<PAGE>
                                                                 EXHIBIT 10.13.3

                   THIRD AMENDMENT TO COLLABORATION AGREEMENT

      This Third Amendment to Collaboration Agreement (this "Third Amendment")
dated as of December 21, 2005, is by and between Regeneron Pharmaceuticals,
Inc., a corporation organized and existing under the laws of the State of New
York and having its principal office at 777 Old Saw Mill River Road, Tarrytown,
New York 10591 ("Regeneron ") and Aventis Pharmaceuticals Inc., a corporation
organized and existing under the laws of the State of Delaware and having a
principal place of business at 200 Crossing Blvd., Bridgewater, New Jersey 08807
("Aventis").

                                  INTRODUCTION

      WHEREAS, Regeneron and Aventis are Parties to a Collaboration Agreement,
having an effective date of September 5, 2003, as amended on December 31, 2004,
and January 7, 2005 (the "Collaboration Agreement"); and

      WHEREAS, Regeneron and Aventis have determined that it is desirable to
amend certain provisions of the Collaboration Agreement to include Japan in the
Territory under the terms and conditions set forth herein.

      NOW, THEREFORE, in consideration of the following mutual promises and
obligations and for good and valuable consideration, the receipt and sufficiency
of which are hereby acknowledged, the Parties, intending to be legally bound,
hereby agree as follows:

Capitalized terms used in this Third Amendment and not defined herein shall have
the meanings ascribed to them in the Collaboration Agreement.

1.    ARTICLE 1. "DEFINITIONS". Article 1 of the Collaboration Agreement shall
      be amended as follows:

      (a) Section 1.2 "Additional Major Market Country" shall be amended by
      adding the words "Japan and" after the words "other than" and before the
      words "the Major Market Countries referred to in clause (i) of the
      definition thereof" therein.

      (b) Section 1.41 "Consolidated Net Profit/Loss Report" shall be amended by
      adding the following sentence at the end thereof. "This report shall also
      include, in reasonable detail, Net Sales in Japan, ******* (as defined in
      Section 9.1(b)), and the Japan Royalty Payment in sufficient detail to
      calculate the Japan True-Up for such calendar quarter."

      (c) Section 1.53 "Develop" or "Development" shall be amended by adding the
      phrase "in the case of all countries in the Territory except Japan," after
      the reference to "(c)" therein.

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      (d) Section 1.158 "Territory" shall be amended by deleting the words
      ", excluding Japan" therein.

2.    SECTION 2.6 "JAPAN". Section 2.6 of the Collaboration Agreement shall be
      deleted in its entirety.

3.    SECTION 4.1 "LICENSE GRANTS". Section 4.1 of the Collaboration Agreement
      shall be amended by deleting the reference to "(i)" therein and deleting
      the phrase "and (ii) the foregoing license grant shall not restrict or
      prohibit Regeneron's right to manufacture and supply Regeneron VEGF
      Products for importation into or use or sale in Japan."

4.    SECTION 4.3 "SUBLICENSES; SUBCONTRACTING". Section 4.3 of the
      Collaboration Agreement shall be amended by adding the phrase "other than
      Japan" after the reference to the defined term "Rest of World Country" in
      clause (A) therein.

5.    SECTION 6.5 "VEGF PRODUCT PRICING AND PRICING APPROVALS". Section 6.5 of
      the Collaboration Agreement shall be amended by adding ", Japan"
      immediately before the phrase "as well as the United States" in the final
      sentence therein. Section 6.5 of the Collaboration Agreement shall be
      further amended by adding the words "or Japan" at the end thereof after
      the reference to "the United States."

6.    SECTION 9.1(a) "SHARING OF COLLABORATION PROFITS AND LOSSES". Section
      9.1(a) of the Collaboration Agreement shall be amended by adding the words
      "other than Japan" after the defined term "Rest of World Countries"
      therein. Section 9.1(a) shall be further amended by adding the following
      sentence at the end thereof: "In addition, in consideration of the license
      grants herein for VEGF Products in Japan, and subject to the other terms
      and conditions of this Agreement, Aventis shall pay to Regeneron as part
      of the Quarterly True-Up a royalty on Net Sales in Japan calculated in
      accordance with the formula described in Schedule 1A (the 'Japan Royalty
      Payment')."

