Document:

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                                                                  Exhibit 10.4.4

                 AMENDMENT NO. 4 TO THE MANUFACTURING AGREEMENT

This AMENDMENT No. 4 dated as of July 18, 2002 (the "Amendment") to the
Manufacturing Agreement dated as of September 18, 1995, as amended (the
"Manufacturing Agreement"), by and between Merck & Co., Inc. ("MERCK") and
Regeneron Pharmaceuticals, Inc. ("REGENERON"). Capitalized terms used in this
Amendment but not defined herein shall have the meaning set forth in the
Manufacturing Agreement.

WHEREAS, MERCK and REGENERON have been in discussions regarding certain matters
relating to the Manufacturing Agreement;

WHEREAS, both parties wish to amicably settle their differences in order to
facilitate future relations between the parties;

WHEREAS, based upon the foregoing discussions, MERCK and REGENERON with to amend
the Manufacturing Agreement pursuant to the terms and conditions of this
Amendment;

NOW, THEREFORE, in consideration of the mutual covenants and promises herein
contained, the receipt and sufficiency of which are hereby acknowledged, the
parties agree to the following:

1.    Over the past few months, REGENERON has raised an issue that the
      Manufacturing Agreement does not provide the bargained-for compensation,
      including profitability of the Manufacturing Agreement. MERCK disagrees
      with REGENERON's position and believes that REGENERON has received the
      bargained-for compensation. Notwithstanding the foregoing, and without
      agreeing upon nor acknowledging the validity of REGENERON's position, in
      order to resolve fully and finally the issue relating to bargained-for
      compensation, including, profitability of the Manufacturing Agreement,
      MERCK shall pay to REGENERON the amount of One Million U.S. Dollars
      ($1 Million) no later than thirty (30) days after the execution of this
      Amendment. MERCK's decision to make the payment described in this
      Paragraph 1 is based solely on its desire to facilitate future relations
      between the parties and is not an admission that any such payment is
      required under the Manufacturing Agreement and does not establish any
      precedent to that effect.

2.    In consideration of the payments and compromises set forth herein and with
      the intent of facilitating future relations between the parties, the
      sufficiency of which is hereby acknowledged, REGENERON hereby releases and
      forever waives any claim it has or may have against MERCK relating to the
      bargained-for compensation, including, without limitation, the
      profitability of the Manufacturing Agreement or any other compensation
      required under the Manufacturing Agreement, except for payment of
      compensation as expressly set forth in Paragraph 7 or Amendment No. 3 and
      Article 13 and Article 19 of the Manufacturing Agreement, or as may
      otherwise be agreed to in writing by the parties.

3.    REGENERON expressly agrees that it will abide by the terms of the
      Manufacturing Agreement, including, without limitation, to deliver
      INTERMEDIATE in accordance

<PAGE>

      with MERCK's delivery schedule, subject to the terms and conditions set
      forth in the Manufacturing Agreement.

4.    Section 7.1 of the Manufacturing Agreement is hereby amended to add the
      following sentence at the end of the existing Section 7.1

      "Notwithstanding anything in this Agreement to the contrary, no quarterly
      delivery schedule provided by MERCK in any PURCHASE ORDER shall require
      the delivery of more than [**] BATCHES, unless otherwise agreed in writing
      by the parties."

5.    Section 12.3 of the Manufacturing Agreement is hereby amended to add the
      following sentences at the end of the existing Section 12.3;

      "For purposes of determining if REGENERON has met its quarterly delivery
      obligation and the BATCH FEES payable to REGENERON only, REGENERON shall
      be deemed to have delivered INTERMEDIATE to MERCK as of the date of
      receipt of the conditional release package by MERCK plus thirty (30) days
      (the "Deemed Delivery Date").

