Exhibit 10.4
EXECUTION COPY
RESEARCH, DEVELOPMENT AND COMMERCIALIZATION AGREEMENT
BETWEEN
PREDIX PHARMACEUTICALS HOLDINGS, INC.
AND
CYSTIC FIBROSIS FOUNDATION THERAPEUTICS INCORPORATED
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Research, Development and Commercialization Agreement
TABLE OF CONTENTS
Page
ARTICLE I - DEFINITIONS..................................................... 2
ARTICLE II - RESEARCH PROGRAM............................................... 8
2.1 Commencement; Objective............................................. 8
2.2 Term................................................................ 9
2.3 Research Diligence.................................................. 9
2.4 Research Plan....................................................... 9
2.5 Joint Research Committee............................................ 10
2.6 Exchange of Information............................................. 11
ARTICLE III - PAYMENTS...................................................... 12
3.1 Staffing and Research Support Payments.............................. 12
3.2 Payments............................................................ 14
3.3 Records............................................................. 15
ARTICLE IV - COMMERCIALIZATION; ROYALTIES................................... 16
4.1 Discovery and Commercialization of a CFTR Corrector-Based Product;
Commercialization of P2(Y)2 Product....................................... 16
4.2 Due Diligence....................................................... 16
4.3 Royalties........................................................... 17
4.4 Sales Reports....................................................... 17
ARTICLE V - CONFIDENTIALITY................................................. 19
5.1 Undertaking......................................................... 19
5.2 Exceptions.......................................................... 20
5.3 Publicity........................................................... 21
ARTICLE VI - PUBLICATION.................................................... 22
ARTICLE VII - INDEMNIFICATION............................................... 24
7.1 Indemnification by Predix........................................... 24
7.2 Claims Procedures................................................... 25
ARTICLE VIII - PATENTABLE INVENTIONS........................................ 26
8.1 Ownership........................................................... 26
8.2 Preparation......................................................... 27
8.3 Costs............................................................... 27
ARTICLE IX - TERM AND TERMINATION........................................... 27
9.1 Term................................................................ 27
9.2 Termination of the Research Programs Without Cause.................. 28
9.3 Termination of the Research Program by CFFT for Cause............... 28
9.4 Termination of the Research Program by Predix for Cause............. 28
9.5 General Effect of Termination....................................... 29
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9.6 Consequences of an Interruption..................................... 29
ARTICLE X - REPRESENTATIONS AND WARRANTIES.................................. 30
10.1 Representations and Warranties of Predix............................ 30
10.2 Representations and Warranties of CFFT.............................. 31
ARTICLE XI - MISCELLANEOUS PROVISIONS....................................... 31
11.1 Governing Law, and Jurisdiction..................................... 31
11.2 Waiver.............................................................. 31
11.3 Force Majeure....................................................... 32
11.4 Severability........................................................ 32
11.5 Government Acts..................................................... 32
11.6 Assignment.......................................................... 33
11.7 Counterparts........................................................ 33
11.8 No Agency........................................................... 34
11.9 Notice.............................................................. 34
11.10 Headings............................................................ 35
11.11 Authority........................................................... 35
11.12 Entire Agreement.................................................... 36
11.13 Notice of Pharmaceutical Side-Effects............................... 36
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RESEARCH, DEVELOPMENT AND COMMECIALIZATION AGREEMENT
This Agreement (this "Agreement") is made on this 7th day of March, 2005
(the "Effective Date"), between Predix Pharmaceuticals Holdings, Inc.
("Predix"), a Delaware corporation with principal offices at 10K Xxxx Xxxxxx,
Xxxxxx, XX 00000, and Cystic Fibrosis Foundation Therapeutics Incorporated, a
Delaware corporation with its principal offices at 0000 Xxxxxxxxx Xxxx,
Xxxxxxxx, Xxxxxxxx 00000 ("CFFT"). Collectively, Predix and CFFT shall be
referred to hereinafter as the "Parties".
WHEREAS, Predix has expertise in 3D technology and the discovery and
development of small molecule compounds addressing a variety of diseases; and
WHEREAS, CFFT is significantly focused on the discovery and development of
methods of treatment of cystic fibrosis, to which CFFT and its Affiliates bring
significant scientific and human resources and financial support; and
WHEREAS, CFFT wishes to support the Research Programs specified
hereinafter to be undertaken by Predix;
NOW, THEREFORE, in consideration of the mutual covenants set forth in this
Agreement, and other good and valuable consideration, the Parties agree as
follows:
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ARTICLE I - DEFINITIONS
For purposes of this Agreement, the terms defined in this Article 1 shall
have the following meanings whether used in their singular or plural forms. Use
of the singular shall include the plural and vice versa, unless the context
requires otherwise:
1.1 "Affiliate" shall mean, with respect to any Person, any other Person
who directly or indirectly, by itself or through one or more intermediaries,
controls, or is controlled by, or is under direct or indirect common control
with, such Person. The term "control" means the possession, direct or indirect,
of the power to direct or cause the direction of the management and policies of
a Person, whether through the ownership of voting securities, by contract or
otherwise. Control will be presumed if one Person owns, either of record or
beneficially, more than fifty percent (50%) of the voting stock of any other
Person. For the avoidance of any doubt, the Cystic Fibrosis Foundation and CFFT
are considered to be Affiliates.
1.2 "Agreement" means this agreement, together with all appendices,
exhibits and schedules hereto, and as the same may be amended or supplemented
from time to time hereafter by a written agreement duly executed by authorized
representatives of each party hereto.
1.3 "Budget" shall mean the total amount to be paid by CFFT to Predix for
each of Research Program I and Research Program II as specified in Article III.
1.4 "CF" means the disease known as Cystic Fibrosis.
1.5 "CF Field" means the treatment of humans diagnosed with CF.
1.6 "CFTR" shall mean a CF transmembrane conductance regulator protein
which has the biological effect of transporting molecules across human cellular
membranes.
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1.7 "Commercially Reasonable Efforts" shall have the definition set forth
in Section 4.2.
1.8 "Controlled" (except in the context of Section 1.1) shall mean the
legal authority or right of a party hereto to grant a license or sublicense of
intellectual property rights to another party hereto, or to otherwise disclose
proprietary or trade secret information to such other party, without breaching
the terms of any agreement with a Third Party, infringing upon the intellectual
property rights of a Third Party, or misappropriating the proprietary or trade
secret information of a Third Party.
1.9 "Corrector" shall mean a compound which, as its principal mode of
therapeutic action, modulates the biological effect of CFTR by increasing the
amount of functional AF508 CFTR present at the apical cell membrane.
1.10 "Effective Date" shall mean the date specified in the first paragraph
of this Agreement.
1.11 "Field" shall mean the treatment of conditions or diseases in the CF
Field and the Pulmonary Field.
1.12 "First Commercial Sale" shall mean the first sale of a P2(Y)2 Product
by Predix or an Affiliate, licensee or sublicensee of Predix in a country in the
Territory following Regulatory Approval of the P2(Y)2 Product in that country
or, if no such Regulatory Approval or similar marketing approval is required,
the date upon which the P2(Y)2 Product is first commercially launched in that
country.
1.13 "FTE" shall mean the equivalent of the work of one Predix scientist
or other project managerial professional, full time for one year, on or directly
related to the Research
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Program. Activities included in calculating FTE's shall not include negotiation
of this Agreement or modifications or extensions thereof or administration
activities such as accounting, invoicing, personnel related activities or the
like.
1.14 "Hit" shall have the meaning ascribed to it in Section 3.1.2 of this
Agreement.
1.15 "Interruption" shall occur (i) if at any time before the First
Commercial Sale of a P2(Y)2 Product, Predix, its Affiliates and sublicensees,
all cease to conduct, or have conducted, research activities associated with the
development of such Product for a period of one hundred and eighty (180)
consecutive days; and (ii) as specified in Section 4.1.1.
1.16 "Joint Research Committee" or "JRC" shall have the meaning ascribed
to it in Section 2.5 of Agreement.
1.17 "Net Sales" with respect to any product shall mean the gross amount
invoiced by the selling party and its Affiliates, licensees or sublicensees for
products sold in bona fide, arms-length transactions to Third Parties for use in
the Field, less (i) quantity and/or cash discounts from the gross invoice price
which are actually allowed or taken; (ii) freight, postage and insurance
included in the invoice price; (iii) amounts repaid or credited by reasons of
rejections or return of goods or because of retroactive price reductions
specifically identifiable to such product; (iv) amounts payable resulting from
government (or agency thereof) mandated rebate programs; (v) third-party rebates
or charge-backs to the extent actually allowed; (vi) invoiced customs duties and
sales taxes (excluding income, value-added and similar taxes), if any, actually
paid and directly related to the sale that are not reimbursed by the buyer; and
(vii) any other specifically identifiable amounts included in the product's
gross invoice price that should be credited for reasons substantially equivalent
to those listed above; all as determined in
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accordance with the selling party's usual and customary accounting methods,
which are in accordance with generally accepted accounting principles.
In the case of any sale or other disposal of a product between or
among the selling party and its Affiliates, licensees and sublicensees, for
resale, Net Sales shall be calculated as above only on the value charged or
invoiced on the first arm's-length sale thereafter to a Third Party;
In the case of any sale which is not invoiced or is delivered before
invoice, Net Sales shall be calculated at the time of shipment or when the
product is paid for, if paid for before shipment or invoice;
In the case of any sale or other disposal for value, such as barter
or counter-trade, of any product, or part thereof, other than in an arm's length
transaction exclusively for money, Net Sales shall be calculated as above on the
value of the consideration received;
In the event the product is sold in a finished dosage form
containing the product in combination with one or more other active ingredients
(a "Combination Product"), the Net Sales of the product, for the purposes of
determining royalty payments, shall be determined by multiplying the Net Sales
(as defined above in this Section) of the Combination Product by the fraction,
A/(A+B) where A is the weighted (by sales volume) average sale price of the
product when sold separately in finished form and B is the weighted average sale
price of the other product(s) sold separately in finished form, provided that
the above formula in this Section 1.19 shall not apply if the product is only
sold in combination form and if each of the active ingredients in a Combination
Product results from the Research Program and in each such event the following
sentence shall apply. In the event that such average sale price cannot be
determined for both the product and the other product(s) in combination, Net
Sales for purposes
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of determining royalty payments shall be mutually agreed by the Parties based on
relative value contributed by each component, and such agreement shall not be
unreasonably withheld.