7.    SECTION 9.1(b) "SHARING OF COLLABORATION PROFITS AND LOSSES". Section
      9.1(b) of the Collaboration Agreement shall be amended by adding the
      following sentences at the end thereof: "Notwithstanding the foregoing,
      Regeneron and Aventis shall each be responsible for paying fifty percent
      (50%) of all *********** incurred in accordance with the terms of this
      Agreement and the applicable Co-Development Budget, subject to the terms
      and conditions set forth in Schedules 1 and 1A. As used herein, the term
      ************ shall mean Development Costs incurred by the Parties for JDC
      approved Clinical Trials conducted in Japan (and/or such other Asian
      countries as may be agreed upon by the Parties) in *********************
      *******************************."

8.    SECTION 9.2 "PERIODIC REPORTS". Section 9.2(c) of the Collaboration
      Agreement shall be amended by adding "Japan," after the words "in Major
      Market Countries," in clause (ii) therein. Section 9.2(c) of the
      Collaboration Agreement shall be further amended by adding the words "and
      Japan" after the phrase "with respect to the United States" in clause
      (iii) therein. Section 9.2(c) of the Collaboration Agreement shall be
      further

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      amended by adding the words "and Japan" after the defined term "Major
      Market Countries" in clause (iv) therein.

9.    SECTION 16.1(c) "CONFIDENTIAL PARTY INFORMATION". Section 16.1 of the
      Collaboration Agreement shall be amended by deleting paragraph (c) in its
      entirety and substituting the words "INTENTIONALLY BLANK" after the
      reference to "(c)" therein.

10.   SECTION 17.1 "INDEMNITY AND INSURANCE". Section 17.1(a) of the
      Collaboration Agreement shall be amended by adding a reference to a "; or
      " after clause (ii) therein and inserting the following new clause (iii):
      "(iii) notwithstanding anything to the contrary in this Agreement, the
      Development or Commercialization of a VEGF Product in Japan under this
      Agreement, except to the extent that Damages arise out of the negligence,
      recklessness, bad faith or intentional wrongful acts, or omissions
      committed by Regeneron or its Affiliates."

11.   SCHEDULE I "QUARTERLY TRUE-UP". Schedule 1 of the Collaboration Agreement
      shall be deleted in its entirety and replaced with Schedule 1 attached to
      this Third Amendment, which is marked to reflect changes.

12.   SCHEDULE 1A "JAPAN TRUE-UP". The Collaboration Agreement shall be amended
      by adding a new Schedule 1A in the form attached to this Third Amendment.

13.   UP-FRONT PAYMENT. In consideration for Regeneron's agreement to enter into
      this Third Amendment and extend the Territory to include Japan on the
      terms set forth herein, Aventis shall pay to Regeneron, on or before
      January 10, 2006, a non-refundable, non-creditable payment of Twenty-Five
      Million US Dollars (US$25,000,000.00) (which shall not be reduced by any
      withholding or similar taxes).

14.   SCHEDULE 2 "MILESTONE PAYMENTS". Schedule 2 of the Collaboration Agreement
      shall be amended by adding the milestones and milestone payments set forth
      in Schedule 2 attached to this Third Amendment.

15.   SCHEDULE 15.3(c) "JAPAN PATENT APPLICATIONS". Schedule 15.3(c) of the
      Collaboration Agreement shall be amended by adding the Regeneron Patent
      Applications set forth in Schedule 15.3(c) attached to this Third
      Amendment.

