Exhibit No. 10.7(g)

 

Millennium/Aventis

Third Amendment to Collaboration and License Agreement

Execution Version

 

Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Asterisks denote omissions.

 

THIRD AMENDMENT TO COLLABORATION AND LICENSE AGREEMENT

 

This Third Amendment to Collaboration and License Agreement (this “Third
Amendment”) effective as of October 31, 2005 (the “Third Amendment Date”) is by
and between Millennium Pharmaceuticals, Inc., a corporation organized and
existing under the laws of the State of Delaware and having its principal office
at 75 Sidney Street, Cambridge, Massachusetts 02139 (“Millennium”) and Aventis
Pharmaceuticals Inc., a member of the sanofi-aventis Group and a corporation
organized and existing under the laws of the State of Delaware and having its
principal office at Route 202-206, P.O. Box 6800, Bridgewater, New Jersey 08807
(“Aventis”). All capitalized terms used in this Third Amendment and not
otherwise defined in this Third Amendment have the meanings assigned them in the
Collaboration Agreement (as that term is defined in the first recital paragraph,
below).

 

RECITALS

 

WHEREAS, Millennium and Aventis entered into a Collaboration and License
Agreement dated as of June 22, 2000 (as previously amended, the “Collaboration
Agreement”);

 

WHEREAS, in general, the Research Program Term under the Collaboration Agreement
expired on July 21, 2005, but the Parties entered into a letter agreement dated
July 20, 2005  extending certain aspects of the Research Program for a limited
time to permit the Parties to discuss further collaborative activities (the
“Extension Letter”); and

 

WHEREAS, Millennium and Aventis have agreed to the following changes to the
Collaboration Agreement to facilitate the Parties’ continued work together.

 

AGREEMENT

 

NOW, THEREFORE, Millennium and Aventis hereby agree as follows:

 

1.                                       End of Research Program Term. Effective
as of the Third Amendment Date, the Research Program and the Research Program
Term have expired for all matters for which the Research Program Term was
extended under the Extension Letter. The Parties acknowledge the Research
Program Term expired on July 21, 2005 for all other matters.

 

2.                                       Interim Research Period. After the
expiration of the Research Program Term, the Parties will continue to conduct
Pre-EDC Research Evaluation solely on the Program Compounds identified in this
Section 2 and for the specific period (the “Interim Research Period”) applicable
to that Program Compound. The sole purpose of this continued Pre-EDC Research
Evaluation will be to determine whether one or more of the listed compounds
qualifies

 

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as an EDC pursuant to the terms of the Collaboration Agreement as amended by
this Third Amendment. For this purpose, the Parties will apply the same EDC
qualification criteria, governing structures and decision-making processes as if
the Research Program Term had not expired and the Parties will have the same
“opt-in” and “opt-out” rights for any resulting EDCs as for EDCs identified
prior to the expiration of the Research Program Term. The research licenses
granted by each Party to the other Party pursuant to Sections 7.1.1(a) and
7.2.1(a) of the Collaboration Agreement will be extended during the applicable
Interim Research Period solely to permit the work contemplated under this
Section 2.

 

a.                                       [**] and [**]. The Parties acknowledge
that the only data remaining to determine whether the Program Compounds known as
[**] and/or [**], both of which are aimed at the Program Target known as [**],
meet the requirements to be classified as an EDC is data for each compound [**]
at Aventis as of the date of signature of this Third Amendment. The Interim
Research Period will end as to each of [**] and [**] upon the earliest to occur
of (a) a determination that such Program Compound meets the requirements for
EDC, (b) a determination that such Program Compound does not meet the
requirements for EDC, or (c) 30 days or the next meeting of the Joint
Development Committee, whichever is later, after receipt of the [**] Program
Compound.