      Notwithstanding the foregoing paragraph, in the event that MERCK has not
      been able to deliver MATERIALS and/or SUBSTANCE to REGENERON by the
      agreed-up delivery dates for such MATERIALS and/or SUBSTANCE (as agreed
      from time to time by MERCK and REEGENERON) or MERCK has delivered to
      REGENERON MATERIALS and/or SUBSTANCE which fail to meet the agreed-upon
      specifications then with respect to any such affected BATCHES of
      INTERMEDIATE, REGENERON shall not be obligated to meet MERCK's delivery
      schedule, but rather, shall make all reasonable effort to deliver
      INTERMEDIATE to MERCK as soon as possible; provided, however, that, in an
      such case, REGERNON shall deliver such affected BATCHES of INTERMEDIATE to
      MERCK no later than the CALENDAR QUARTER immediately following REGENERON's
      receipt of such delayed MATERIALS and/or SUBSTANCE unless the parties
      agree in writing to an alternate delivery schedule; provided, further,
      that, REGENERON shall not be obligated to deliver in any CALENDAR QUARTER
      more than [*****] BATCHES of INTERMEDIATE. If such affected BATCHES cannot
      be made up in full in the first CALENDAR QUARTER immediately following
      REGENERON's receipt of such delayed MATERIALS and/or SUBSTANCE due to the
      [*****] BATCH limitation set forth in the previous sentence, then such
      remaining BATCHES shall be made up in the next CALENDAR QUARTER or
      QUARTERS, subject to the [*****] BATCH limitation set forth in the
      previous sentence.

6.    Section 16.2 of the Manufacturing Agreement is hereby amended to add the
      following sentence at the end of the existing Section 16.2;

      "Notwithstanding the foregoing, in the event that MERCK gives REGENERON at
      least three hundred sixty five (365) days' notice of termination, then
      MERCK shall not be obligated to, and shall not, pay to REGENERON the
      aforementioned sum of [*****].

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      A termination notice delivered by MERCK to REGENERON pursuant to this
      Section 16.2 shall be non-revocable."

7.    Section 13.1 of the Manufacturing Agreement shall be amended by adding an
      "(a)" immediately prior to the existing language and adding the following
      paragraphs (b), (c) and (d) immediately after the existing Section 13.1;

      "(b) Notwithstanding paragraph (a) above and Section 13.2 herein, with
      respect to all BATCHES of INTERMEDIATE for which a [***] release package
      has been delivered to MERCK prior to a Resumption Date (as such term is
      defined in the last sentence of this paragraph (b)), REGENERON shall
      invoice MERCK for such BATCHES once the [***] release package has been
      delivered to MERCK and MERCK shall pre-pay to REGENERON [***] of the
      invoiced amount within forty five (45) days after the later of (i) receipt
      of REGENERON's invoice or (ii) the Deemed Delivery Date. The remaining
      [***] of the invoiced amount shall be paid by MERCK to REGERNON within
      thirty (30) days after the later of actual receipt by MERCK of (a)
      INTERMIATE or (b) REGENERON's invoice for such remaining amount. In the
      event that any BATCH is subsequently not RELEASED by MERCK, upon notice to
      REGENERON of such rejection, REGENERON shall, within thirty (30) days,
      either issue a credit or a check, at MERCK's option, to MERCK in the full
      amount pre-paid by MERCK for the rejected BATCH. No late than thirty (30)
      days after the start of a Prepayment Period (as such term is defined in
      the last sentence of this paragraph (b)), MERCK shall pay REGENERON all
      amounts due under this paragraph (b) relating to the BATCHES which have
      triggered the start of a Prepayment Period. For purposes of this
      Agreement, (x) "Prepayment Period" shall mean each period in which MERCK
      is making a prepayment pursuant to this paragraph (b) and (y) "Resumption
      Date" shall mean the day after the date in which MERCK has RELEASED and
      paid REGENERON for [***] consecutive BATCHES of INTERMEDIATE within [***]
      days of receipt by MERCK of the [***] release package.

      (c) From and after any Resumption Date, Merck shall have no further
      obligation to pre-pay any amount, as provided in paragraph (b) above, and
      paragraph (a) above shall govern all deliveries until such time that MERCK
      fails to RELEASE and pay for [***] consecutive BATCHES of INTERMEDIATE
      within [***] days of receipt by MERCK of the applicable [***] release
      packages for such BATCHES, at which time a new Prepayment Period shall
      commence and the terms of paragraph (b) shall again become in full force
      and effect until the ensuing Resumption Date.