16.   COMMERCIALIZATION. It is agreed that Regeneron shall not Co-Promote VEGF
      Products in Japan. However, notwithstanding anything to the contrary in
      the Collaboration Agreement, the Parties shall establish a Joint Country
      Commercialization Sub-Committee in Japan, which shall have the
      responsibilities set forth in Section 3.9(b). For the purpose of clarity,
      unless specifically delineated, Section 3.9(b) shall not be interpreted to
      include the responsibilities set forth in Section 3.9(a); either with
      respect to Joint Country Commercialization Sub-Committee in Japan or with
      respect to any Joint Country Commercialization Sub-Committee in each Rest
      of World Country. However, nothing in the preceding sentence shall limit
      or restrict any responsibilities included in sections of the Collaboration
      Agreement other than 3.9(b).

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17.   JAPAN CO-DEVELOPMENT PLAN. The Parties acknowledge that finalization of a
      plan for Development of the VEGF Products in Japan (the "Japan Development
      Plan") will require close interaction between the Parties as well as
      ***************************. Toward that end, the Parties shall each
      expend such necessary internal resources as required for timely
      finalization of the Japan Development Plan. The JDC shall finalize, and
      the JSC shall approve, the Japan Development Plan as soon as reasonably
      practicable following the date of this Third Amendment, which shall
      incorporate the activities, timelines, and budget included in Schedule 3
      attached hereto unless otherwise mutually agreed to by the Parties. The
      Parties presently anticipate that it will be possible to finalize a Japan
      Development Plan within ********* of the date hereof. It is understood
      that the Development plan attached hereto is preliminary, and that the
      Scenarios outlined in the "Timelines and Costs" section are nonbinding. It
      is understood that, at present, Scenario 2 is the most probable scenario
      based upon regulatory approvals and current conditions in the Japan
      market. The JSC approved development plan for Japan shall be incorporated
      into and made a part of the Co-Development Plan.

18.   CONTINUING EFFECT. Except as specifically modified by this Third
      Amendment, all of the provisions of the Collaboration Agreement are hereby
      ratified and confirmed to be in full force and effect, and shall remain in
      full force and effect.

19.   ENTIRE AGREEMENT; SUCCESSORS AND ASSIGNS. The Collaboration Agreement,
      this Third Amendment, and any written agreements executed by both Parties
      pertaining to the subject matter therein, constitute the entire agreement
      between the Parties hereto with respect to subject matter hereof and
      thereof. Said documents supersede all other agreements and understandings
      between the Parties with respect to the subject matter hereof and thereof,
      whether written or oral. This Third Amendment shall be binding upon and
      shall inure to the benefit of the Parties and their respective heirs,
      administrators, executors, Affiliates, successors and permitted assigns.

20.   HEADINGS. The section headings contained in this Third Amendment are for
      reference purposes only and shall not affect in any way the meaning or
      interpretation of this Third Amendment.

21.   COUNTERPARTS. This Third Amendment may be executed in one or more
      counterparts, all of which shall be considered one and the same agreement,
      and shall become a binding agreement when one or more counterparts have
      been signed by each Party and delivered to the other Party.

22.   MISCELLANEOUS. This Third Amendment shall be governed by the laws of the
      State of New York, without regard to its principles of conflicts of laws.
      Each Party hereby irrevocably and unconditionally consents to the
      exclusive jurisdiction of the courts of the State of New York, and the
      United States District Court for the Southern District of New York for any
      action, suit or proceeding arising out of or relating to this Third
      Amendment, waives any objections to such jurisdiction and venue and agrees
      not to commence any action, suit or proceeding relating to this Third
      Amendment except in such courts. This Third Amendment supersedes all prior
      understandings and agreements, whether written or oral, among the Parties
      hereto relating to the essence of this Third

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      Amendment. If there is a direct conflict between the provisions of the
      Collaboration Agreement and this Third Amendment, this Third Amendment
      shall govern. This Third Amendment may be amended only by a written
      instrument executed by each of the Parties.

                      [SIGNATURES APPEAR ON FOLLOWING PAGE]

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      IN WITNESS WHEREOF, each of the Parties has caused this Third Amendment to
be executed as of the date hereof by a duly authorized corporate officer.

