Document:

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                                                            Execution Copy

                                                                 EXHIBIT 10.10.1

                             AMENDMENT AND AGREEMENT

This Amendment and Agreement (this "Amendment") is made as of the 30th of
June, 2005.

BETWEEN:

REGENERON PHARMACEUTICALS, INC. a New York corporation having its principal
office at 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707,
(hereinafter with its Affiliates, "Regeneron")

AND:

THE PROCTER & GAMBLE COMPANY, an Ohio corporation having its principal offices
at One Procter & Gamble Plaza, Cincinnati, Ohio 45202, (hereinafter together
with its Affiliate Procter & Gamble Pharmaceuticals, Inc., "P&G").

WHEREAS Regeneron and P&G entered into the Focused Collaboration Agreement on
December 31, 2000 ,as amended by the Parties on August 11, 2004 (the
"Agreement");

WHEREAS the Parties have mutually agreed that the activities contemplated by the
Parties during the Research Term have been completed;

NOW THEREFORE in consideration of the mutual promises contained herein, the
parties agree as follows:

1)    Because the activities contemplated during the Research Term have been
      completed, the Term shall expire effective as of June 30, 2005 (the
      "Expiration Date").

2)    P&G shall forthwith:

            i.    deliver promptly to Regeneron any and all confidential
                  information and materials relating to ******************
                  (including, without limitation, a **********************
                  *************************************** ***************, the
                  GPCR Field, and the DDR Field, whether

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                  provided by Regeneron or generated by P&G during the term of
                  the Agreement. Such confidential information shall now be
                  considered Regeneron's Information. Regeneron may use and
                  disclose such information without restriction and P&G shall
                  treat such Information in accordance with the confidentiality
                  and non-use obligations set forth in Article VIII of the
                  Agreement; and

            ii.   grant to Regeneron an exclusive, royalty free, worldwide,
                  fully paid up license, with the right to grant sublicenses, to
                  any Inventions (including any P&G Patent Right included
                  therein) and Know-how in, to or claiming*********************
                  **********, the GPCR Field and/or the DDR Field (including the
                  manufacture, use, offer for sale or sale thereof) that P&G (or
                  its Affiliate) might have at the Expiration Date and any
                  Patents filed after the Expiration Date which claim any such
                  Invention. Notwithstanding the license granted above, P&G
                  shall only grant to Regeneron a non-exclusive, royalty free
                  license under Procter & Gamble Know-how and P&G Patent Rights,
                  with the right to sublicense, to make, have made, and use
                  Procter & Gamble Compounds solely for research purposes. For
                  clarity, this non-exclusive license to Procter & Gamble
                  Compounds does not include the right to have sold or sell
                  Procter & Gamble Compounds, under Procter & Gamble Know-how
                  and P&G Patent Rights.

            iii.  at any time prior to************, promptly notify Regeneron of
                  any decision to not advance the Hercules Compound (as defined
                  below) to the next stage of development. Upon such
                  notification the obligations under Section 2.11(b) of the
                  Agreement shall no longer be applicable to the Hercules
                  Compound.

3)    Regeneron shall forthwith:

            i.    grant to P&G an exclusive, worldwide license, with the right
                  to grant sublicenses, to any Inventions (including any
                  Regeneron Patent Rights included therein) and Know-how in, to
                  or claiming ***************************("Hercules Project"),
                  including the Development
                  Compound***********************************************, the

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                  "Hercules Compound") (including the manufacture, use, offer
                  for sale or sale thereof) that Regeneron might have at the
                  Expiration Date and any Patents filed after the Expiration
                  Date which claim any such Invention; and

            ii.   deliver promptly to P&G any and all confidential information
                  and materials relating to the Hercules Project or the Hercules
                  Compound whether provided by P&G or generated by Regeneron
                  during the term of the Agreement. Such confidential
                  information shall now be considered P&G's Information. P&G may
                  use and disclose such information without restrictions and
                  Regeneron shall treat such Information in accordance with the
                  confidentiality and non-use obligations set forth in Article
                  VIII of the Agreement.