      (d) For the avoidance of any doubt, the initial Prepayment Period shall
      commence as of the date hereof. No later than thirty (30) days after the
      receipt by Merck of REGENERON's invoice, MERCK shall prepay all amounts
      due under paragraph (b) above for the following BATCHES: [***].

8.    Schedule F shall be amended by deleting the existing Schedule F and in its
      place by inserting a new Schedule F, attached hereto as Attachment 1.

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9.    Except as specifically set forth above, all other terms and conditions of
      the Manufacturing Agreement shall remain unchanged and in full force and
      effect.

10.   Each and every referenced to the Manufacturing Agreement shall hereinafter
      refer to the Manufacturing Agreement as amended by this Amendment.

11.   This Amendment, together with the Manufacturing Agreement, are the only,
      entire and complete agreement of the parties relating to the subject
      matter hereof. All prior discussions, negotiations and agreements have
      been and are merged, cancelled and integrated into, and are superseded by,
      the Manufacturing Agreement, as amended by this Amendment. None of the
      parties hereto shall be bound by any conditions, definitions, warranties,
      understandings or representations with respect to such subject matter
      other than as expressly provided herein.

12.   The parties acknowledge agreement to the terms of this Amendment by having
      an authorized representative sign one copy in the space provided below.
      Each party represents and warrants that the authorized representative has
      actual power and authority to execute this Amendment on behalf of the
      respective company, and that this Amendment shall be binding upon the
      respective company, its successors and assigns.

13.   This Amendment shall be interpreted by the construed according to the
      substantive laws of the State of New York without reference to any rules
      of conflict of laws or renvoi.

14.   This Amendment may be executed in one or more counterparts, each of which
      shall for all purposes be deemed an original and all of which shall
      constitute one of the same agreement.

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

MERCK & CO., INC.                   REGENERON PHARMACEUTICALS, INC.

By: /s/Bernard J. Kelley            By: /s/Murray A. Goldberg
    -----------------------------       ---------------------------------------
    Name: Bernard J. Kelley             Name:  Murray A. Goldberg
    Title: President, MMD               Title: SVP, Finance & Administration
                                               and CFO

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                                                                    ATTACHMENT 1

                                   SCHEDULE F

                                     [*****]<PAGE>

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                                                                  Exhibit 10.4.5

                 AMENDMENT NO. 5 TO THE MANUFACTURING AGREEMENT

This AMENDMENT No. 5, dated as of January 1, 2005 (this "Amendment"), to the
Manufacturing Agreement dated as of September 18, 1995, as amended, (the
"Manufacturing Agreement"), by and between Merck & Co., Inc. ("MERCK") and
Regeneron Pharmaceuticals, Inc. ("REGENERON"). Capitalized terms used in this
Amendment but not defined herein shall have the meanings set forth in the
Manufacturing Agreement.

WHEREAS, MERCK and REGENERON, have been in discussions regarding certain matters
relating to the extension of the term of the Manufacturing Agreement;

WHEREAS, both parties wish to extend the term of the Manufacturing Agreement and
make such other changes to the Manufacturing Agreement as are set forth in this
Amendment;

NOW, THEREFORE, in consideration of the mutual covenants and promises herein
contained, the receipt and sufficiency of which are hereby acknowledged, the
parties agree to the following:

      1.    Section 1.3 of the Manufacturing Agreement shall be amended by
            replacing Section 1.3 in its entirety with the following text:

            "1.3 The term "BATCH" shall mean one production run of INTERMEDIATE
            using a [******] fermenter and related purification equipment with a
            purification run starting with no less than [***] grams and no more
            than [**************]."

      2.    Section 1.8 of the Manufacturing Agreement shall be amended by
            replacing Section 1.8 in its entirety with the following text:

            "The term `CONTRACT YEAR' shall mean the period of twelve (12)
            consecutive calendar months commencing on the 1st day of November,
            1999 and ending on the 31st day of October 2000, and each seven
            consecutive twelve (12) month periods from November 1 through
            October 31 thereafter, such that the seventh CONTRACT YEAR shall end
            on October 31, 2006."