 

b.                                      [**]. Millennium will conduct additional
Pre-EDC Research Evaluation of the Program Compound known as [**], which is
aimed at the Program Target known as [**], to determine whether [**] meets the
requirements to be classified as an EDC. Aventis will reimburse Millennium
[**]percent ([**]%) of the FTE Costs and other costs incurred by Millennium in
the course of conducting this Pre-EDC Research Evaluation during the extended
Research Program Term and the Interim Research Period for [**] up to a maximum
of $[**] U.S. The Interim Research Period will end as to [**] upon the earliest
to occur of (a) a determination that [**] meets the requirements for EDC, or (b)
a determination that [**] does not meet the requirements for EDC. If [**] does
not meet the requirements to become an EDC, [**] will be distributed to
Millennium as a Millennium Single-Party Research Target, effective as of the end
of the Interim Research Period for [**]. If [**] is so distributed, then
Millennium will have the same rights and obligations with regard to [**] and the
Small Molecules related to [**] as if [**] was a Pre-EDC Exempt Target
distributed to Millennium upon expiration of the Research Program through the
selection process described in Section 2.7.5(c)(ii) of the Collaboration
Agreement. For clarity, and subject to the exclusivity period regarding SPRT
Compounds specified in Section 2.7.3(b) of the Collaboration Agreement, Aventis
retains the right at any time to use [**] for further validation and drug
discovery activities, [**]. For further clarity, this Section 2(b) provides the
final disposition of [**] made during the Research Program Term and such
research assets shall not be further subject to Section 2.7.5 of the
Collaboration Agreement.

 

c.                                       [**]. Aventis will, at its sole cost,
conduct additional Pre-EDC Research Evaluation of the Program Compound known as
[**], which is aimed at the Program Target known as [**], to determine whether
[**] meets the requirements to be classified as an EDC. The Interim Research
Period will end as to [**] upon the earliest to occur of (a) a determination
that [**] meets the requirements for EDC, or (b) a determination that

 

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[**] does not meet the requirements for EDC. If [**] does not meet the
requirements to become an EDC, [**] will be distributed to Aventis as an Aventis
Single-Party Research Target, effective as of the end of the Interim Research
Period for [**]. If [**] is so distributed, then Aventis will have the same
rights and obligations with regard to [**] related to [**] as if [**] was a
Pre-EDC Exempt Target distributed to Aventis upon expiration of the Research
Program through the selection process described in Section 2.7.5(c)(ii) of the
Collaboration Agreement. For clarity, and subject to the exclusivity period
regarding SPRT Compounds specified in Section 2.7.3(b) of the Collaboration
Agreement, Millennium retains the right at any time to use [**] for further
validation and drug discovery activities, [**]. For further clarity, this
Section 2(c) provides the final disposition of [**] made during the Research
Program Term and such research assets shall not be further subject to Section
2.7.5 of the Collaboration Agreement.

 

3.                                       [**]. Effective as of the Third
Amendment Date, the Program Target known as [**] will become an Aventis
Single-Party Research Target. Aventis will have the same rights and obligations
with regard to [**] related to [**] as if [**] was a Pre-EDC Exempt Target
distributed to Aventis upon expiration of the Research Program through the
selection process described in Section 2.7.5(c)(ii) of the Collaboration
Agreement. For clarity, and subject to the exclusivity period regarding SPRT
Compounds specified in Section 2.7.3(b) of the Collaboration Agreement,
Millennium retains the right at any time to use [**] for further validation and
drug discovery activities, [**]. For further clarity, this Section 3 provides
the final disposition of [**] made during the Research Program Term and such
research assets shall not be further subject to Section 2.7.5 of the
Collaboration Agreement.

 

4.                                       Additional Indications for Current
JDCs. The Parties agree to cooperate in investigating additional indications,
[**], for all JDCs in the interest of maximizing the value of those assets.
Decisions regarding new indications will be made jointly by the Parties in
accordance with the procedures in the Collaboration Agreement as amended by this
Third Amendment, including, but not limited to, the governing structures,
decision-making processes, cost sharing and profit sharing provisions.

 

5.                                       “Second Generation” Programs for [**].
A new Section 3.13 is added to the Collaboration Agreement to read as follows:

 

3.13                           “Second Generation” Programs

 

3.13.1                  Programs. Aventis may , at its sole cost but in its
discretion, make efforts to identify, test and qualify Small Molecules to serve
as back-up or follow-on compounds for any EDCs approved by the Parties aimed at
[**].