4)    All references to the Tail Period in the Agreement (and the respective
      rights and obligations of the Parties during the Tail Period) are deleted.
      Except as set forth herein, all obligations of, and licenses and rights
      granted by, the Parties under the Agreement shall automatically terminate
      as of the Expiration Date. However, neither Party shall be relieved of any
      obligations (including payment obligations) arising prior to the
      Expiration Date, including, without limitation, any payment obligations
      pursuant to Section 3.2 of the Agreement for activities prior to June 30,
      2005. P&G shall pay to Regeneron the sum of Two Million Seven Hundred
      Fifty-two Thousand Four Hundred Eighty-five dollars ($2,752,485.00) upon
      the Expiration Date for activities performed under the Agreement in the
      second Fiscal Quarter of 2005.

5)    Each Party shall forthwith:

            i.    deliver promptly to the other Party copies or samples of any
                  and all confidential information and materials relating to the
                  New Target Field, whether provided by the delivering Party or
                  generated by the other Party during the term of the Agreement.
                  Such information may be used and disclosed by both Parties
                  without regard to any of the confidentiality and non-use
                  obligations in Article VIII of the Agreement; and

            ii.   grant to the other Party a non-exclusive, royalty free,
                  worldwide, fully paid up license, with the right to grant
                  sublicenses, to any Inventions (including any P&G Patent Right
                  or Regeneron Patent Right included therein) and

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                  Know-how having utility in the New Target Field (including the
                  manufacture, use, offer for sale or sale thereof) that the
                  granting Party (or its Affiliate) might have at the Expiration
                  Date and any Patents filed after the Expiration Date which
                  claim any such Invention. Notwithstanding the above, P&G shall
                  only grant to Regeneron a non-exclusive, royalty free license
                  under Procter & Gamble Know-how and P&G Patent Rights, with
                  the right to sublicense, to make, have made, and use Procter &
                  Gamble Compounds in the New Target Field solely for research
                  purposes. For clarity, this non-exclusive license to Procter &
                  Gamble Compounds does not include the right to have sold or
                  sell Procter & Gamble Compounds, under Procter & Gamble
                  Know-how and P&G Patent Rights. P&G agrees that it shall not,
                  directly or indirectly, sell or have sold any Procter & Gamble
                  Compounds discovered during the Term in the New Target Field.

6)    With respect to all other Inventions having utility in the Muscle Field
      not covered by paragraphs 2, 3, and 5 of this Amendment, each Party grants
      to the other Party a non-exclusive, royalty free, worldwide, fully paid up
      license, without the right to grant sublicenses, to make, have made, and
      use P&G Technology or Regeneron Technology, as the case may be, for
      research purposes in the Muscle Field.

7)    Without limiting anything in paragraphs 2, 3, 5, and 6 of this Amendment,
      within thirty (30) days following the Expiration Date, each Party shall be
      responsible for providing the other Party with the materials and
      information set forth in Attachment I hereto.

8)    P&G shall pay Regeneron Five Million Six Hundred Thirty-nine Thousand Nine
      Hundred Sixty Dollars ($5,639,960) upon the Expiration Date

9)    Regeneron shall pay P&G Nine Hundred Fifty Thousand Dollars ($950,000.00)
      upon the Expiration Date to acquire all right, title and interest in all
      capital equipment bought by or on behalf of P&G during the Term and
      residing at Regeneron's facilities. P&G represents and warrants that it
      has good and marketable title to such capital equipment, free and clear of
      liens and encumbrances.

10)   All payments due upon the Expiration Date shall be paid within thirty (30)
      days of receipt of an invoice for such amount. Once the payments in
      Sections 4, 8, and 9 of

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                                                                  Execution Copy

      this Amendment are made in full, each Party shall release and discharge
      the other Party from any and all claims, counterclaims, causes of actions,
      liabilities or charges asserted or which could have been asserted, with
      respect to such matters or the payments made by the Parties under the
      Agreement during the Research Term.