      3.    Section 4.2 of the Manufacturing Agreement shall be amended by
            replacing the reference to "[******]" BATCHES of INTERMEDIATE per
            CONTRACT YEAR therein with a reference to "[********] BATCHES of
            INTERMEDIATE per CONTRACT YEAR."

      4.    Section 5.4 of the Manufacturing Agreement shall be amended by
            replacing the phrase "Upon the termination of this Agreement," in
            the first sentence

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            therein with the sentence "Within thirty (30) days after the
            effective date of the termination of this Agreement, MERCK shall
            notify REGENERON in writing of its intent to remove any articles or
            components of the machinery and equipment identified in Schedule E
            and the parties shall agree on an appropriate schedule for such
            removal; provided, that, (i) such schedule affords MERCK a
            reasonable time during normal business hours to remove such articles
            or components and (ii) such schedule does not unnecessarily
            interfere with REGENERON's use of the FACILITY."

      5.    Section 6.1 of the Manufacturing Agreement shall be amended by
            replacing the third sentence therein with the following sentence:

            "The SUBSTANCE at REGENERON's FACILITY shall be stored by REGENERON
            in accordance with the KNOW-HOW."

      6.    Section 7.1 of the Manufacturing Agreement shall be amended by
            adding the following sentence to the end thereof:

            "Notwithstanding anything in this Agreement to the contrary for
            CONTRACT YEAR 6, CONTRACT YEAR 7 and CONTRACT YEAR 8 (if applicable)
            only, no quarterly delivery schedule provided by MERCK in any
            PURCHASE ORDER shall require delivery of more than [******] BATCHES,
            and, for any full CONTRACT YEAR, the sum of the four quarterly
            delivery schedules provided by MERCK in the four respective PURCHASE
            ORDERS for that CONTRACT YEAR shall not require the delivery of more
            than [******] BATCHES, unless otherwise agreed in writing by the
            parties."

      7.    Section 7.2 of the Manufacturing Agreement shall be amended by
            replacing paragraph (a) therein in its entirety with the following
            text:

            "(a) If both the original and revised PURCHASE ORDERS include the
            delivery of no more than [**] BATCHES per CONTRACT YEAR and no more
            than [**] BATCHES per CONTRACT QUARTER, REGENERON shall MANUFACTURE
            INTERMEDIATE for the balance of the CONTRACT YEAR in accordance with
            the revised PURCHASE ORDER."

      8.    Article 8 of the Manufacturing Agreement shall be amended by adding
            a new Section 8.12 with the following text:

            "8.12 Subsequent to the execution of this Amendment, the parties
            shall enter into that certain Quality Agreement (the "QUALITY
            AGREEMENT") within three (3) months of the execution of this
            Amendment, which shall supplement the terms of this Article 8."

      9.    Section 8.3 of the Manufacturing Agreement shall be amended by
            replacing Section 8.3 in its entirety with the following text:

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            "8.3 REGENERON hereby agrees that MERCK or an AFFILIATE shall have
            the right to have reasonable access to the FACILITY during normal
            business hours in order to ascertain compliance by REGENERON with
            the terms of this Agreement, including but not limited to,
            inspection of MANUFACTURE of INTERMEDIATE, storage facilities for
            SUBSTANCE, MATERIALS, and SUPPLIES, all equipment and machinery used
            in the MANUFACTURING of INTERMEDIATE, and all records relating to
            such MANUFACTURE, storage facilities, equipment, and machinery.
            Observations and conclusions of any audit by MERCK or an Affiliate
            will be discussed with and then issued to REGENERON, and a written
            response to this audit shall be submitted to MERCK or an AFFILIATE
            by REGENERON within thirty (30) days after MERCK or an AFFILIATE
            delivers its audit report to REGENERON. Corrective action shall be
            agreed upon by MERCK or an AFFILIATE and REGENERON and such
            corrective action shall be implemented by REGENERON and MERCK within
            the time period agreed upon by the parties. MERCK shall have the
            right to request copies of all necessary documents, reports, test
            results, etc. evidencing completion of any such corrective action.