1.18 "Patents" means all existing patents and patent applications and all
patent applications hereafter filed, including any continuation,
continuation-in-part, division, provisional or any substitute applications, any
patent issued with respect to any such patent applications, any reissue,
reexamination, renewal or extension (including any supplementary protection
certificate) of any such patent, and any confirmation patent or registration
patent or patent of addition based on any such patent, and all foreign
counterparts of any of the foregoing.
1.19 "Person" means any individual, corporation, partnership, association,
joint-stock company, trust, unincorporated organization or government or
political subdivision thereof.
1.20 "Predix CF Technology" shall mean all data, technical information,
know-how, inventions (whether or not patented) trade secrets, processes and
methods discovered or developed, and Controlled by Predix or its Affiliates, in
the performance of the Research Program under this Agreement, including without
limitation, the 3D coordinates of the CFTR to be developed by Predix hereunder;
provided, however, that notwithstanding the foregoing, the term "Predix CF
Technology" shall not include any data, technical information, know-how,
inventions (whether or not patented) trade secrets, processes or methods owned
or Controlled by Predix prior to, or outside of, Predix's performance of the
Research Program under this Agreement, including without limitation, Predix's
general receptor and ion channel modeling technology, or computational drug
discovery, drug optimization and drug design technology, or any enhancements or
improvements to any of the foregoing.
1.21 "Predix Patents" shall mean any Patents Controlled by Predix or its
Affiliates claiming Predix CF Technology.
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1.22 "Prime Rate" shall mean the average prime rate published in the Wall
Street Journal during the relevant period.
1.23 "Pulmonary Field" shall mean the treatment of diseases of the human
pulmonary tract or lungs, other than CF.
1.24 "P2Y(2) Product" shall have the meaning set forth in Section 2.1.
1.25 "Regulatory Approval" shall mean, with respect to any country, all
authorizations by the appropriate governmental entity or entities necessary for
commercial sale of a pharmaceutical product in that country including, without
limitation and where applicable, approval of labeling, price, reimbursement and
manufacturing. "Regulatory Approval" in the United States shall mean final
approval of a new drug application pursuant to 21 CFR Section 314, permitting
marketing of the P2(Y)2 Product in interstate commerce In the United States.
"Regulatory Approval" in the European Union shall mean final approval of a
Marketing Authorization Application, or equivalent.
1.26 "Research Plan" shall have the meaning set forth in Section 2.4
hereof.
1.27 "Research Program I" shall have the meaning set forth in Section 2.1.
1.28 "Research Program II" shall have the meaning set forth in Section
2.1.
1.29 "Research Programs" shall mean collectively all research activities
undertaken under this Agreement relating to Research Program I and Research
Program II.
1.30 "Research Termination Date" shall mean the date which is thirty six
(36) months following the Effective Date for Research Program I and the date
which is twenty four (24)
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months following the Effective Date for Research Program II, in both cases
subject to extension as provided in Section 2.2.
1.31 "Territory" shall mean worldwide.
1.32 "Third Party" shall mean any person or entity which is not a party or
an Affiliate of any party to this Agreement.
ARTICLE II - RESEARCH PROGRAM
2.1 COMMENCEMENT; OBJECTIVE.
Predix will be responsible for the conduct of the Research Programs as set
forth herein. CFFT will provide the financial support hereinafter specified, and
consultation and advice as provided herein through its participation on the JRC
as provided below. The Research Program will consist of two sets of separate
activities, as set forth in the Research Plan, and generally described as
follows: (i) Predix will use its 3D technology and modeling expertise to model
the 3D structure of the CFTR (such activities are the "Research Program I") and
(ii) Predix will use its 3D GPCR technology to discover a small-molecule P2Y(2)
agonist that once optimized will be a novel compound for the treatment of CF
(such activities are "Research Program II" and any product containing a
small-molecule P2Y(2) agonist discovered during the performance of Research
Program II, whether or not the molecule has been further optimized, is a "P2Y(2)
Product").
Following the successful completion of Research Program I (or prior to its
completion if the Parties so desire), the Parties agree to negotiate in good
faith towards an agreement pursuant to which a molecule that will act as a CFTR
Corrector will be discovered, optimized, developed
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and commercialized, all as more fully set forth in Section 4.1. Subject to
CFFT's rights in the event of an Interruption pursuant to Section 9.6 of this
Agreement, Predix shall have exclusive rights to further develop and
commercialize all P2Y(2) Products.
2.2 TERM.
The Research Programs shall commence on the Effective Date and will
conclude on the Research Termination Date, unless extended by agreement of the
Parties, or unless earlier terminated in accordance with the provisions of
Article IX hereof. The Parties may discuss at any time whether, and upon what
basis, the Research Program might be extended beyond the initial Research
Termination Date.
2.3 RESEARCH DILIGENCE.
Predix will work diligently and use reasonable efforts, consistent with
prudent business judgment, to accomplish the goals of the Research Programs.
Predix will dedicate to the Research Programs at least that level of staffing
referenced in Section 3.1 hereof, and expects to employ an appropriate
combination of experience and training in the CF Field.
2.4 RESEARCH PLAN.
Predix and CFFT have agreed upon an overall research plan for the
Research Programs, a copy of which is attached to this Agreement as Exhibit 2.4.
The JRC will review and evaluate the Research Plan, taking into consideration
ongoing research outcomes and other scientific and commercial developments, at
each meeting of the JRC after the Effective Date, and any resulting
modifications will be incorporated into the Research Plan (the original plan,
and any such modifications are referred to herein as the "Research Plan").
Modifications to the Research Plan may be proposed by either Predix or CFFT and
must be approved by the JRC
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before being adopted. Any modification to the Research Plan proposed by Predix
that would (a) reduce the levels of FTE resources to be devoted by Predix to the
Research Programs below; or (b) increase the Budget for either Research Program
I or Research Program II, shall not be adopted without the approval of CFFT,
which will act expeditiously on any such proposal.
2.5 JOINT RESEARCH COMMITTEE.
2.5.1 Composition and Purposes. Predix and CFFT shall establish a
Joint Research Committee ("JRC") consisting of at least six (6) representatives
(as may be increased or decreased by the JRC), half of whom shall be designated
from time to time by each party. Each party shall choose a Program Coordinator
who may be changed from time to time by designation of each party. The Program
Coordinator for Predix shall be Xxxx Xxxxxx, PhD. The Program Coordinator for
CFFT shall be Xxxxx Xxxxxxx. If the JRC chooses to designate a Committee Chair,
the Chair will be Predix's Program Coordinator. The JRC shall meet formally no
less frequently than once in each three (3) month period during the Research
Program, and at such time and location, as may be established by the Committee.
However, the JRC will make its schedule flexible in order to xxxxxx the
successful completion of the Research Programs. The JRC shall meet for the
following purposes:
(I) to review and discuss the Research Plan and evaluate any
proposed revisions to any of those plans;
(II) to determine whether milestones have been achieved; and
(III) to provide guidance to the research team if such
guidance is needed on next steps to implement the Research Programs.
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At least five (5) working days prior to each JRC meeting, Predix
will send a written report to CFFT detailing the progress made in the respective
Research Programs during the preceding quarter. Within thirty (30) days after
the date of each meeting, Predix shall prepare and deliver minutes of the
meeting to the members of the JRC, setting forth, inter alia, all decisions of
the JRC, and including as an attachment the report on the progress of work
performed required by this Section 2.5.1.
2.5.2 MILESTONE DECISION-MAKING. The JRC shall determine whether or
not milestone events have been achieved. Each of Predix and CFFT shall have one
vote on such matter, to be exercised by their respective Program Coordinators.
In the event a deadlock occurs or whether or not a milestone event has been
successfully completed, the Parties shall mutually select a Third Party who
shall make such determination. The determination of such party shall be binding
on the Parties.
Each party shall retain the rights, powers, and discretion granted
to it under this Agreement, and the JRC shall not be delegated or vested with
any such rights, powers or discretion except as expressly provided in this
Agreement. The JRC shall not have the power to amend or modify this Agreement,
which may only be amended or modified as provided in Section 11.12.
2.6 EXCHANGE OF INFORMATION.
Predix will share information with the JRC when available and
necessary to facilitate mutual understanding of the status of the Research
Program and decision-making in connection therewith.
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ARTICLE III - PAYMENTS
3.1 STAFFING AND RESEARCH SUPPORT PAYMENTS.
CFFT will make the payments to Predix specified below during the
Term in support of the Research Programs under this Agreement.
3.1.1.RESEARCH PROGRAM I
Item in Estimated FTE Out-sourced Total
Exhibit 2.4 Time Research activities Budgeted
(Months)* Funding (# Amount
FTEs
charged at
$[*******
**********]
a) [******************]: to be paid on the date of execution $2,000,000
b) Base Research Funding:
Modeling the [**] and [**] or less $[*****](6) $[*****]; $[********]
3D structure [**] $[*****]
of
[***********
*********
*******] and
**********
[*******
*********]
Structure [**] and [**] or less $[*****](6) $[***** $[********]
based [**] *****]
analysis and
experimental
validation of
[*********
******] and
[********
********]
Modeling 3D [**] [**] or less $[*****](6) $[******** $[*********]
structure of *********
the [******** ********]
*********
**********]
Structure [**] [**] or less $*****](6) $[******** $[********]
based ********]
analysis and
Experimental
validation of
[**********]
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c) Milestones:
(1) 3D Model of [**************] (as defined in section 13.1 of Exhibit 2.4) $[********]
(2) 3D Model of [**************] (as defined in section 13.2 of Exhibit 2.4) $[********]
(3) Identification of a route for [**************] (as defined in section 13.3 of Exhibit 2.4) $[********]**
Aggregate Budgeted Amount for Research Program I $10,500,000
Each milestone shall be due and payable thirty (30) days after it is achieved.