11)   P&G shall pay Regeneron, as an Opting Out Party, the following royalty on
      the Hercules Compound:

            i.    P&G shall pay to Regeneron a royalty based on P&G's Net Sales
                  of a Hercules Compound in all countries in the Territory. Such
                  royalty will be calculated by multiplying the Net Sales by the
                  applicable rates listed below: ****************of Net Sales in
                  any Fiscal Year up to and including ***************(Threshold
                  I); and
                  ****************of Net Sales in any Fiscal Year above
                  Threshold 1 and up to and including ****************; and
                  **************** of Net Sales in any Fiscal Year greater than
                  *************.

      Such royalty will be paid on a quarterly basis for a period of **********
from the date of first sale to a customer of such Hercules Compound in a
particular country, or for so long as the manufacture, use, importation or sale
of the Hercules Compound would infringe a Valid Claim of a Patent in such
country, whichever is longer.

            ii.   If P&G licenses the Hercules Compound to a Third Party or
                  Parties, Regeneron's share of the royalty received from such
                  Third Parties shall be a percentage of the total royalty from
                  each such licensee(s). Such percentage will be based on when
                  in the development by P&G of the Hercules Compound, the Third
                  Party license is completed according to the following
                  schedule:

<TABLE>
<CAPTION>
                        % of Third Party      % of Third Party
Time of License      Royalties to Regeneron   Royalties to P&G
------------------   ----------------------   ----------------
<S>                  <C>                      <C>
******************          ******                  *****
</TABLE>

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                                                                  Execution Copy

<TABLE>
<S>                         <C>                     <C>
******************          ******                  *****

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

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

P&G may receive, without sharing with Regeneron, reimbursement from such
licensee for reasonable, ****************************** costs of research,
development and/or marketing costs (whether internal or Third Party) incurred by
P&G for work conducted on behalf of the licensee. Any amounts in excess of such
reimbursement plus any other payments or income received by P&G from a licensee,
including, but not limited to, upfront, milestone and termination payments and
licensing fees, shall be shared with Regeneron in the proportion outlined in the
above table.

All amounts from licensees received by P&G shall be fully disclosed to Regeneron
and be subject to audit (including without limitation the calculation of
fully-loaded costs) pursuant to Section 6.5 of the Agreement.

      iii.  If P&G elects to distribute or sublicense a Hercules Compound in any
            country, and a license must be obtained from a Third Party to
            manufacture and/or market such Hercules Compound to avoid a
            non-frivolous claim of patent infringement, P&G shall offset *****
            of the Third Party license fee, royalty or other similar payments
            solely in connection with the license of such patent for use to
            manufacture, use or sell a Hercules Compound ("Licensee Fees")
            against Regeneron's royalty. Any portion of Licensee Fees paid by
            P&G that is to be offset against Regeneron's royalty but that
            exceeds Regeneron's royalty payable, shall be carried forward and
            accrue interest pursuant to Section 6.4 of the Agreement and be
            offset against future royalties as such royalties become payable.

12) Except as set forth herein with respect to the Tail Period, sections 2.1,
2.2, 2.11(b), 5.1, 5.3(a), each of 6.2, 6.3, 6.4 and 6.5 (in the case of 6.2,
6.3, 6.4, and 6.5, solely with respect to royalty payments made to Regeneron
under this Amendment), 8.1, 8.2, 9.3, 11.2, 11.3, 11.5, 11.6, 11.7, and Article
1 of the Agreement shall survive the expiration of the Agreement. For the
avoidance of doubt, this paragraph 11 shall replace Section 11.8 of the
Agreement in its entirety.

13) Capitalized terms not defined herein shall have the meaning ascribed to them
in the Agreement.

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                                                                  Execution Copy

14) This Amendment and, to the extent specifically referenced herein, the
Agreement constitute the entire agreement between the Parties hereto with
respect to the subject matter hereof. Said agreements supersede all other
agreements and understanding between the Parties with respect to the subject
matter hereof and thereof, whether written or oral. If there is a direct
conflict between the provisions of the Agreement and this Amendment, this
Amendment shall govern. This Amendment may be amended only by a written
instrument executed by both Parties. This Amendment shall be binding upon and
inure to the benefit of the Parties and their respective Affiliates, successors
and assigns.