      10.   Section 8.7 of the Manufacturing Agreement shall be amended by
            replacing Section 8.7 in its entirety with the following text:

            "8.7 Should any BATCH (i) suffer an atypical process event, as such
            term is described in the KNOW-HOW, (ii) be exposed to conditions
            which exceed environmental action limits agreed upon by MERCK and
            REGENERON, or (iii) otherwise fail to meet the quality control
            specifications, as defined in the KNOW-HOW, MERCK shall be
            IMMEDIATELY notified of any such circumstances upon REGENERON's
            discovery thereof. MERCK and REGENERON shall agree in each case on
            the nature and scope of any investigations to be conducted regarding
            such occurrence or circumstance and actions to be taken to correct
            any problem discovered and suitability for use relating to any BATCH
            involved. The final disposition, RELEASE and use of any BATCH for
            the generation of PRODUCT shall be at MERCK's sole discretion."

      11.   Section 12.3 of the Manufacturing Agreement shall be amended by
            replacing Section 12.3 in its entirety with the following text:

            "12.3 REGENERON shall deliver the RELEASED INTERMEDIATE, which has
            been packed in accordance with the KNOW-HOW, to a carrier designated
            by MERCK so as to allow delivery to [***], at MERCK's cost, in
            accordance with the mutually agreed upon delivery schedule provided
            by MERCK unless otherwise agreed to by the parties.

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            The parties agree that the delivery schedule is dependent upon
            multiple factors including but not limited to the supply of
            MATERIALS and SUBSTANCE by MERCK to REGENERON, the performance of
            equipment [***] to the production of INTERMEDIATE and the
            communication and processing of PROCESS CHANGE REQUESTS and other
            routine documentation; therefore the parties shall meet on a
            quarterly basis to review, revise and mutually agree upon the
            production and delivery schedules.

            For purposes of determining if REGENERON has met its quarterly
            delivery obligation and the BATCH FEES payable to REGENERON only,
            REGENERON shall be deemed to have delivered INTERMEDIATE to MERCK as
            of the date of the receipt of the [***] plus thirty (30) days (the
            "Deemed Delivery Date")."

      12.   Section 13.1.b of the Manufacturing Agreement shall be amended by
            replacing the last sentence therein with the following sentence:

            "For the purposes of this Agreement, (x) "Prepayment Period" shall
            mean each period in which MERCK is making a prepayment pursuant to
            this paragraph (b) and (y) "Resumption Date" shall mean the day
            after the date in which MERCK has RELEASED and paid REGENERON for
            [**] consecutive BATCHES of INTERMEDIATE within ninety (90) days of
            receipt by MERCK of the [***] release package."

      13.   Section 13.2 of the Manufacturing Agreement shall be amended by
            adding a new table in clause (ii) thereof following the existing
            table, as follows:

<TABLE>
<CAPTION>
"Number of BATCHES                     CONTRACT YEAR 7
------------------                     ---------------
<S>                                    <C>
 BATCHES [***]                          [$********]
 BATCHES [*****]                        [$********]
</TABLE>

      14.   Section 13.3 of the Manufacturing Agreement shall be amended by
            adding clauses (iv) and (v), as follows:

            (iv)  The DIRECT STANDARD COST of any additional [***] run(s)
                  required to be conducted by REGENERON (above the single run
                  set forth in the KNOW-HOW) in order to have at least [*****]
                  of INTERMEDIATE available to MANUFACTURE a BATCH.

            (v)   The cost of REGENERON's FTEs (calculated using the UNIT LABOR
                  COST) and any out-of-pocket costs associated with AGENCY
                  inspections of the FACILITY related to the INTERMEDIATE or its
                  MANUFACTURE, except for costs associated with any "for cause"
                  inspections to the extent and only to the extent arising as a
                  result of an act or omission of REGENERON. REGENERON will
                  invoice MERCK for such FTE costs up to a maximum of [*******]
                  per Inspection Day (as hereinafter defined) or

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                  up to a maximum of [*****] for each such AGENCY inspection.
                  For the avoidance of doubt, the costs referred to in this
                  Section 13.3(v) shall include the FTE and out-of-pocket costs
                  required to prepare for such inspections, to respond to AGENCY
                  observations, and related follow-up activities. As used in
                  this Section 13.3(v), the term "Inspection Day" shall mean any
                  calendar day on which AGENCY inspectors are present at the
                  FACILITY related to the INTERMEDIATE or its MANUFACTURE. If
                  extenuating circumstances arise resulting in a prolonged
                  AGENCY inspection of the FACILITY, the parties shall negotiate
                  in good faith to agree on the funding of such inspection,
                  provided, however, that nothing herein shall obligate MERCK to
                  pay any additional costs of REGENERON relating to any such
                  inspection.