All milestones under Research Program I that are not achieved prior to the
Research Termination Date will nevertheless be paid by CFFT to Predix if
achieved within 180 days after the Research Termination Date.
* Periods are estimates. The parties anticipate that particular aspects of
the Research Programs may take longer than the periods indicated but that
the Research Programs will likely be completed on or prior to the Research
Termination Date.
** This payment shall be reduced to $[********] if this milestone is
accomplished before the milestone in subparagraph (c)(2) above ("Milestone
(c)(2)"); and, the remaining $[********] shall be added to the amount
specified for Milestone (c)(2) and paid to Predix upon the accomplishment
of Milestone (c)(2).
3.1.2.RESEARCH PROGRAM II
The total Budget for Research Program II shall be $2 million consisting of
up to [******] FTEs per year and/or the expense of out-sourced activities, for
the [******] period beginning on the Effective Date. FTEs budgeted amounts shall
be billed by Predix to CFFT [******]; provided that, total FTE billing in
[*************************] during which Research Program II will be conducted
will not exceed [*****] FTEs billable at $[****] per FTE in each such
[*************] period. If Predix does not identify a hit for the P2Y(2)
receptor that has an [***************] in a [**************] (or an equivalent
assay) (a "Hit"), within the [***************] period following the Effective
Date of this Agreement, CFFT will terminate payments for FTE payments for
Research Program II, after payment for the FTE's allocable to the initial
[********] period until a Hit is identified; provided that, FTE payments for the
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additional [***********] period budgeted for Research Program II will resume
when a Hit is identified if such identification occurs within
[******************] of such termination.
3.2 PAYMENTS.
Budgeted payments due on account of internal FTEs shall be made by
CFFT [******] within thirty (30) days of the receipt of invoices for such
amounts. Budgeted payments on account of external costs shall be made by CFFT
[******] in arrears within thirty (30) days following receipt of an invoice for
such external costs accompanied by usual and customary documentation of such
costs. Amounts budgeted for outsourced activities may be reallocated among
different outsourced activities so long as the total costs to be reimbursed by
CFFT do not exceed the total amount budgeted for outsourced activities. In
addition to the amounts indicated above for outsourced activities, CFFT shall
arrange for and direct pay a service provider for the site directed mutagenesis
services described in Section 10.2.1 of Exhibit 2.4. All payments shall be made
without deduction for withholding or other similar taxes, in United States
dollars to the credit of such bank account as may be designated by Predix in
writing to CFFT. Any payments which fall due on a date which is a legal holiday
in the State of Maryland may be made on the next following day which is not a
legal holiday in the State of Maryland. On or before each of March 1, 2006 and
March 1, 2007 Predix will provide CFFT with an accounting of all internal FTE
costs (consisting of the names and dates worked for those persons who are
included within the reimbursed FTE costs) and outsourcing costs incurred under
the Research Programs during the most recently concluded calendar year. Internal
FTE costs will be calculated at an annual rate of $[******] per FTE. Costs
incurred will be compared with funds provided by CFFT on account of that year,
and any excess of funds paid to Predix over costs incurred will be refunded to
CFFT within thirty (30) days or, as to amounts due on account of 2005
activities, applied as a credit against amounts due for 2006 activities.
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OMISSIONS.
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3.3 RECORDS.
Predix shall keep accurate records and books of accounts containing
all data reasonably required for the calculation and verification of the number
of FTE's employed in the performance of the Research Programs, and outsourcing
costs incurred by Predix in the Research Program during the term of this
Agreement and for a period of thirty six (36) months thereafter. CFFT, through
an independent accounting firm unaffiliated with either CFFT or Predix, shall
have the right at its expense to audit Predix's relevant records to verify
compliance with FTE and other research funding allocation requirements
hereunder. At CFFT's request, Predix shall make those records available, no more
than [********], during reasonable working hours, for review by a recognized
independent accounting firm acceptable to both Parties, at CFFT's expense, for
the sole purpose of verifying the accuracy of those records in the calculation
of Research Program FTEs and outsourcing costs. Predix shall not, however, be
required to retain or make available to CFFT or its accountants, any such
records or books of account for either [*****] or [*****] beyond
[***************] from the Research Termination Date. CFFT shall cause the
accounting firm to retain all such information in confidence. Such accounting
firm shall report to CFFT only the existence and amount of any variance between
the amount paid and the amount that was actually due hereunder. In the event
that the aggregate costs actually chargeable to the Research Programs during any
calendar year are less than the amount previously advanced to Predix by CFFT and
properly attributable to that calendar year (a "Negative Difference"), in
addition to reimbursing CFFT for the Negative Difference
[*************************** **************************], if the Negative
Difference is more than [*****] percent ([*****]%) of the amounts properly
attributable to that calendar year, then Predix shall [*****************
****************************************************] in the review.
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OMISSIONS.
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ARTICLE IV - COMMERCIALIZATION; ROYALTIES
4.1 DISCOVERY AND COMMERCIALIZATION OF A CFTR CORRECTOR-BASED PRODUCT;
COMMERCIALIZATION OF P2(Y)2 PRODUCT.
4.1.1 DISCOVERY AND COMMERCIALIZATION OF A CFTR CORRECTOR-BASED
PRODUCT. Following the completion of the work set forth in the Research Plan
relating to Research Program I (or prior to its completion if the Parties so
desire), the Parties agree to negotiate in good faith, for a period of up to
sixty (60) days, towards an agreement pursuant to which Predix will, building
upon the Predix CF Technology, explore a structure-based route for the discovery
and commercialization of a molecule that will act as a CFTR Corrector with the
financial support of CFFT and subject to a royalty or similar obligation to
CFFT. Other than participating in such good faith negotiations, however, neither
party shall be obligated to enter into such an agreement. If the Parties do not
enter into such an agreement during such sixty (60) day period, an Interruption
shall be deemed to have occurred with respect to Research Program I with the
attendant consequences provided for in Section 9.6.
4.1.2 COMMERCIALIZATION OF P2Y(2) PRODUCT. Except in the event of an
Interruption, Predix and/or its licensees and sublicensees shall have exclusive
rights to market, sell and distribute any or all P2Y(2) Products throughout the
Territory.
4.2 DUE DILIGENCE.
Predix shall use diligent and commercially reasonable efforts
consistent with the requirements of the Development Program and sound and
reasonable business practices and judgment to effect introduction of P2(Y)2
Products into major markets in North America and Europe as soon as reasonably
practicable, devoting the same degree of attention and diligence to
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those efforts that it devotes to similar activities for its other products of
comparable market potential (such efforts are "Commercially Reasonable
Efforts").
4.3 ROYALTIES.
Within thirty (30) days following the [***************] of the first
P2(Y)2 Product, Predix shall pay a [*****] royalty to CFFT of $[*****]. If
aggregate Net Sales of such P2(Y)2 Product in the [***************] following
the month the [*************] is granted ("Relevant [**]") exceed $250 million,
Predix shall pay to CFFT an additional [*****] royalty of $[*****]; or, if such
Net Sales exceed $[************], Predix shall pay to CFFT an additional [*****]
royalty of $[*****] (in lieu of the $[**********] payment). The additional
royalty shall be paid within 60 days following the close of the relevant
[*************] period.
4.4 SALES REPORTS.
(A) Within sixty (60) days after the conclusion of the Relevant
[**], Predix shall furnish or cause to be furnished to CFFT a written report or
reports covering the Relevant [**] showing, for Net Sales, (i) the Net Sales for
the first P2(Y)2 Product in each country in the world during the reporting
period by Predix and each Affiliate, licensee and sublicensee; (ii) any royalty,
payable in U.S. dollars ("Dollars"), which shall have accrued under Section 4.3
hereof in respect of such sales and the basis of calculating the royalty; and
(iii) the exchange rates used in converting into Dollars, from the currencies in
which sales were made, any amounts which are included within Net Sales; and (iv)
dispositions of P2(Y)2 Products other than pursuant to sale for cash. With
respect to sales of P2(Y)2 Products invoiced in Dollars, the Net Sales amounts
and the amounts due to CFFT hereunder shall be expressed in Dollars. With
respect to sales of P2(Y)2 Products invoiced in a currency other than Dollars,
the Net Sales and amounts due to
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CFFT hereunder shall be expressed in the domestic currency of the party making
the sale, together with the Dollar equivalent of the amount payable to CFFT,
calculated by translating foreign currency sales into U.S. dollars at the
exchange rates for the [********************* ******************] as reported in
The Wall Street Journal, Eastern US Edition. If any licensee or sublicensee
makes any sales invoiced in a currency other than its domestic currency, the Net
Sales shall be converted to its domestic currency in accordance with the
licensee's or sublicensee's normal accounting principles. Predix shall keep
accurate records in sufficient detail to enable the amounts due hereunder to be
determined and to be verified by CFFT.
(B) Amounts shown to have accrued by each sales report provided for
under Section 4.4(a), above, shall be due and payable on the date that sales
report is due.
(C) All payments shall be made in Dollars.