15)   This 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 counterpart has been signed by each Party and delivered
      to the other Party.

16)   This Amendment shall be governed by the laws of the Sate of Delaware, as
      such laws are applied to contracts entered into and to be performed within
      such state. Regeneron shall have the right to file or register this
      Amendment with the United States Securities and Exchange Commission.

17)   Regeneron represents to P&G that it has made available to P&G during the
      Term the results of all material preclinical studies using its
      ****************. P&G represents to Regeneron that it has made available
      to Regeneron during the Term the results of all material preclinical
      studies in the Hercules Project.

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                                                                  Execution Copy

IN WITNESS WHEREOF the Parties have executed this Amendment as of the date first
written above.

THE PROCTER & GAMBLE COMPANY                     REGENERON PHARMACEUTICALS, INC.

/s/ Mark A. Collar                               /s/ Leonard Schleifer
----------------------------------------         -------------------------------
Name:  Mark A. Collar                            Name:  Leonard S. Schleifer
Title: President, Global Pharmaceuticals         Title: President & CEO

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                                                                  Execution Copy

                        ATTACHMENT I INFORMATION TRANSFER

           Information/Materials to be transferred to Regeneron by P&G

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           Information/Materials to be Transferred to P&G by Regeneron

Reagents

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Information

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

The Parties need to provide the Information above only to the extent it is
available.

                                       -9-<PAGE>

                              ALLEGHANY CORPORATION
                     SUBSIDIARY DIRECTORS' STOCK OPTION PLAN

1. PURPOSE. The purpose of the Alleghany Corporation Subsidiary Directors' Stock
Option Plan (the "Plan") is to advance the interests of Alleghany Corporation
(the "Corporation"), its Subsidiaries (as defined below) and its stockholders by
encouraging increased stock ownership by members of the boards of directors of
the Subsidiaries who are not employees or directors of the Corporation or
employees of any of the Subsidiaries, in order to promote long-term stockholder
value through continuing ownership of the Corporation's common stock.

2. ADMINISTRATION. The Plan shall be administered by the Compensation Committee
of the Board of Directors of the Corporation (the "Committee"). The Committee
shall have all the powers vested in it by the terms of the Plan, such powers to
include selecting the Non-Employee Subsidiary Directors (as defined below) who
shall receive awards of nonqualified stock options made under the Plan
("Options"), determining the amount of Options to be awarded and the terms and
conditions of awards of Options, and prescribing the form of the agreement
embodying awards of Options, all within the limitations described herein. The
Committee shall have the power to construe the Plan, to determine all questions
arising thereunder and, subject to the provisions of the Plan, to adopt and
amend such rules and regulations for the administration of the Plan as it may
deem desirable. Any decision of the Committee in the administration of the Plan
shall be final and conclusive. Except to the extent prohibited by applicable law
or the applicable rules of a stock exchange, the Committee may allocate all or
any portion of its responsibilities and powers to any one or more of its members
and may delegate all or any part of its responsibilities and powers to any
person or persons selected by it. Any such allocation or delegation may be
revoked by the Committee at any time. No member of the Committee shall be liable
for anything done or omitted to be done by him or her or by any other member of
the Committee in connection with the Plan, except for his or her own willful
misconduct or as expressly provided by statute.

3. PARTICIPATION. Each member of a board of directors of any Subsidiary of the
Corporation who is not an employee or director of the Corporation or an employee
of any of the Subsidiaries (a "Non-Employee Subsidiary Director") shall be
eligible to receive Options under the Plan. As used herein, the term
"Subsidiary" means any corporation at least 40 percent of whose outstanding
voting stock is owned, directly or indirectly, by the Corporation.

4. AWARDS UNDER THE PLAN.

      (a) Types of Awards. Awards under the Plan shall consist only of Options,
which are rights to purchase shares of common stock, par value $1.00 per share,
of the Corporation (the "Common Stock" ). Such Options are subject to the terms,
conditions and restrictions specified in Paragraph 5 below.