      15.   Section 15.1 of the Manufacturing Agreement shall be amended by
            replacing Section 15.1 in its entirety with the following text:

            "The initial term of this Agreement shall begin on the date first
            appearing above and shall continue through the termination of the
            seventh (7th) CONTRACT YEAR as defined herein. MERCK shall have an
            option to renew this AGREEMENT for one (1) additional CONTRACT YEAR
            exercisable with written notice to REGENERON twelve (12) months
            prior to the end of the seventh (7th) CONTRACT YEAR. Such renewal
            shall be on the same terms and conditions as set forth herein."

      16.   Section 16.2 of the Manufacturing Agreement shall be amended by
            replacing Section 16.2 in its entirety with the following text:

            "MERCK shall have the right to terminate this Agreement at any time
            on ninety (90) days' notice prior to the date such termination shall
            be effective. Upon the effective date of such termination by MERCK
            without cause, MERCK shall pay to REGENERON the sum of
            [************] as liquidated damages in total satisfaction of all
            amounts which would otherwise thereafter become due under this
            Agreement. MERCK's obligation to compensate REGENERON under this
            Section shall not apply to the natural expiration of this Agreement
            or to termination of this Agreement pursuant to any other Section
            hereof. MERCK shall have no right to terminate this Agreement
            pursuant to this Section if REGENERON has properly notified MERCK
            under Section 16.1 that MERCK is in breach of a material provision
            of this Agreement, which breach remains uncured as of the date MERCK
            seeks to invoke the termination provisions of this Section 16.2."

      17.   Schedule A-1 of the Manufacturing Agreement shall be replaced with
            the revised and updated Schedule A-1 attached hereto.

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      18.   Schedule C shall be amended by replacing the reference to
            "[*****************]" therein with a reference to
            "[****************]."

      19.   Schedule E shall be replaced with the revised and updated Schedule E
            attached hereto.

      20.   Schedule H shall be amended by (i) replacing the reference to
            "CONTRACT YEARS 5 and 6." in section 1(c) therein with a reference
            to "CONTRACT YEARS 5 through 7." and (ii) replacing section 2
            therein in its entirety with the following text:

            "2.   CALCULATION OF DIRECT STANDARD COST

                  2(a). DIRECT STANDARD COST per BATCH shall equal the sum of
            STANDARD LABOR COST, STANDARD UTILITIES COST, STANDARD SUPPLIES COST
            and STANDARD WASTE HAULING COST, as those terms are defined in this
            Section, and shall be agreed to by MERCK and REGENERON at the
            beginning of each CONTRACT YEAR.

                  2(b). Components of STANDARD LABOR COST are as follows:

                  (i)   BASE UNIT LABOR COST shall equal [**************]
                        Dollars ($[*******]) per full time equivalent ("FTE")
                        person.

                  (ii)  UNIT LABOR COST in any CONTRACT YEAR shall equal BASE
                        LABOR COST multiplied by the COST ADJUSTMENT FACTOR for
                        that CONTRACT YEAR.

                  2(c). STANDARD LABOR COST shall be calculated as follows:
            REGENERON and MERCK shall agree on the STANDARD LABOR COST at the
            beginning of each CONTRACT YEAR based on (i) the FTEs required to
            MANUFACTURE the number of BATCHES in the BATCH ORDER for that
            CONTRACT YEAR in accordance with the KNOW-HOW, (b) the UNIT LABOR
            COST for that CONTRACT YEAR, and (c) any adjustment needed for
            overtime or premium labor.

                  2(d). STANDARD UTILITIES COST shall equal the sum of STANDARD
            ELECTRICITY COST and STANDARD WFI COST.

