect Payment 1 through Payment 13.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 13.
Payment 15 $ 100,000 Achievement or satisfaction of each condition set forth in
Year 4 - Quarter 3 this APPENDIX D in respect Payment 1 through Payment 14.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 14.
Payment 16 $ 100,000 Achievement or satisfaction of each condition set forth in
Year 4 - Quarter 4 this APPENDIX D in respect Payment 1 through Payment 15.
The completion by the Foundation, in accordance with SECTION
3(c), of the Quarterly Payment adjustment review and
calculation procedures in respect of the Quarterly FTE
Notice delivered by the Company for the Quarterly FTE Notice
Period covered by Payment 15.
MILESTONE PAYMENTS
Payment 1 $ 40,000 Phase 2B screening has been completed for all Approved
Primary Screening Assays and the results of such screening
have been delivered to the Research Committee within 39
months of the Effective Date
Payment 2 $ 100,000 With respect to each Phase 5 Approved Compound Combination
licensed to an entity (other than the Company) pursuant to a
Commercial License granted in accordance with SECTION 10 of
this Agreement.
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EXECUTION COPY
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