<PAGE>

      (b) Maximum Number of Shares That May Be Issued. There may be issued under
the Plan pursuant to the exercise of Options an aggregate of not more than
25,000 shares of Common Stock, subject to adjustment as provided in Paragraph 6
below.

      (c) Rights With Respect to Shares. A Non-Employee Subsidiary Director to
whom an Option is granted (and any person succeeding to such a Non-Employee
Subsidiary Director's rights pursuant to the Plan) shall have no rights as a
stockholder with respect to any shares of Common Stock issuable pursuant to any
such Option until the date of the issuance of a stock certificate to him or her
for such shares. Except as provided in Paragraph 6 below, no adjustment shall be
made for dividends, distributions or other rights (whether ordinary or
extraordinary, and whether in cash, securities or other property) for which the
record date is prior to the date such stock certificate is issued.

5. NONQUALIFIED STOCK OPTIONS. Each Option granted under the Plan shall be
evidenced by an agreement in such form as the Committee shall prescribe from
time to time in accordance with the Plan and shall comply with the following
terms and conditions:

      (a) The Option exercise price shall be the fair market value of the shares
of Common Stock subject to such Option on the date the Option is granted, which
shall be the average of the high and the low sales prices of a share of Common
Stock on the date of grant as reported on the New York Stock Exchange Composite
Transactions Tape or, if the New York Stock Exchange is closed on that date, on
the last preceding date on which the New York Stock Exchange was open for
trading.

      (b) Subject to Section 5(d) hereof and except as otherwise determined by
the Committee, the Option shall have a term of 10 years from the date it is
granted.

      (c) The Option shall be transferable only by will or the laws of descent
and distribution, and shall be exercisable during the optionee's lifetime only
by him or her.

      (d) The Option shall not be exercisable:

            (i) before the expiration of one year from the date it is granted or
      after the expiration of ten years from the date it is granted and may be
      exercised during such period as follows: one-third (33-1/3 percent) of the
      total number of shares of Common Stock covered by the Option shall become
      exercisable each year beginning with the first anniversary of the date it
      is granted; provided that an Option shall automatically become immediately
      exercisable in full when the Non-Employee Subsidiary Director ceases to be
      a Non-Employee Subsidiary Director for any reason other than death;

            (ii) unless payment in full is made for the shares of Common Stock
      being acquired thereunder at the time of exercise; such payment shall be
      made

                  (A) in United States dollars by cash or check, or

                                     -2-
<PAGE>

                  (B) in lieu thereof, by tendering to the Corporation shares of
            Common Stock owned by the person exercising the Option and having a
            fair market value equal to the cash exercise price applicable to
            such Option, such fair market value to be the average of the high
            and the low sales prices of a share of Common Stock on the date of
            exercise as reported on the New York Stock Exchange Composite
            Transactions Tape, or, if the New York Stock Exchange is closed on
            that date, on the last preceding date on which the New York Stock
            Exchange was open for trading, or

                  (C) by a combination of United States dollars and shares of
            Common Stock as aforesaid; and

            (iii) unless the person exercising the Option has been, at all times
      during the period beginning with the date of grant of the Option and
      ending on the date of such exercise, a Non-Employee Subsidiary Director,
      except that

                  (A) if such person shall cease to be such a Non-Employee
            Subsidiary Director for reasons other than death, while holding an
            Option that has not expired and has not been fully exercised, such
            person, at any time within one year of the date he or she ceased to
            be such a Non-Employee Subsidiary Director (but in no event after
            the Option has expired under the provisions of subparagraph 5(d)(i)
            above), may exercise the Option with respect to any shares of Common
            Stock as to which he or she has not exercised the Option on the date
            he or she ceased to be such a Non-Employee Subsidiary Director; or

                  (B) if any person to whom an Option has been granted shall die
            holding an Option that has not been fully exercised, his or her
            executors, administrators, heirs or distributees, as the case may
            be, may, at any time within one year after the date of such death
            (but in no event after the Option has expired under the provisions
            of subparagraph 5(d)(i) above), exercise the Option with respect to
            any shares of Common Stock as to which the decedent could have
            exercised the Option at the time of his or her death.