            (i)   STANDARD ELECTRICITY COST in any CONTRACT YEAR shall equal
            BASE ELECTRICITY USAGE multiplied by UNIT ELECTRICITY COST for that
            CONTRACT YEAR. BASE ELECTRICITY USAGE per BATCH in kilowatt-hours
            shall be agreed to

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                                   [RESTRICTED CONFIDENTIAL LIMITED ACCESS LOGO]

            by MERCK and REGENERON within thirty (30) days following the end of
            the CONSISTENCY AND VALIDATION PERIOD based on REGENERON's
            experience in MANUFACTURING INTERMEDIATE during the CONSISTENCY AND
            VALIDATION PERIOD. BASE ELECTRICITY USAGE shall be subject to
            adjustment based on actual electricity usage as measured by
            electricity meters in subsequent CONTRACT YEARS. UNIT ELECTRICITY
            COST in any CONTRACT YEAR shall equal $[***] per kilowatt-hour
            multiplied by the WHOLE LOT LOSS FACTOR multiplied by the COST
            ADJUSTMENT FACTOR for that CONTRACT YEAR.

            (ii)  STANDARD WFI COST in any CONTRACT YEAR shall equal BASE WFI
            USAGE multiplied by UNIT WFI COST for that CONTARCT YEAR. BASE WFI
            USAGE per BATCH in gallons shall be agreed to by MERCK and REGENERON
            within thirty (30) days following the end of the CONSISTENCY AND
            VALIDATION PERIOD based on REGENERON's experience in MANUFACTURING
            INTERMEDIATE during the CONSISTENCY AND VALIDATION PERIOD. UNIT WFI
            COST in any CONTRACT YEAR shall equal [***********] per thousand
            gallons multiplied by the WHOLE LOT LOSS FACTOR multiplied by the
            COST ADJUSTMENT FACTOR for that CONTRACT YEAR.

                  2(e). BASE SUPPLIES COST shall be agreed to by MERCK and
            REGENERON within thirty (30) days following the end of the
            CONSISTENCY AND VALIDATION PERIOD based on REGENERON's experience in
            MANUFACTURING INTERMEDIATE during the CONSISTENCY AND VALIDATION
            PERIOD. BASE SUPPLIES COST shall be subject to adjustment based on
            actual usage of SUPPLIES in subsequent CONTRACT YEARS. STANDARD
            SUPPLIES COST in any CONTRACT YEAR shall equal BASE SUPPLIES COSTS
            multiplied by the WHOLE LOT LOSS FACTOR multiplied by the COST
            ADJUSTMENT FACTOR for that CONTRACT YEAR.

                  2(f). BASE WASTE HAULING COST shall be agreed to by MERCK and
            REGENERON within thirty (30) days following the end of the
            CONSISTENCY AND VALIDATION PERIOD based on REGENERON's experience in
            MANUFACTURING INTERMEDIATE during the CONSISTENCY AND VALIDATION
            PERIOD. BASE WASTE HAULING COST shall be subject to adjustment based
            on actual waste quantities and associated disposal cost in
            subsequent CONTRACT YEARS. STANDARD WASTE HAULING COST in any
            CONTRACT YEAR shall equal BASE WASTE HAULING COST for that CONTRACT
            YEAR multiplied by the WHOLE LOT LOSS FACTOR.

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                  2(g). BASE LABOR UNITS, BASE ELECTRICITY USAGE, BASE WFI
            USAGE, BASE SUPPLIES COST, BASE WASTE HAULING COST, and the WHOLE
            LOT LOSS FACTOR shall all be subject to adjustment, without maximum
            or minimum, at any time that the KNOW-HOW or MANUFACTURING process
            is changed in response to MERCK's instructions or to comply with
            AGENCY regulations, guidelines, or directions.

                  2(h). At any time that a revision is made to the PURCHASE
            ORDER pursuant to Section 7.2 of the Agreement:

            (i)   If the revision is made pursuant to Section 7.2(a), the DIRECT
            STANDARD COST per BATCH for the CONTRACT YEAR shall be recalculated
            based on the revised BATCH ORDER. The revised DIRECT STANDARD COST
            shall be applied to BATCHES RELEASED thereafter. With respect to
            BATCHES RELEASED previously, either, as appropriate, MERCK shall
            PROMPTLY make an additional payment to REGENERON reflecting the
            increase in DIRECT STANDARD COST or REGENERON shall issue a credit
            to MERCK to be applied against BATCHES to be RELEASED subsequently.