 

(a)                                  The Joint Research Committee will meet no
less frequently than [**] to discuss Aventis’s activities and progress in
identifying, testing and qualifying such Small Molecules or, if the Parties
agree in a particular instance, Aventis may provide to

 

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Millennium a written report of its activities and progress in lieu of a meeting.

 

(b)                                 Millennium will cooperate reasonably with
Aventis in transferring any Program Technology or Program Materials necessary
for Aventis to fulfill its obligations under this Section 3.13.1.

 

(c)                                  Any decision whether any Small Molecule
identified by Aventis in accordance with this Section 3.13.1 qualifies as an EDC
will be made jointly by the Parties using the same EDC qualification criteria,
governing structures and decision-making processes as if the Research Program
Term had not expired and the Parties will have the same “opt-in” and “opt-out”
rights for any resulting EDCs as for EDCs identified prior to the expiration of
the Research Program Term.

 

(d)                                 In addition to the above, Aventis will
provide to Millennium a research plan describing the activities that Aventis
intends to undertake to identify, test and qualify such Small Molecules aimed at
[**] within [**] days after signature of the Third Amendment to this Agreement.
If at any time Aventis fails to pursue the activities described in the research
plan for a consecutive [**] period, Aventis will, at Millennium’s request,
transfer the program back to Millennium at no cost to Millennium, and Millennium
will have the right, in its discretion, to continue to identify, test and
qualify such Small Molecules. If Millennium decides to continue to identify,
test and qualify such Small Molecules, then the provisions of Section 3.13.1(c)
shall apply to any Small Molecules identified by Millennium.

 

3.13.2                  Royalty and Profit-Sharing Adjustments.

 

(a)                                  If any Small Molecule directed to [**]
identified by Aventis under Section 3.13.1 becomes a Joint Development Product
or a Unilateral Development Product, all applicable royalties due Millennium
will be [**] percent ([**]%) from what is provided in Section 8 of this
Agreement.

 

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(b)                                 If (i) a Small Molecule directed to
[**]identified by Aventis under Section 3.13.1 becomes a Joint Development
Product or a Unilateral Development Product and (ii) such Joint Development
Product or Unilateral Development Product is not based on or derived from [**],
then:

 

1.                                       In the case of a Joint Development
Product, Aventis will receive [**] percent ([**]%) and Millennium will receive
[**] percent ([**]%) of the resulting Pre-tax Profit or Loss; and

 

2.                                       In the case of a Joint Development
Product or a Unilateral Development Product, all applicable royalties due
Millennium will be [**] percent ([**]%) from what is provided in Section 8 of
this Agreement.

 

(c)                                  If (i) a Small Molecule directed to [**]
identified by Aventis under Section 3.13.1 becomes a Joint Development Product
or a Unilateral Development Product and (ii) such Joint Development Product or
Unilateral Development Product is not based on or derived from [**], then:

 

1.                                       In the case of a Joint Development
Product, Aventis will receive [**] percent ([**]%) and Millennium will receive
[**]e percent ([**]%) of the resulting Pre-tax Profit or Loss; and

 

2.                                       In the case of a Joint Development
Product or a Unilateral Development Product, all applicable royalties due
Millennium will be [**] percent ([**]%) from what is provided in Section 8 of
this Agreement.

 

(d)                                 Except as expressly set forth in this
Section 3.13.2, all other sharing of Pre-tax Profit or Loss or payment of
royalties will be in accordance with Section 8 of this Agreement.

 

3.13.3                  Designation of EDC Family Compounds.

 

(a)                                  All compounds first synthesized by either
Party after [**] pursuant to Section 3.13.1 directed to [**]

 

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that are based on or are made through the use of Program Technology or Program
Materials shall be deemed members of the EDC Family for [**] and [**] (even if
such compounds number more than [**]).