(D) Upon the written request of CFFT, at CFFT's expense and not more
than [***] time in the [*************] period following the receipt by CFFT of
the report required under Section 4.4(a), Predix shall permit an independent
accountant of national prominence selected by CFFT, to have access during normal
business hours to those records of Predix as may be reasonably necessary to
verify the accuracy of the report furnished by Predix pursuant to this Section
4.4. The report prepared by such independent accountant, a copy of which shall
be sent or otherwise provided to Predix by such independent accountant at the
same time it is sent or otherwise provided to CFFT, shall contain the
conclusions of such independent accountant regarding the existence and amount of
any variance between the amount paid and the amount that was actually due
hereunder. If such independent accountant's report shows any underpayment,
Predix shall remit to CFFT within thirty (30) days after Predix's receipt of
such report (i) the amount of such underpayment[********************************
*************************************************] and (ii) if such underpayment
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exceeds [*****] percent ([*****]%) of the total amount owed, the [*****] and
[*****] and [**********]. Any overpayment shall be refunded by CFFT to Predix
within thirty (30) days following CFFT's receipt of the auditor's report. CFFT
agrees that all information subject to review under this Section 4.4 is
confidential and that CFFT shall retain and cause its accountant to retain all
such information in confidence.
(E) In case of any delay in payment by Predix to CFFT not occasioned
by Force Majeure, [**********************************************************
**********************************************].
ARTICLE V - CONFIDENTIALITY
5.1 UNDERTAKING.
During the term of this Agreement, each party shall keep
confidential, and other than as provided herein, shall not use or disclose,
directly or indirectly, any trade secrets, confidential or proprietary
information, or any other knowledge, information, documents or materials, owned,
developed or possessed by the other party, whether in tangible or intangible
form, the confidentiality of which such other party takes reasonable measures to
protect ("Confidential Information"). Neither CFFT nor Predix will use the other
party's Confidential Information except as expressly permitted in this
Agreement:
(A) Each party shall take any and all lawful measures to
prevent the unauthorized use and disclosure of the other party's
Confidential Information, and to prevent unauthorized persons or
entities from obtaining or using that Information.
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(B) Each party will refrain from directly or indirectly
taking any action which would constitute or facilitate the
unauthorized use or disclosure of the other party's Confidential
Information. Each party may disclose that Information to its
officers, employees and agents, to authorized licensees and
sublicensees, and to subcontractors in connection with the
development or manufacture of P2(Y)2 Products, to the extent
necessary to enable such parties to perform their obligations
hereunder or under the applicable license, sublicense or
subcontract, as the case may be; provided, that such officers,
employees, agents, licensees, sublicensees and subcontractors have
entered into appropriate confidentiality agreements for secrecy and
non-use of such Confidential Information which by their terms shall
be enforceable by injunctive relief at the instance of the
disclosing party.
(C) Each party shall be liable for any unauthorized use
and disclosure of the other party's Confidential Information by its
officers, employees and agents and any such sublicensees and
subcontractors.
5.2 EXCEPTIONS.
Notwithstanding the foregoing, the provisions of Section 5.1 hereof
shall not apply to Confidential Information which the receiving party can
conclusively establish:
(A) has entered the public domain without such party's
breach of any obligation owed to the disclosing party;
(B) is permitted to be disclosed by the prior written
consent of the disclosing party;
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(C) has become known to the receiving party from a source
other than the disclosing party, other than by breach of an
obligation of confidentiality owed to the disclosing party;
(D) is independently developed by the receiving party
without breach of this Agreement; or
(E) is required to be disclosed by the receiving party to
comply with applicable laws or regulations, to defend or prosecute
litigation or to comply with governmental regulations, provided that
the receiving party provides prior written notice of such disclosure
to the disclosing party and takes reasonable and lawful actions to
avoid or minimize the degree of such disclosure.
Either Predix or CFFT may at any time, by notice in writing to the
other party, waive any or all of the confidentiality obligations to which the
other party is subject hereunder, for any length or time or with respect to any
specific information.
5.3 PUBLICITY.
The Parties will agree upon the timing and content of any initial
press release or other public communications relating to this Agreement and the
transactions contemplated herein.
(A) Except to the extent already disclosed in that initial
press release or other public communication, no public announcement
concerning the terms of this Agreement or concerning the
transactions described herein shall be made, either directly or
indirectly, by Predix or CFFT, except (i) as may be legally required
by applicable laws, regulations, or judicial order, (ii) as may be
required
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by the rules of any stock exchange on which such party's securities
are listed, or (iii) if limited to the fact that the Research
Programs exist, that research is in progress, and its anticipated
completion without first obtaining the approval of the other party
and agreement upon the nature, text, and timing of such
announcement, which approval and agreement shall not be unreasonably
withheld.
(B) The party desiring to make any such public
announcement shall provide the other party with a written copy of
the proposed announcement in sufficient time prior to public release
to allow such other party to comment upon such announcement, prior
to public release.
ARTICLE VI- PUBLICATION
Each of Predix and CFFT reserves the right to publish or publicly present
the data generated during the performance of the Research Programs (the
"Results"), subject to the following terms and conditions. The party proposing
to publish or publicly present the Results (the "publishing party") will submit
a draft of any proposed manuscript or speech to the other party (the
"non-publishing party") for comments at least sixty (60) days prior to
submission for publication or oral presentation. The non-publishing party shall
notify the publishing party in writing within thirty (30) days of receipt of
such draft whether such draft contains (i) information of the non-publishing
party which it considers to be confidential under the provisions of Article V
hereof, (ii) information that if published would have an adverse effect on a
patent application which the non-publishing party intends to file, or (iii)
information which the non-publishing party reasonably believes would be likely
to have a material adverse impact on the development
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or commercialization of a P2(Y)2 Product or a CFTR Corrector-based product. In
any such notification, the non-publishing party shall indicate with specificity
its suggestions regarding the manner and degree to which the publishing party
may disclose such information. In the case of item (ii) above, the
non-publishing party may request a delay and the publishing party shall delay
such publication, for a period not exceeding an additional ninety (90) days, to
permit the timely preparation and filing of a patent application or an
application for a certificate of invention on the information involved. In the
case of item (i) above, no party may publish Confidential Information of the
other party without its consent in violation of Article V of this Agreement. In
the case of item (iii) above, if the publishing party shall disagree with the
non-publishing party's assessment of the impact of the publication, then the
issue shall be referred to the Chief Executive Officer of CFFT and the Chief
Executive Officer of Predix who shall attempt in good faith to reach a fair and
equitable resolution of this disagreement. If the disagreement is not resolved
in this manner within two (2) weeks of referral to the respective Chief
Executive Officers, then the decision of the publishing party as to publication
of any information generated by it, subject always to the confidentiality
provisions of Article V hereof, shall be final, provided that such decision
shall be exercised with reasonable regard for the interests of the
non-publishing party. The Parties agree that authorship of any publication will
be determined based on the customary standards then being applied in the
relevant scientific journal. The Parties will use their reasonable best efforts
to gain the right to review proposed publications relating to the subject matter
of the Research Programs by consultants or contractors.
Notwithstanding the foregoing and subject to the last sentence of this
paragraph, Predix intends to advance the body of general scientific knowledge of
CF and its potential therapies, and to contribute to the identification of
chemical tools as optimal scientific benchmarks, all in a manner consistent with
its general scientific and commercial objectives in entering into the
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collaboration with CFFT to which this Agreement relates. In furtherance of that
objective, Predix will publish the 3D structure of the CFTR to be developed by
Predix by the first (1st) anniversary after the achievement of the second
milestone set forth in Section 3.1.1, or the termination of this Agreement,
whichever occurs first. CFFT's funding of the research will be acknowledged by
the publication; and by the third (3rd) anniversary after the achievement of
such second milestone, Predix shall cause the 3D structure of the CFTR developed
by Predix to become part of the public domain. In addition, Predix shall grant
to up to [******] requesting qualified, not-for-profit research institutions,
reasonably acceptable to Predix, a nonexclusive license to use the 3D structure
of the CFTR solely for research purposes. Such non-exclusive licenses shall
include restrictions on the disclosure of Predix' confidential information,
including without limitation, the structure of the CFTR (if not previously
published by Predix); provided that the licensee shall be permitted to publish
the data, including mutagenesis data, it may generate in the exercise of the
license. Notwithstanding the foregoing publication and licensing obligations in
this paragraph, if at any time such obligations are scheduled to occur, CFFT has
a license pursuant to Section 9.6, CFFT (and not Predix) shall determine the
timing and scope of such publication and the recipients of such sublicenses with
respect to the rights covered by the license granted to CFFT.
ARTICLE VII - INDEMNIFICATION
7.1 INDEMNIFICATION BY PREDIX.
Predix will indemnify and hold CFFT and its Affiliates, and their
employees, officers and directors harmless against any loss, damage, action,
suit, claim, demand, liability, expense, bodily injury, death or property damage
(a "Loss"), that may be brought, instituted or arise against or be incurred by
such persons to the extent such Loss is based on or arises out of:
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(A) the conduct of the Research Programs by Predix or its
Affiliates or their representatives, agents, authorized licensees,
sublicensees or subcontractors under this Agreement, or any actual
or alleged violation of law resulting therefrom; or
(B) the breach by Predix of any of its covenants,
representations or warranties set forth in this Agreement; and
(C) provided however, that the foregoing indemnification
shall not apply to any Loss to the extent such Loss is caused by the
negligent or willful misconduct of CFFT or its Affiliates or a
breach of this Agreement by CFFT or its Affiliates.