            (ii)  If the revision is made pursuant to Section 7.2(b), REGENERON
            and MERCK shall agree on the STANDARD LABOR COST and DIRECT STANDARD
            COST to be applied to BATCHES MANUFACTURED and RELEASED in the
            balance of the CONTRACT YEAR in accordance with the revised PURCHASE
            ORDER."

                  2(i). DIRECT STANDARD COST to manufacture an extra [***] run
            (as per Section 13.3 (iv)) shall be calculated analogous to DIRECT
            STANDARD COST per BATCH, but shall only take into account the
            incremental FTE cost, UTILITIES COST, SUPPLIES COST, and WASTE
            HAULING COST required to manufacture such extra [***] run.

      21.   In consideration of Regeneron's agreement to extend the term of the
            Manufacturing Agreement as set forth in this Amendment, Merck hereby
            agrees to make payments to Regeneron in an amount equal to the
            EXTENSION PAYMENT on each November 1 and May 1 of the seventh and
            eighth CONTRACT YEARS. As used above, the term "EXTENSION PAYMENT"
            shall equal the product of (i) [**********] and (ii) the sum of one
            plus the percentage increase in the annual CPI from (a) December 31,
            1999 to December 31, 2004 for the seventh CONTRACT YEAR or (b)
            December 31, 1999 to December 31, 2005 for the eighth CONTRACT YEAR
            if such CONTRACT YEAR is entered into as defined in Section 15.1. It
            is agreed that the EXTENSION PAYMENTS shall only be made on the
            dates specified in this Section 20 if the Manufacturing Agreement
            remains in effect

<PAGE>

                                   [RESTRICTED CONFIDENTIAL LIMITED ACCESS LOGO]

            on the date in question, as Merck's obligation to make any such
            payment ceases with the termination of the Manufacturing Agreement.
            A breach of this Section 20 shall be deemed a breach of a material
            provision of the Manufacturing Agreement.

      22.   Except as specifically set forth above, all other terms and
            conditions of the Manufacturing Agreement shall remain unchanged and
            in full force and effect.

      23.   Each and every reference to the Manufacturing Agreement shall
            hereinafter refer to the Manufacturing Agreement as amended by this
            Amendment.

      24.   This Amendment, together with the Manufacturing Agreement, are the
            only, entire and complete agreement of the parties relating to the
            subject matter hereof. All prior discussions, negotiations, and
            agreements have been and are merged, canceled, and integrated into,
            and are superseded by, the Manufacturing Agreement, as amended by
            this Amendment. None of the parties hereto shall be bound by any
            conditions, definitions, warranties, understandings, or
            representations with respect to such subject matter other than as
            expressly provided herein.

      25.   The parties acknowledge agreement to the terms of this Amendment by
            having an authorized representative sign one copy in the space
            provided below. Each party represents and warrants that the
            authorized representative has actual power and authority to execute
            this Amendment on behalf of the respective company, and that this
            Amendment shall be binding upon the respective company, its
            successors and assigns.

      26.   This Amendment shall be interpreted by and construed according to
            the substantive laws of the State of New York without reference to
            any rules of conflict of laws or renvoi.

      27.   This Amendment may be executed in one or more counterparts, each of
            which shall for all purposes be deemed an original and all of which
            shall constitute one and the same agreement.

<PAGE>

                                   [RESTRICTED CONFIDENTIAL LIMITED ACCESS LOGO]

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

            MERCK & CO., INC.                 REGENERON PHARMACEUTICALS, INC.

            By: /s/ Robert E. Dolan           By: /s/ Murray Goldberg
                ----------------------            ---------------------
               Name: Roberg E. Dolan          Name:  Murray Goldberg
               Title: VP, Vaccine & Sterile   Title: VP, Finance &
               Operations                            Administration and CFO
<PAGE>

                                  SCHEDULE A-1
                               [****************]
<PAGE>

                                   SCHEDULE E
                               [****************]

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