 

(b)                                 All compounds directed to [**] first
synthesized by Aventis pursuant to Section 3.13.1 or by Millennium that are (i)
based on or made through the use of Program Technology or Program Materials; and
either (ii) based on or derived from [**]; or (iii) not based on or derived from
[**] but first synthesized prior to [**],  shall be deemed members of the EDC
Family for [**] (even if such compounds number more than [**]) if [**] is
declared an EDC. If [**] is not declared an EDC, then the last 4 sentences of
Section 2.b of this Third Amendment shall apply.

 

(c)                                  All compounds directed to [**] first
synthesized by Aventis pursuant to Section 3.13.1 or by Millennium that are (i)
based on or made through the use of Program Technology or Program Materials; and
either (ii) based on or derived from [**]; or (iii) not based on or derived from
[**] but first synthesized prior to [**],  shall be deemed members of the EDC
Family for [**] (even if such compounds number more than [**]) if [**] is
declared an EDC. If [**] is not declared an EDC then the last 4 sentences of
Section 2.c of this Third Amendment shall apply.

 

(d)                                 The provisions of this Section 3.13.3 will
only apply as long as the Parties wish to continue working together on Small
Molecules aimed at the relevant Program Target, either because the Parties are
working together on a JDC or JDP directed at the relevant Program Target or, in
the absence of a JDC or JDP, the Parties are continuing to work together to
qualify EDCs aimed at the relevant Program Target.

 

6.                                       Development Program Governance. The
following new Section 3.3.3 is added to the Collaboration Agreement:

 

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3.3.3                        Identification of Development Lead Party.

 

(a)                                  In addition to the allocation of
Development activities provided under Section 3.3.2, the Global Development Plan
for each JDC will designate one Party or the other as the lead Party for the
implementation of the Development Plan of the applicable JDC through the Proof
of Concept Study (the “Pre-POC Development Lead”). For the purposes of this
Section 3.3.3, “Proof of Concept Study” means the first clinical study in the
target patient population for the applicable indication where the JDC is shown
to be active as defined by the agreed-upon clinical endpoints or validated
surrogate endpoints or such other endpoints as the Joint Development Committee
agrees demonstrate proof of concept, thereby validating the mechanism of action
of the JDC.

 

(i)                                     The Pre-POC Development Lead will be
permitted to execute against the approved plan and within the budget approved by
the Joint Steering Committee, plus the allowable variance from that budget
approved by the Joint  Steering Committee at the time of budget approval, for
the activities for which the Party has been designated as Pre-POC Development
Lead. As long as activities are within that range, the “non-lead” Party would
have input, but the Pre-POC Development Lead would have final decision
authority. This right would include, but not be limited to, the right to
subcontract activities without the consent of the “non-lead” Party as long as
the activities were within the range of expenditures permitted under the
approved budget and the arrangements otherwise met the requirements of Section
3.11. Any activities that would result in expenditures outside of the permitted
range would have to be approved by the Joint Development Committee and the Joint
Steering Committee. For avoidance of doubt, as part of the approval of the
plan,  “non-lead” Party will have the right to approve the key elements of the
design of all clinical trials contemplated in the plan and the right to approve
any material alterations to those elements.

 

(ii)                                  Without limiting the generality of the
foregoing, the Parties agree that (a) Millennium will be the Pre-POC Development
Lead for the JDCs known as [**]; and (b) Aventis will be the Pre-POC Development
Lead should any of those Program Compounds become EDCs for [**] and any Program
Compounds aimed at [**] developed under Section 3.13.1.

 

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(iii)                               Notwithstanding anything to the contrary in
Section 5.2.1, except in extraordinary circumstances as determined by the Joint
Development Committee, the Pre-POC Development Lead for a particular JDC in a
particular indication will also be the global Regulatory Lead for all activities
relating to that JDC in that indication.

 

(b)                                 If a JDC progresses beyond Proof of Concept,
the Global Development Plan for such JDC will designate one Party or the other
as the lead Party for the Development of the applicable JDC for each post-Proof
of Concept clinical study (the “Post-POC Development Lead”).

 

(i)                                     Responsibilities for Post-POC
Development Lead will be assigned according to the following principles:

 

(1)                                  Aventis will be the Post-POC Development
Lead for all trials in [**].