7.2 CLAIMS PROCEDURES.
In order to be indemnified by Predix, pursuant to Section 7.1, CFFT
shall give notice to Predix promptly after CFFT has actual knowledge of any
threatened or asserted claim as to which indemnity may be sought, and shall
permit Predix to assume the defense of any such claim or any litigation
resulting therefrom; provided:
(A) that counsel for Predix, who shall conduct the defense
of such claim or any litigation resulting therefrom, shall be
approved by CFFT (the approval of which shall not unreasonably be
withheld) and CFFT may participate in such defense at its expense,
unless (i) the employment of counsel by CFFT has been authorized by
Predix; or (ii) there is a conflict of interest that would prevent
Predix and CFFT from being represented by a single law firm in the
defense of such action, in each of which instance Predix shall pay
the reasonable fees and
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expenses of one law firm serving as counsel for CFFT, which law firm
shall be subject to approval, not to be unreasonably withheld, by
Predix; and
(B) the failure of CFFT or its Affiliates to give notice
as provided herein shall relieve Predix of its obligations under
this Agreement to the extent that the failure to give notice
prejudices a defense that otherwise may have been available or
increases the amount of the Loss or otherwise results in harm to
Predix.
(C) Predix shall not, in the defense of any such claim or
litigation, except with the approval of CFFT which approval shall
not be unreasonably withheld, consent to entry of any judgment or
enter into any settlement which (i) would result in injunctive or
other relief being imposed against CFFT and its Affiliates; or (ii)
does not include, as an unconditional term thereof, the giving by
the claimant or plaintiff to CFFT and its Affiliates of a release
from all liability in respect to such claim or litigation.
(D) CFFT and its Affiliates shall cooperate in the defense
of such claim as reasonably requested by Predix, including without
limitation, by furnishing such information regarding itself or the
claim in question as Predix may reasonably request in writing.
ARTICLE VIII - PATENTABLE INVENTIONS
8.1 OWNERSHIP.
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All inventions made and all data and know-how generated exclusively
by either party or its Affiliates (directly or through others acting on its
behalf) prior to and during the term of this Agreement relating to the Research
Program shall be owned by the party making the invention or generating the data
or know-how claimed, or if such invention is made jointly (a "Joint Invention"),
shall be owned jointly, all as determined in accordance with United States laws
of inventorship; provided that, CFFT hereby grants to Predix an exclusive (even
as to CFFT) worldwide license to its rights in any Joint Invention and any
invention made by a CFFT employee resulting from the Research Program for the
purposes specified in this Agreement.
8.2 PREPARATION.
Predix shall take responsibility for the preparation, filing,
prosecution and maintenance of all Predix Patents, and any patents and patent
applications claiming Joint Inventions, and CFFT shall take responsibility for
the preparation, filing, prosecution and maintenance of all CFFT Patents. Predix
shall provide the JRC with periodic reports listing, by name, Patents filed by
Predix in the United States and other jurisdictions, along with a general
summary of the claims made and the jurisdictions of filing.
8.3 COSTS.
Predix shall be responsible for all costs incurred in the
preparation, prosecution and maintenance of Predix Patents and Joint Patents.
ARTICLE IX - TERM AND TERMINATION
9.1 TERM.
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This Agreement will expire upon the Research Termination Date as
defined herein, unless earlier terminated by either party hereto in accordance
with this Agreement, or unless extended by mutual agreement of the Parties.
9.2 TERMINATION OF THE RESEARCH PROGRAMS WITHOUT CAUSE.
CFFT may terminate either or both of the Research Programs without
cause upon one hundred and twenty (120) day's notice.
9.3 TERMINATION OF THE RESEARCH PROGRAM BY CFFT FOR CAUSE.
Without limitation of its ability to seek damages for breach of this
Agreement, CFFT may at its sole discretion unilaterally terminate the Research
Program and this Agreement upon the occurrence of any of the following events:
(A) Predix shall materially breach any of its material
obligations under this Agreement, and such material breach shall not
have been remedied or material steps initiated to remedy the same to
CFFT's reasonable satisfaction, within thirty (30) days after CFFT
sends written notice of breach to Predix; or
(B) Predix shall cease to function as a going
concern by suspending or discontinuing its business for any
reason except for interruptions caused by events of Force Majeure.
In the event of any valid termination under this Section 9.3,
CFFT shall not be required to make any payments which have not accrued prior to
receipt by Predix of the notice of breach referenced under Section 9.3(a) or
receipt by Predix of the notice of termination pursuant to this Section 9.3(b),
as the case may be.
9.4 TERMINATION OF THE RESEARCH PROGRAM BY PREDIX FOR CAUSE.
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Without limitation of its ability to seek damages for breach of this
Agreement, Predix may at its sole discretion terminate this Agreement upon
written notice to CFFT upon the occurrence of the following event:
CFFT shall materially breach any of its material obligations under
this Agreement and such material breach shall not have been remedied or material
steps initiated to remedy the same to Predix's reasonable satisfaction, within
thirty (30) days after Predix sends written notice of breach to CFFT.
9.5 GENERAL EFFECT OF TERMINATION.
(A) The termination of this Agreement for any reason, or
expiration of this Agreement, will not affect obligations which have
accrued as of the date of termination or expiration, and obligations
and rights under the following Sections, each of which shall survive
any expiration or termination: Sections 2.5.2, 3.1.1 (solely for
payment for milestones completed within [*****************] of such
expiration), 3.3, 9.5 and 9.6 and Articles IV, V, VI, VII, VIII, X
and XI.
(B) Subject to Section 4.1 hereof, and subject to the
license that may be granted under Section 9.6(a), upon termination
or expiration of this Agreement, Predix will retain ownership or
exclusive rights to the Predix CF Technology and the inventions
licensed to it by CFFT pursuant to Section 8.1 of this Agreement
(including intellectual property rights).
9.6 CONSEQUENCES OF AN INTERRUPTION.
Upon the effective date of any Interruption with respect to Research
Program I and/or Research Program II, the following license in favor of CFFT
shall become effective:
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(A) CFFT shall have an irrevocable, with respect to the
Research Program to which an Interruption has occurred, exclusive
(even as to Predix) worldwide license, with the right to sublicense,
under the Predix CF Technology and Joint Inventions to develop,
manufacture, have manufactured, use, sell, offer to sell and import
CFTR Corrector-based products or P2Y(2) Products, as applicable, in
the Field.
(B) In lieu of any research funding obligation owed by
CFFT to Predix pursuant to this Agreement, except obligations that
accrued prior to the date of termination and obligations that
survive termination of this Agreement, CFFT shall pay Predix a
[*****] percent ([*****]%) royalty on the annual Net Sales of any
CFTR Corrector-based products discovered or developed using the
Predix CF Technology or P2Y(2) Products, as applicable, thereafter
sold by CFFT or any Affiliate, licensee or sublicensee of CFFT, to
which the foregoing licenses relate.
(C) In connection with either or both of the foregoing
licenses, Predix shall deliver to CFFT, expeditiously upon the
occurrence of an Interruption, all materials and data generated in
the performance of Research Program I or Research Program II as
applicable and the Predix CF Technology, including without
limitation, the 3D coordinates of the CFTR, that are relevant to
Research Program I or Research Program II, as applicable.
ARTICLE X - REPRESENTATIONS AND WARRANTIES
10.1 REPRESENTATIONS AND WARRANTIES OF PREDIX.
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Predix represents and warrants to CFFT that this Agreement has been
duly executed and delivered by Predix and constitutes the valid and binding
obligation of Predix, enforceable against Predix in accordance with its terms
except as enforceability may be limited by bankruptcy, fraudulent conveyance,
insolvency, bankruptcy, reorganization, moratorium and other laws relating to or
affecting creditors' rights generally and by general equitable principles. The
execution, delivery and performance of this Agreement have been duly authorized
by all necessary action on the part of Predix, its officers and directors.
10.2 REPRESENTATIONS AND WARRANTIES OF CFFT.
CFFT represents and warrants to Predix that this Agreement has been
duly executed and delivered by CFFT and constitutes the valid and binding
obligation of CFFT, enforceable against CFFT in accordance with its terms except
as enforceability may be limited by bankruptcy, fraudulent conveyance,
insolvency, bankruptcy, reorganization, moratorium and other laws relating to or
affecting creditors' rights generally and by general equitable principles. The
execution, delivery and performance of this Agreement have been duly authorized
by all necessary action on the part of CFFT, its officers and directors.
ARTICLE XI - MISCELLANEOUS PROVISIONS
11.1 GOVERNING LAW, AND JURISDICTION.
This Agreement shall be governed and construed in accordance with
the internal laws of the State of Maryland.
11.2 WAIVER.
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No provision of this Agreement may be waived except in writing by
both Parties hereto. No failure or delay by either party hereto in exercising
any right or remedy hereunder or under applicable law will operate as a waiver
thereof, or a waiver of any right or remedy on any subsequent occasion.
11.3 FORCE MAJEURE.
Neither party will be in breach hereof by reason of its delay in the
performance of or failure to perform any of its obligations hereunder, if that
delay or failure is caused by strikes, acts of God or the public enemy, riots,
incendiaries, interference by civil or military authorities, compliance with
governmental priorities for materials, or any fault beyond its reasonable
control or without its fault or negligence.
11.4 SEVERABILITY.
Should one or more provisions of this Agreement be or become
invalid, then the Parties hereto shall attempt to agree upon valid provisions in
substitution for the invalid provisions, which in their economic effect come so
close to the invalid provisions that it can be reasonably assumed that the
Parties would have accepted this Agreement with those new provisions. If the
Parties are unable to agree on such valid provisions, the invalidity of such one
or more provisions of this Agreement shall nevertheless not affect the validity
of the Agreement as a whole, unless the invalid provisions are of such essential
importance for this Agreement that it may be reasonably presumed that the
Parties would not have entered into this Agreement without the invalid
provisions.
11.5 GOVERNMENT ACTS.
In the event that any act, regulation, directive, or law of a
country or its government, including its departments, agencies or courts, should
make impossible or prohibit,
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restrain, modify or limit any material act or obligation of CFFT or Predix under
this Agreement, the party, if any, not so affected, shall have the right, at its
option, to suspend or terminate this Agreement as to such country, if good faith
negotiations between the Parties to make such modifications therein as may be
necessary to fairly address the impact thereof, are not successful after a
reasonable period of time in producing mutually acceptable modifications to this
Agreement.