                                        AVENTIS PHARMACEUTICALS INC.

                                        By:  /s/ Juergen Lasowski
                                           -------------------------------------

                                        Name: Juergen Lasowski

                                        Title: Vice President, Business
                                        Development and Strategy

                                        Date:  December 21, 2005

                                        By:  /s/ Gregory Irace
                                           -------------------------------------

                                        Name:  Gregory Irace

                                        Title: Chief Financial Officer

                                        Date: December 21, 2005

                                        REGENERON PHARMACEUTICALS, INC.

                                        By:  /s/ Murray Goldberg
                                            ------------------------------------

                                        Name:  Murray Goldberg

                                        Title:  SVP, Finance & Administration
                                        and CFO

                                        Date:  December 21, 2005

                                       6
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                                   SCHEDULE 1

                                Quarterly True-Up

The true-up in a calendar quarter (the "Quarterly True-Up") shall be equal to
the sum of the Major Market True-Up (as set forth in Part I), plus the Rest of
World True-Up (as set forth in Part II), plus the Regeneron Development
Reimbursement Amount (as set forth in Part III), plus the Japan True-Up (as set
forth in Schedule 1A), less the Development Payment (commencing in the calendar
quarter of the First Commercial Sale of a VEGF Product in any country in the
Territory other than Japan) (as set forth in Part IV). In the event that the
Quarterly True-Up is an amount greater than zero, such amount will be payable by
Aventis to Regeneron in accordance with the terms set forth in Section 9.3. In
the event that the Quarterly True-Up is an amount less than zero, the absolute
value of such amount shall be payable by Regeneron to Aventis in accordance with
the terms set forth in Section 9.3. An example of the Quarterly True-up is shown
in Part V.

                             I. MAJOR MARKET TRUE-UP

The "Major Market True-Up" shall mean the Major Market Profit Split, plus 100%
of Shared Promotion Expenses incurred by Regeneron. The "Major Market Profit
Split" shall mean the product of (x) aggregate Net Sales in Major Market
Countries less aggregate VEGF Product Expenses, and (y) .50. "VEGF Product
Expenses" shall mean the sum of COGS and Shared Promotion Expenses incurred by
both Parties for such calendar quarter. For the avoidance of doubt, the Major
Market Profit Split shall apply independent of the detailing effort provided by
either Party, such that, for example, if Regeneron provided none of the
detailing efforts, it will still be entitled to 50% of the sum of aggregate Net
Sales in the Major Market Countries less aggregate VEGF Product Expenses in
Major Market Countries.

An example of a calculation for a Major Market True-Up would be:
<TABLE>
<CAPTION>

                                                      Aventis      Regeneron
                                         Aggregate    50%          50%
                                         ---------    -------      ---------
<S>                                      <C>          <C>          <C>
Net Sales in Major Market Countries           1000       1000

VEGF Product Expenses:

-        COGS                                 (100)      (100)            (0)
-        Shared Promotion Expenses            (500)      (400)          (100)
                                         ---------    -------      ---------
income or expenses incurred                    400        500           (100)

Major Market Profit-Split                                 200            200

Major Market True-Up                                     (300)           300
</TABLE>

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<PAGE>




                            II. REST OF WORLD TRUE-UP

The "Rest of World True-Up" shall mean the Rest of World Profit Split plus 100%
of Regeneron's Sales Force Costs and Regeneron's Medical Affairs Costs, in each
case as it relates to a Rest of World Country. The "Rest of World Profit Split"
shall mean the product of (x)**************************, (y) *****************
******, and (z) .50.