 

(2)                                  The Post-POC Development Lead for all other
trials will be determined by the Joint Development Committee such that the
Parties have substantially equal opportunities, subject to the factors set forth
below, to act as the Post-POC Development Lead within the collaboration.
Assignment of such responsibilities shall, where possible, be on an
indication-by-indication basis for each JDC. In making this determination, the
Joint Development Committee may take into account the capacity and capabilities
of the Parties given such factors as the cost of the trial, the number of
patients in the trial, the number of sites in the trial, the Parties’ relative
experience and expertise, the Parties’ relative resources (including whether the
work will be conducted internally or externally), and the existence and timing
of either Parties’ development programs for Small Molecules aimed at the same
Program Target taking place outside the Parties’ collaborative efforts.

 

(ii)                                  Notwithstanding anything to the contrary
in Section 5.2.1, except in extraordinary circumstances as determined by the
Joint Development Committee, the Post-POC Development Lead for a particular JDC
in a particular indication will also be the global Regulatory Lead for all
activities relating to that JDC in that indication. It is the understanding of
the

 

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Parties that the term Regulatory Lead has the meaning set forth in Article 5 of
this Agreement. For the avoidance of doubt, the final decision making authority
for the Post-POC Development Lead with respect to development matters does not
mean that such Party shall have final decision making authority with respect to
regulatory matters.

 

(iii)                               The Post-POC Development Lead will be
permitted to execute against the approved plan and within the budget approved by
the Joint Steering Committee, plus the allowable variance from that budget
approved by the Joint  Steering Committee at the time of budget approval, for
the activities for which the Party has been designated as Post-POC Development
Lead. As long as activities are within that range, the “non-lead” Party would
have input, but the Post-POC Development Lead would have final decision
authority. This right would include, but not be limited to, the right to
subcontract activities without the consent of the “non-lead” Party as long as
the activities were within the range of expenditures permitted under the
approved budget and the arrangements otherwise met the requirements of Section
3.11. Activities that would result in expenditures outside of the permitted
range would have to be approved by the Joint Development Committee and the Joint
Steering Committee. For avoidance of doubt, as part of the approval of the plan,
“non-lead” Party will have the right to approve the key elements of the design
of all clinical trials contemplated in the plan and the right to approve any
material alterations to those elements.

 

(c)                                  Notwithstanding anything to the contrary in
Article 12, if the Joint Development Committee is unable to agree on which Party
will be the Post-POC Development Lead for any set of activities, the dispute
will be immediately referred to the Joint Steering Committee for resolution. If
the Joint Steering Committee is unable to resolve the dispute within ten (10)
working days after such referral, then the chairs of the Joint Steering
Committee shall each choose an arbitrator which arbitrators shall then agree on
a third arbitrator which will form an arbitration panel of three for arbitration
on the sole question of which Party should be the Post-POC Development Lead for
the applicable set of activities. The arbitrators will be required to render a
decision within three (3) months after submission of the question for decision.
In rendering a decision, the arbitrators will only be empowered to select the
proposal of one Party or the other in its entirety on the issue(s) submitted for
decision (i.e., “baseball style”  arbitration) based on

 

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the criteria in Section 3.3.3(b)(i)(3). The arbitrators’ decision (majority
rule) will be final and binding on both Parties. The Parties agree to discuss
and agree upon the process for selection of the arbitrator and the procedures to
be followed in the arbitration within six (6) months after the execution of the
Third Amendment to this Agreement.

 

7.                                       CMC Lead. Section 4.1 of the
Collaboration Agreement is deleted in its entirety and replaced with the
following:

 