11.6 ASSIGNMENT.
This Agreement may not be assigned or otherwise transferred by
either party without the prior written consent of the other party; provided,
however, that either party may assign this Agreement, without the consent of the
other party, (i) to any of its Affiliates, if the assigning party guarantees the
full performance of its Affiliates' obligations hereunder, or (ii) in connection
with the transfer or sale of all or substantially all of its assets or business
to which this Agreement relates or in the event of its merger or consolidation
with another company. Any purported assignment in contravention of this Section
11.6 shall, at the option of the non-assigning party, be null and void and of no
effect. No assignment shall release either party from responsibility for the
performance of any accrued obligation of such party hereunder. This Agreement
shall be binding upon and enforceable against the successor to or any permitted
assignees from either of the Parties hereto.
11.7 COUNTERPARTS.
This Agreement may be executed in duplicate, each of which shall be
deemed to be original and both of which shall constitute one and the same
Agreement.
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11.8 NO AGENCY.
Nothing herein contained shall be deemed to create an agency, joint
venture, amalgamation, partnership or similar relationship between CFFT and
Predix. Notwithstanding any of the provisions of this Agreement, neither party
to this Agreement shall at any time enter into, incur, or hold itself out to
third parties as having authority to enter into or incur, on behalf of the other
party, any commitment, expense, or liability whatsoever, and all contracts,
expenses and liabilities in connection with or relating to the obligations of
each party under this Agreement shall be made, paid, and undertaken exclusively
by such party on its own behalf and not as an agent or representative of the
other.
11.9 NOTICE.
All communications between the Parties with respect to any of the
provisions of this Agreement will be sent to the addresses set out below, or to
such other addresses as may be designated by one party to the other by notice
pursuant hereto, by prepaid, certified air mail (which shall be deemed received
by the other party on the seventh business day following deposit in the mails),
or by facsimile transmission, or other electronic means of communication (which
shall be deemed received when transmitted), with confirmation by first class
letter, postage pre-paid, given by the close of business on or before the next
following business day:
if to CFFT, at:
Cystic Fibrosis Foundation Therapeutics Incorporated
0000 Xxxxxxxxx Xxxx
Xxxxxxxx, Xxxxxxxx 00000
Attention: Xx. Xxxxxx X. Xxxxx, President
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with a copy to: Xxxxxxx X. Xxxxxxx, Esq.
Xxxxxxx Berlin LLP
0000 X Xxxxxx, X.X., Xxxxx 000
Xxxxxxxxxx, X.X. 00000
if to Predix, at:
Predix Pharmaceuticals Holdings , Inc.
10K Xxxx Xxxxxx
Xxxxxx, XX 00000
Attention: President
with a copy to: Xxxxxxxxxxx X. Xxxx, Esq.
Mintz, Levin, Cohn, Ferris, Glovsky and Popeo PC
Xxx Xxxxxxxxx Xxxxxx
Xxxxxx, XX 00000
11.10 HEADINGS.
The paragraph headings are for convenience only and will not be
deemed to affect in any way the language of the provisions to which they refer.
11.11 AUTHORITY.
The undersigned represent that they are authorized to sign this
Agreement on behalf of the Parties hereto. The Parties each represent that no
provision of this Agreement will
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violate any other agreement that such party may have with any other person or
company. Each party has relied on that representation in entering into this
Agreement.
11.12 ENTIRE AGREEMENT.
This Agreement contains the entire understanding of the Parties
relating to the matters referred to herein, and may only be amended by a written
document, duly executed on behalf of the respective Parties.
11.13 NOTICE OF PHARMACEUTICAL SIDE-EFFECTS.
During the term of this Agreement, the Parties shall keep each other
promptly and fully informed and will promptly notify appropriate authorities in
accordance with applicable law, after receipt of information with respect to any
serious adverse event (as defined by the ICH Harmonized Tripartite Guideline on
Clinical Safety Data Management), directly or indirectly attributable to the use
or application of any P2(Y)2 Product, and any other product for which royalties
are payable under this Agreement.
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Agreed and acknowledged as of the Effective Date.
PREDIX PHARMACEUTICALS HOLDINGS, INC.
By: /s/ XXXXXXX X. XXXXXXXX, MD
-------------------------------
Title: President and CEO
--------------------------
CYSTIC FIBROSIS FOUNDATION THERAPEUTICS INCORPORATED
By: /s/ XXXXXX X. XXXXX
-------------------------------
Title: President and CEO
--------------------------
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CONFIDENTIAL
EXHIBIT 2.4
CFTR PROGRAM WORK PLAN
MODELING THE 3D STRUCTURE OF CFTR AND EXPLORING A ROUTE FOR THE DISCOVERY OF
A CYSTIC FIBROSIS "CORRECTOR" DRUG
1. The objective of this study is to identify potential sites for therapeutic
intervention on the 3D model of the Cystic Fibrosis Transmembrane
Conductance Regulator protein (CFTR).
2. To achieve this objective Predix will use its 3D Drug Discovery technology
to model the 3D structure of CFTR and to suggest a structure-based route
for future discovery of a CFTR "corrector" drug.
3. The overall work plan consists of the following steps:
1.1[*****]
a. Modeling the 3D structure of the [*****].
b. Structure-based analysis and experimental validation of the
[*****].
c. Attempt to identify a site for therapeutic intervention in
the [*****].
2.1[*****]
a. Modeling the 3D structure of the [*****].
b. Structure-based analysis and experimental validation of the
[*****].
c. Attempt to identify a site for therapeutic intervention in
the [*****].
3.1 The [*****]
a. Modeling the 3D structure of the [*****].
b. Structure-based analysis and experimental validation of the
[*****].
c. Attempt to identify a site for therapeutic intervention in
the [*****].
4. Modeling the 3D structure of [*****]
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1.1 Predix will use its PREDICT(TM) technology and its
modeling expertise to generate a 3D model of the [*****].
2.1 It is understood that the [*****]:
4.2.1 Modeling the [*****].
4.2.2 Modeling the [*****].
4.2.3 Modeling the [*****].
4.2.4 Packing the [*****].
4.2.5 The resulting 3D model of the [*****].
3.1Modeling will be guided by [*****], including (but not limited to):
4.3.1 The [*****].
4.3.2 [*****]
4.3.3 [*****].
5. The [*****] will be subject to structure-based analysis and
experimental validation.
1.1 The 3D model of the [*****].
2.1 This process will involve the following steps:
5.2.1 Structural analysis of the [*****].
5.2.2 [*****].
5.2.3 [*****].
5.2.4 Analysis of the [*****].
5.2.5 Repeating steps [*****].
3.1 The validated structure will be re-examined in an attempt to identify
a site or a route for therapeutic intervention in the form of a CFTR
"corrector" drug.
6. Modeling the 3D structure of [*****]
1.1 Predix will use its modeling expertise to generate a 3D model of
the [*****].
2.1 Modeling the [*****]:
6.2.1 [*****].
6.2.2 Modeling the [*****].
6.2.3 [*****]
7. The [*****].
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8. Modeling the 3D structure of the [*****]
1.1 Following the generation of a 3D model for the [*****]:
8.1.1 Combining the [*****].
8.1.2 Modeling [*****]
8.1.3 Packing of [*****].
8.1.4 [*****].
2.1 The resulting 3D model will be [*****].
3.1 Modeling will be guided by the [*****].
4.1 Additional experiments that can assist in the modeling process,
such as [*****].
9. Structure-based analysis and experimental validation of the [*****]
The 3D model of the [*****].
10. Experiments for structural data and model validation
1.1 At various points throughout the modeling process [*****].
2.1 Such studies may include the following:
10.2.1 [*****].
10.2.2 [*****].
10.2.3 [*****].
3.1CFFT will [*****].
11. Screening and optimization of CFTR "corrector" compounds
1.1 As soon as a [*****].
2.1 Hence, screening for a [*****].
3.1 This screening effort is [*****].
12. The timeline for this project is as follows:
- Modeling the [*****]
- Initiation of [*****].
- Analysis and validation of the [*****]
- Modeling the [*****]
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- Analysis and validation of the [*****]
- Some activities [*****]. Total Expected timeline is 36 months.
13. Milestones
1.1 - 1st milestone - 3D model of the [*****].
2.1 - 2nd milestone - 3D model of the [*****].
3.1 - 3rd milestone - [*****].
14.Predix and the CFFT will maintain interaction throughout the duration of
the project. A Joint Research Committee (JRC) will meet at least on a
quarterly basis to follow the progress of the project. The JRC will also
establish a Joint Subcommittee for Validation Assays. This subcommittee
will meet on an ad hoc basis and its task will be to identify the most
suitable assays to support the various modeling tasks, as well as the
research labs that can perform them.
15. The Cystic Fibrosis Foundation will [*****]:
1.1 [*****].
2.1 [*****].
3.1 [*****].
4.1 [*****].
In addition, CFFT will introduce Predix to expert labs and key scientists, and
in general will use its internal expertise and network of alliances to assist
the program.
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FIRST AMENDMENT TO
RESEARCH, DEVELOPMENT AND COMMERCIALIZATION AGREEMENT BETWEEN
PREDIX PHARMACEUTICALS HOLDINGS, INC. AND CYSTIC FIBROSIS FOUNDATION
THERAPEUTICS INCORPORATED
This First Amendment (this "Amendment") to Research, Development and
Commercialization Agreement Between Predix Pharmaceuticals Holdings, Inc. and
Cystic Fibrosis Foundation Therapeutics Incorporated is made as of this 18th day
of May, 2006 (the "Effective Date"), by and between Predix Pharmaceuticals
Holdings, Inc., a Delaware corporation with its principal place of business
located at 0 Xxxxxxx Xxxx, Xxxxxxxxx, XX 00000 ("Predix") and Cystic Fibrosis
Foundation Therapeutics Incorporated, a Delaware corporation with its principal
place of business located at 0000 Xxxxxxxxx Xxxx, Xxxxxxxx, XX 00000 ("CFFT").