An example of a calculation for a Rest of World True-Up would be:
<TABLE>
<CAPTION>

                                                         Aventis     Regeneron
                                          Aggregate      50%         50%
                                          ---------      -------     ---------
<S>                                       <C>            <C>         <C>
Net Sales in Rest of World Countries             20           20

Regeneron Sales Force Cost                                                  (2)
Regeneron Medical Affairs Cost                                              (0)

****************                                ***

Rest of World Profit Split                       10            5             5
                                          ---------      -------     ---------

Rest of World True-Up                                         (7)            7
</TABLE>

                    III. REGENERON DEVELOPMENT REIMBURSEMENT

The "Regeneron Development Reimbursement Amount" shall mean the aggregate amount
of Development Costs incurred by Regeneron anywhere in the Territory (including
Japan) in such calendar quarter.

An example of the Regeneron Development Reimbursement Amount would be:    20

                             IV. DEVELOPMENT PAYMENT

*************************************************************

An example of a calculation of Development Payment would be:
<TABLE>
<CAPTION>
                                                      Aventis      Regeneron
                                         Aggregate    50%          50%
                                         ---------    -------      ---------
<S>                                      <C>          <C>          <C>
***********                              ****         ****         ****

***********                              ****
                                         -----        ----         ----
Development Payment                                    (10)          10
</TABLE>

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                         V. EXAMPLE OF QUARTERLY TRUE-UP

An example of a calculation of Quarterly True-up would be:

Major Market True-up =                                           300

Rest of World True-up =                                            7

Japan True-Up =                                                    5

Regeneron Development Reimbursement Amount =                      20

Development Payment =                                            (10)

Quarterly True-up =                                              322

In this example, Aventis would pay Regeneron 322 in accordance with the terms
set forth in Section 9.3.

                                       9
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                                   SCHEDULE 1A

                                  Japan True-Up

Commencing in the calendar quarter of the First Commercial Sale of a VEGF
Product in Japan, the Quarterly True-Up shall include a potential payment to
Regeneron (the "Japan True-Up"). The Japan True-Up shall equal the Japan Royalty
Payment (as set forth in Part I), less ************* (as set forth in Part II).
An example of a quarterly Japan True-Up is shown in Part III.

                            I. JAPAN ROYALTY PAYMENT

The Japan Royalty Payment shall equal the sum of (i) the Japan Royalty and (ii)
**********. The "Japan Royalty" shall equal *******************************. The
Japan Royalty Payment for a calendar quarter shall be calculated based on Net
Sales in such calendar quarter using a royalty rate(s) ********************** in
accordance with the formula set forth above.

********************are set forth below:

****************************************

The ************** in any calendar quarter shall equal ***********************
****** for such calendar quarter. The ************ will be calculated as
follows:

***************************************

Examples of the calculation of the Japan Royalty Adjustment are shown in Section
III below.

                                II. ************

*****************************

                    III. EXAMPLES OF QUARTERLY JAPAN TRUE-UP

Examples of calculations of a quarterly Japan True-Up would be:

******************************************

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The Japan True-Up is included in the calculation of the Quarterly True-Up in
accordance with Schedule 1.

For the avoidance of doubt, in no event shall the Japan True-Up require a
payment from Regeneron to Aventis.

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                                   SCHEDULE 2

                            Japan Milestone Payments
<TABLE>
<CAPTION>
MILESTONE
---------
<S>                <C>                      <C>
   10              US$**********            *******************.
   11              US$**********            *******************.
   12              US$**********            *******************.
   13              US$**********            *******************.
   14              US$**********            *******************.
</TABLE>

* For the avoidance of doubt,*********************.

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                                   SCHEDULE 3

                             Japan Development Plan






                         ******************************







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                                SCHEDULE 15.3(c)
                      Regeneron's Japan Patent Applications
<TABLE>
<CAPTION>
                                                             Japanese National
                                     PCT                        Phase
                                   -----------------------------------------------------------------
Case                                             Filing
No.                 Title          Appln. No.     Date        Priority Date     Status    Appln. No.
---                 -----          ----------    ------      --------------     ------    ----------
<S>                 <C>            <C>           <C>         <C>                <C>       <C>
                                            ***************************************

                                            ***************************************

                                            ***************************************

                                            ***************************************

                                            ***************************************

                                            ***************************************
</TABLE>

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