4.1                                 Clinical Supply. As part of the first Global
Development Plan for each Joint Development Compound, the Joint Development
Committee shall specify which Party shall be responsible for manufacturing
quantities of such compound for use in pre-clinical and clinical trials (the
“CMC Lead”). It is expected that only one Party shall be responsible for
manufacturing all quantities of a Joint Development Compound and the related
Joint Development Product necessary for pre-clinical and clinical studies
throughout the Territory. The CMC Lead will be permitted to execute against the
approved plan and within the budget approved by the Joint Steering Committee,
plus the allowable variance from that budget approved by the Joint  Steering
Committee at the time of budget approval, for the activities for which the Party
has been designated as CMC Lead. As long as activities are within that range,
the “non-lead” Party would have input, but the  CMC Lead would have final
decision authority. This right would include, but not be limited to, the right
to subcontract activities without the consent of the “non-lead” Party as long as
the activities were within the range of expenditures permitted under the
approved budget and the arrangements otherwise met the requirements of Section
4.4. Any activities that would result in expenditures outside of the permitted
range would have to be approved by the Joint Development Committee and the Joint
Steering Committee. The Parties agree that (a) Millennium will be the CMC Lead
for [**]; and (b) Aventis will be the CMC Lead for all other JDCs.

 

8.                                       Regulatory Lead. The phrase “Except as
provided in Section 3.3.3(b),” is added to the beginning of the second sentence
of Section 5.2.1.

 

9.                                       Freeze of FTE Rate. Notwithstanding
anything to the contrary in Exhibit B to the Collaboration Agreement, the FTE
Rate will remain $[**] U.S. per FTE per year until [**]. Thereafter, the FTE
Rate will increase by [**] percent ([**]%) per annum to reflect inflation.

 

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The Parties will, no later than [**], commence good faith discussions regarding
different ways of calculating the FTE Rate after [**].

 

10.                                 Change to Roll-In Letter. The phrase
“Aventis and Millennium shall each have” at the beginning of Paragraph 3(iii) of
the letter agreement between the Parties dated July 27, 2001 is amended to read
“Millennium shall have.”

 

12.                                 Elimination of June 3, 2003 Letter
Agreement. The Parties acknowledge that (a) the Program Compound known as [**]
(formerly known as [**]) ceased to be part of the Research Program when it was
designated as an EDC on June 6, 2005; and (b) none of the other Program
Compounds that were Designated Compounds under the terms of the June 3, 2003
letter agreement between the Parties regarding “Addition of Research Rights
Relating to Certain Program Compounds” (the “[**] Research Letter”) reached EDC
status by July 21, 2005 when the Research Program expired as to those Program
Compounds. Therefore, the Parties acknowledge that, except for the obligation to
share data from research conducted under the auspices of the [**] Research
Letter that was commenced prior to June 6, 2005 with regard to [**] and July 22,
2005 with regard to the other Designated Compounds, the [**]Research Letter is
of no further force and effect.

 

13.                                 Publication Approval Process. The reference
in the fifth sentence Section 10.4 of the Collaboration to “sixty (60) days” is
amended to read “forty-five (45) days.” Further, the reference in the sixth
sentence of Section 10.4 to “ninety (90) days” is amended to read “sixty (60)
days.”

 

14.                                 Changes to Dispute Resolution Provisions.
The Parties agree to discuss possible changes in the method of resolving
disputes that may arise between the Parties relating to JDCs within three (3)
months after the execution of this Third Amendment.

 

15.                                 Continuing Effect. Except as otherwise
specifically set forth herein, all terms and conditions of the Collaboration
Agreement remain in full force and effect.

 

16.                                 Counterparts. This Third Amendment may be
executed in one or more counterparts, each of which counterparts, when so
executed and delivered, shall be deemed to be an original, and all of which
counterparts, taken together, shall constitute one and the same instrument.

 

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IN WITNESS WHEREOF, each of the Parties has caused this Third Amendment to be
executed as of the date first set forth above.

 

Millennium Pharmaceuticals, Inc.

 

Aventis Pharmaceuticals Inc.

 

 

 

By:

               /s/

A. Protopapas

 

By:

         /s/

Larry Bangh

 

 

 

 

 

 

 

Name:

 

A. Protopapas

 

Name:

 

Larry Bangh

 

 

 

 

 

 

Title:

SVP, Corporate Develop.

 

Title:

 

Site Director

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

By:

         /s/

Mark L. Staudenne

 

 

 

 

 

 

 

 

Name:

 

Mark L. Staudenne

 

 

 

 

 

 

 

 

Title:

 

V.P. Finance

 

 

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