Reference is made hereby to that certain Research, Development and
Commercialization Agreement entered into by and between Predix and CFFT and
dated March 7, 2005 (the "Agreement"). Capitalized terms used but not defined
herein shall have the definition provided in the Agreement.
WHEREAS, the Parties entered into the Agreement to research, develop and
commercialize products to treat cystic fibrosis; and
WHEREAS, the Parties now desire to amend the Agreement to better align the
incentives provided to Predix under the Agreement with the goals desired by
CFFT.
NOW, THEREFORE, in consideration of the foregoing and other consideration,
the receipt and sufficiency of which is hereby acknowledged, the Parties hereby
agree as follows.
1. Amendment of Agreement. The Agreement is hereby amended by deleting the
term [********] as it appears in section (c)(1) in the table in Section 3.1.1
and replacing it with the following term: [********].
2. Confirmation of Terms. The Agreement shall otherwise remain
unamended hereby and shall continue in full force and effect in accordance
with its terms.
Agreed and acknowledged as of the Effective Date.
Predix Pharmaceuticals Holdings, Inc. Cystic Fibrosis Foundation
Therapeutics Incorporated
By: /s/ Chen Xxxxx By: /s/ Xxxxxx X. Xxxxx
--------------------------------- ----------------------------------
Title: Chief Business Officer Title: President and CEO
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Second Amendment to
Research Development and Commercialization Agreement Between
Predix Pharmaceuticals Holdings, Inc. ("Predix") and Cystic Fibrosis
Foundation Therapeutics Incorporated ("CFFT")
This Second Amendment (this "Second Amendment") to the Agreement of March
7, 2005 (as amended, the "Agreement") is made as of this second day of August
2006 (the "Effective Date"), by and between Predix and CFFT. Capitalized terms
used but not defined herein shall have the definition provided in the Agreement.
WHEREAS, the Parties entered into the Agreement to research, develop and
commercialize products to treat cystic fibrosis; and
WHEREAS, the Parties now desire to amend the Agreement and add additional
research by Predix for Research Program I and certain additional funding by
CFFT.
NOW, THEREFORE, in consideration of the foregoing, the receipt and
sufficiency of which is hereby acknowledged, the Parties agree as follows:
1. Confirmation of Terms. Except as provided in this Second Amendment, the
Agreement (as amended by the First Amendment) shall remain in full force and
effect.
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2. Definitions.
a) Existing Definitions -- The following existing terms shall be
amended as follows:
(i) For avoidance of doubt, the term "Hit" as utilized in the
Agreement shall remain unamended by this Second Amendment; and
(ii) The term "Budget" shall mean the budget attached to this
Second Amendment as Exhibit A.
b) New Definitions. The following new definitions shall be added:
(i) "Additional Milestone" shall have the meaning ascribed to
it in Section 7 of this Second Amendment.
(ii) "Deferred Potentiator Negotiation Date" shall have the
meaning ascribed to it in Section 5 of this Second Amendment.
(iii) "Hit Corrector Compound" shall mean a compound that has
an [********] in a Corrector biological assay, as specified in the Screening
Research Plan for Research Program I.
(iv) "Hit Potentiator Compound" shall mean a compound that has
an [********] in a Potentiator biological assay, as specified in the Screening
Research Plan for Research Program I.
(v) "Joint Steering Committee" or "JSC" shall have the meaning
ascribed to it in Section 6 of this Second Amendment.
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(vi) "Potentiator" shall mean a Compound which modulates the
biological effect of CFTR by enhancing the gating activity of [DELTA]F508 CFTR
present in the apical cell membrane, as specified in the Screening Research Plan
for Research Program I.
(vii) "Screening Sub-Project" shall mean a full in silico
screening project focusing on one of the potential binding sites, as specified
in the Screening Research Plan for Research Program I.
(viii) "Virtual Hits" shall mean a set of compounds identified
by Predix through in silico screening methodologies which have a high likelihood
of binding to the protein at a specific binding site and exerting the desirable
functional response, as specified in the Screening Research Plan for Research
Program I, attached to this Second Amendment as Exhibit B.
3. Acknowledgements.
a) Research Termination Date. The parties acknowledge and agree that
the Research Termination Date for Research Program I is hereby extended until
the third anniversary of the Effective Date of this Second Amendment.
b) Screening Research Plan. The parties acknowledge and agree that
the Screening Research Plan for Research Program I shall be the screening
research plan attached hereto as Exhibit B and, except as specifically set forth
herein, that such plan shall be part of the Research Plan for all purposes under
the Agreement and the work described therein shall be part of the Research
Program for all purposes under the Agreement.
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4. Additional CFFT Funding.
a) FTE Funding. In addition to the FTE funding specified in the
Agreement, CFFT will provide funding for [********] additional internal FTE, at
[********] per FTE, for each of the remaining three (3) years of Research
Program I.
b) Other Additional Funding. In addition to the current funding
under the Agreement, CFFT will provide additional funding at the request of
Predix (and accompanied by customary documentation), to reimburse Predix for, or
to fund, amounts incurred in connection with the following activities:
(i) Up to an aggregate of [********] to acquire compounds
predicted to bind to the CFTR protein, not to exceed [********] for each
Screening Sub-Project; provided that in case Predix terminates its CFTR program,
any unused compounds remaining shall be promptly transferred to CFFT (or a third
party) in accordance with CFFT's instructions;
(ii) Up to [********] for purchasing Virtual Hit compounds and
compounds to assist in determining or confirming structure-activity
relationships; and
(iii) All costs for biological assays will be paid directly,
or as pass through costs, by the CFFT.
5. Good Faith Negotiation. The Parties acknowledge (i) that the goals of
Research Program I have been expanded by this Second Amendment and, accordingly,
that the good faith negotiations contemplated by Section 4.1.1 will commence
only after Predix notifies CFFT that it has identified a Hit Corrector Compound,
and (ii) that although the principal objective of Research Program I is the
identification of a Hit Corrector Compound, the assays to be conducted pursuant
to the Agreement could yield a Hit Potentiator Compound; and, in such event: (A)
Predix shall continue to focus on the discovery of a Hit Corrector Compound
during
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the remainder of the Research Program; and (B) Section 4.1.1 of the Agreement
and the corresponding good faith negotiations, and the Interruption resulting
from the failure to reach agreement after such negotiations, shall also be
applicable to any such Hit Potentiator Compound; provided that, in lieu of
pursuing negotiations immediately following the identification of a Hit
Potentiator Compound, CFFT may elect in writing to defer such negotiations with
respect to a Hit Potentiator Compound to a subsequent date designated by CFFT
(the "Deferred Potentiator Negotiation Date").
6. JRC and Joint Steering Committee. Existing Section 2.6 of the Agreement
is redesignated as Section 2.7, Section 2.5 of the Agreement is amended and a
new Section 2.6 is inserted as follows:
"2.5 JOINT RESEARCH COMMITTEE.
2.5.1 Composition and Purposes. Predix and CFFT shall establish a
Joint Research Committee ("JRC") consisting of at least six (6) representatives
(as may be increased or decreased by the JRC), half of whom shall be designated
from time to time by each party. Each party shall choose a Program Coordinator
who may be changed from time to time by designation of each party. The Program
Coordinator for Predix shall be Xxxx Xxxxxx, Ph.D. The Program Coordinator for
CFFT shall be Xxxxx Xxxxxxx. If the JRC chooses to designate a Committee chair,
the chair will be Predix's Program Coordinator. The JRC shall meet formally no
less frequently than once in each three (3) month during the Research Program,
and at such time and location, as may be established by the JRC. However, the
JRC will make its schedule
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flexible in order to xxxxxx the successful completion of the Research Programs.
The JRC shall meet for the following purposes:
(i) to review and discuss the Research Plan and evaluate and
make recommendations to the JSC with respect to any proposed revisions;
(ii) to make recommendations to the JSC on whether milestones
have been achieved;
(iii) to provide guidance to the research team if such
guidance is needed on next steps to implement the Research Programs; and
(iv) to recommend the initiation of Screening-Sub Projects.
At least five (5) working days prior to each JRC meeting, Predix will send
a written report to CFFT detailing the progress made in the respective Research
Programs during the preceding quarter. Within thirty (30) days after the date of
each meeting, Predix shall prepare and deliver minutes of the meeting to the
members of the JRC, setting forth, inter alia, all recommendations of the JRC,
and including as an attachment the report on the progress of work performed
required by this Section 2.5.1.
2.6. JOINT STEERING COMMITTEE.
Predix and CFFT shall establish a Joint Steering Committee ("JSC")
which shall consist of an equal number of senior management personnel from each
party with the requisite experience and seniority to enable them to make
decisions on behalf of the Parties with respect to the initiation, planning and
performance of the activities of the Research Program, as may be agreed by the
Parties from time to time. The JSC shall initially have a total of four (4)
members.
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If the JSC chooses to designate a Committee Chair, the Chair will be appointed
from among the members of the JSC designated by Predix. The JSC shall terminate
its activities upon the occurrence of the last Research Termination Date. The
JSC shall meet, in person or by conference telephone, annually, or with such
other frequency and at such time and location or by such means, as may be
established by the Committee, for the following purposes:
(i) To provide general oversight of the Research Program;
(ii) To periodically review the overall goals and strategy of
the Research Program;
(iii) To approve achievement of milestones and record such
approval in JSC minutes; and
(iv) To discuss and attempt to resolve any disagreements
submitted with respect to recommendations made by the JRC, including
recommendations on the completion of milestones events. In the event a deadlock
of the JSC occurs on whether or not a milestone event has been successfully
completed, the Parties shall mutually select a Third Party who shall make such
determination. The determination of the Third Party shall be binding on the
Parties."