6. DILUTION AND OTHER ADJUSTMENTS. In the event of any change in the outstanding
shares of Common Stock by reason of any stock split, stock dividend,
recapitalization, merger, consolidation, reorganization, combination or exchange
of shares or other similar event, the number or kind of shares that may be
issued under the Plan pursuant to subparagraphs 4(a) and 4(b) above shall be
automatically adjusted to give effect to the occurrence of such event, and the
number or kind of shares subject to, or the Option exercise price per share
under, any outstanding Option shall be automatically adjusted so that the
proportionate interest of the participant shall be maintained as before the
occurrence of such event; such adjustment in outstanding Options shall be made
without change in the total Option exercise price applicable to the unexercised
portion of such

                                      -3-

<PAGE>

Options and with a corresponding adjustment in the Option exercise price per
share, and such adjustment shall be conclusive and binding for all purposes of
the Plan.

7. MISCELLANEOUS PROVISIONS.

      (a) Except as expressly provided for in the Plan, no Non-Employee
Subsidiary Director or other person shall have any claim or right to be granted
an Option under the Plan. Neither the Plan nor any action taken hereunder shall
be construed as giving any Non-Employee Subsidiary Director any right to be
retained in the service of a Subsidiary.

      (b) A participant's rights and interest under the Plan may not be assigned
or transferred in whole or in part either directly or by operation of law or
otherwise (except, in the event of a participant's death, by will or the laws of
descent and distribution), including, but not by way of limitation, execution,
levy, garnishment, attachment, pledge, bankruptcy or in any other manner, and no
such right or interest of any participant in the Plan shall be subject to any
obligation or liability of such participant.

      (c) No shares of Common Stock shall be issued hereunder unless counsel for
the Corporation shall be satisfied that such issuance will be in compliance with
applicable federal, state and other securities laws.

      (d) It shall be a condition to the obligation of the Corporation to issue
shares of Common Stock upon exercise of an Option, that the participant (or any
beneficiary or person entitled to act under subparagraph 5(d)(iii)(B) above) pay
to the Corporation, upon its demand, such amount as may be requested by the
Corporation for the purpose of satisfying any liability to withhold federal,
state, local or foreign income or other taxes. If the amount requested is not
paid, the Corporation may refuse to issue shares of Common Stock.

      (e) The expenses of the Plan shall be borne by the Corporation.

      (f) The Plan shall be unfunded. The Corporation shall not be required to
establish any special or separate fund or to make any other segregation of
assets to assure the issuance of shares upon exercise of any Option under the
Plan and issuance of shares upon exercise of Options shall be subordinate to the
claims of the Corporation's general creditors.

      (g) By accepting any Option or other benefit under the Plan, each
participant and each person claiming under or through him or her shall be
conclusively deemed to have indicated his or her acceptance and ratification of,
and consent to, the Plan, the terms and conditions of any agreement embodying
awards of Options and any action taken under the Plan by the Corporation or the
Committee.

      (h) The appropriate officers of the Corporation shall cause to be filed
any reports, returns or other information regarding Options hereunder or any
shares of Common Stock issued pursuant hereto as may be required by Section 13
or 15(d) of the Securities Exchange Act of 1934, as amended, or any other
applicable statute, rule or regulation.

                                       -4-

<PAGE>

8. AMENDMENT OR DISCONTINUANCE. The Plan may be amended by the Committee at any
time and from time to time as the Committee shall deem advisable. No amendment
of the Plan shall materially and adversely affect any right of any participant
with respect to any Option theretofore granted without such participant's
written consent.

9. TERMINATION. The Plan shall terminate upon the earlier of the following dates
or events to occur: (a) upon the adoption of a resolution of the Board
terminating the Plan; or (b) [July 31, 2003]. No termination of the Plan shall
materially and adversely affect any of the rights or obligations of any person,
without his or her consent, under any Option theretofore granted under the Plan.

July 21, 1998

                                      -5-

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