7. Milestones.
(a) Completion of Milestone (c)(2). The Parties hereby agree that
the Milestone specified in Section 3.1.1(c)(3) of the Agreement has been
completed prior to Milestone (c)(2) and that CFFT shall promptly make the
corresponding [********] milestone
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7
payment to Predix as provided for in the Agreement, with the remaining
[********] to be paid upon the completion of Milestone (c)(2) in accordance with
the Agreement.
(b) Additional Milestone. CFFT shall pay to Predix an additional
[********] milestone (the "Additional Milestone") upon the identification of the
[********]; provided that, if the Additional Milestone has not been paid by the
date on which negotiations are required to be commenced with respect to a
[********] under [********] of this Agreement (as amended by this Second
Amendment), or if later by the [********], CFFT shall pay to Predix [********]
of the Additional Milestone, with the remaining amount to be paid upon
identification of a [********]. If CFFT does not elect a [********] that occurs
on or before the Research Termination Date, no Additional Milestone will be paid
for the [********] and the [********] shall remain the property of Predix
notwithstanding an Interruption with respect to the [********]. If there is a
[********] at the time negotiations are required to take place under Section
4.1.1 of this Agreement (as amended by this Second Amendment) with respect to a
[********], the disposition of the [********] also shall be included in such
negotiations and, if no such agreement is reached with respect to such
[********], then [********] shall apply thereto as if such [********] were a
CFTR Corrector-based product.
Agreed and acknowledged as of the Effective Date.
Predix Pharmaceuticals Holdings, Inc. Cystic Fibrosis Foundation
Therapeutics Incorporated
By: Xxxxxxx X. Xxxxxxxx M.D., Ph.D. By: /s/ Xxxxxx X. Xxxxx
--------------------------------- ----------------------------------
Title: President and CEO Title: President and CEO
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8
EXHIBIT A
Revised Budget
PREDIX RESEARCH PROGRAM I REVISED
BUDGET 2006 - 2009
-----------------------------------------------------------------------------------------------------------
BUDGETED
PMT. AMOUNT PROJECTED
SHORT DESCRIPTION FEE TYPE # (MAX) DATE/QTR1 FY STATUS
-----------------------------------------------------------------------------------------------------------
[********] [********] 1 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 2 [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 3 [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 4 [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 5 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 6 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 7 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 8 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 9 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 10 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 11 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 12 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 13 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 14 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 15 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 16 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 17 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 18 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 19 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 20 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 21 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 22 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 23 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 24 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 25 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
-------------
1 The parties acknowledge that expenditure dates are flexible depending on
the scientific progress of the research program.
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OMISSIONS.
9
[********] [********] 26 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 27 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 28 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 29 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 30 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 31 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 32 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 33 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 34 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
[********] [********] 35 [********] [********] [********] [********]
-----------------------------------------------------------------------------------------------------------
TOTAL BUDGET PROJECT I $14,045,000
----------------------------------------------------------
Predix Research
Program II Budget
2006 - 2007 Unchanged $2,000,000
----------------------------------------------------------
TOTAL CONTRACT -
REVISED $16,045,000
==========================================================
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10
EXHIBIT B
Screening Research Plan for Research Program I
CFTR PROGRAM WORK PLAN - SCREENING PHASE
IDENTIFYING "CORRECTOR" OR " POTENTIATOR" HIT COMPOUNDS FOR
THE TREATMENT OF CYSTIC FIBROSIS
Objective
1. The objective of this study is to identify Hit Compounds that bind to the
Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR) and
exert "Corrector" activity. Potential outcome of the screening may be a
"Corrector", a "Potentiator" or a Hit Compound that exert both "Corrector"
and "Potentiator" activity.
Background
2. Since March 2005 Predix and CFFT have been collaborating on a project for
modeling the 3D structure of CFTR with an aim to identify potential sites
on CFTR for therapeutic intervention as "Correctors" or "Potentiators".
3. Now that the CFTR modeling project has reached its mid-point the JRC
believes that such potential sites have been identified. CFFT wants Predix
to use its 3D model of CFTR for in silico screening in search of Hit
Compounds that can act as CFTR Correctors or Potentiators.
4. The JRC recognizes that there are multiple potential binding sites on
CFTR. Since each of these potential sites has different characteristics
Predix will be required to carry out a separate in silico "Screening
Sub-Project" for each site.
5. The JRC also recognizes that additional potential binding sites are likely
to be identified as the CFTR modeling project progresses towards
completion.
6. It is understood by the JRC that the separate in silico Screening
Sub-Projects are completely independent of each other, and success/failure
in one of these sub-projects has no bearing on the success potential of
the other screening sub-projects.
Definitions
7. Following are definitions used in this work-plan
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11
7.1 "Hit Compound" shall mean a compound that has an [********] in a
Corrector biological assay, as defined in section 13 below.
7.2 "Corrector" shall mean a compound which modulates the biological
effect of CFTR by increasing the amount of [DELTA]F508 CFTR present
at the apical cell membrane.
7.3 "Potentiator" shall mean a Compound which modulates the biological
effect of CFTR by enhancing the gating activity of [DELTA]F508 CFTR
present in the apical cell membrane.
7.4 "Screening Sub-Project" shell mean a full in silico screening
project focusing on one of the potential binding sites identified in
the CFTR 3D model prepared by Predix in Research Program I.
7.5 "Virtual Hits" shall mean a set of compounds identified by Predix
through in silico screening methodologies, which have a high
likelihood of binding to the protein at a specific binding site and
exerting the desirable functional response.
Work-plan
8. The work-plan consists of the following steps:
8.1 On an on going basis, hand in hand with progress in the CFTR
modeling effort, identify [********] on CFTR.
8.2 Each [********] that is identified will be characterized for its
potential as a therapeutic intervention site.
8.3 If a [********] qualifies as a potential intervention site and is
approved as such by the JSC Predix will perform in silico screening
on that site ("Screening Sub-Project") in an attempt to [********]
as defined above.
9. Identification of [********]:
9.1 The 3D model of CFTR, or parts of that model, will be examined on an
on going basis in an attempt to identify [********].
9.2 A [********] is defined as a concave region on the protein's surface
with dimensions that roughly correspond to the size of a small
compound.
10. Each [********] will be characterized for its potential as a therapeutic
intervention site, by [********].
10.1 [********] will address the likelihood that a small compound that
binds in that [********] will exert either [********].
10.2 [********] will map the properties of the [********] and give a
[********] of the [********] that can [********]
11. Each separate in silico Screening Sub-Project involves the following steps
11.1 [********] based on the characteristics of the [********] (see item
12 below). The typical size of a [********] is expected to be
[********].
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12
11.2 [********] refinement of the[********]
11.3 Selection of the most [********], and an exploration of the
likelihood that some of the known CFTR [********] to this
[********].
11.4 [********] the [********] into the [********].
11.5 Apply Predix' proprietary [********] and [********] on the
[********].
11.6 Apply [********] and a [********] from Predix ensemble of in silico
methods to [********].
11.7 Select up to [********] for [********] (see item 13 below).
11.8 Acquire [********] in the [********], send them to the lab (or labs)
that will perform the [********], and confirm which of these
[********] qualify as [********].
11.9 For each [********], a set of up to [********] will be identified in
the Predix Library, purchased and sent to [********] in order to
identify qualifying [********]. If no related compounds are found in
the Predix Library, up to [********] will be [********] and sent to
[********].
12. Screening libraries
12.1 A separate [********] will be created and used for each screening
sub-project, optimally, matching the [********] of the [********].
There may be two sources for this [********]:
12.1.1 Predix will use its [********] as the primary source for
[********].
12.1.2 If a suitable [********] cannot be identified within the
[********] for screening will be [********] (see "Budget" in
section 16 below).
13. Biological assays2
13.1 The [********] or [********] in the program will be experimentally
tested for [********] using the following assays:
13.1.1 Correction assay: One or more of the following: [********].
13.1.2 Potentiation assay: Same as above, however [********].
13.2 CFFT will be responsible for [********] necessary to evaluate the
[********].
13.3 Predix will interact directly with the study director(s) performing
the experiments regarding [********].
-------------
2 The parties acknowledge that these assay definitions do not cover the
higher throughput assays under development on the Effective Date. They
agree that they will continue to collaborate on the development of such
assays.
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13
13.4 It is the interest of both CFFT and Predix to ensure rapid turn
around of up to [********] from the receipt of [********] service
providers to the draft results report. CFFT and Predix will work
together to ensure high [********] giving strong incentives to
[********] providers to generate results within [********].
14. Timeline
14.1 The term of this screening project is expected to be three (3) years
from initiation. In this period Predix should complete all the
Screening Sub-Projects against the pool of "potential sites" agreed
upon by the JRC.
14.2 Predix, on its own discretion, will decide on the prioritization of
the different "Screening Sub-Projects" and their internal timelines
and completion dates, as these will vary based on technical
considerations such as availability of screening compounds, the
specific in silico screening methodology most suitable for that
site, queue for biological assay testing, and additional technical
consideration.
15. Joint Research Committee and Joint Steering Committee (JSC)
15.1 The existing JRC for the CFTR modeling project will preside over
this screening project as well.
15.2 Based on the resulting characterization of each [********], and in
view of Predix's recommendations, the JSC will recommend for each
specific [********] whether to initiate a Screening Sub-Project or
not, thus creating a pool of [********]. Minutes of the JSC may
qualify as recommendation for initiation of screening.
15.3 The JRC will be updated, in its regular quarterly meetings, on
progress in the various screening sub-projects.
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14
