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                                                                 Exhibit 10.16.4

                           LOAN MODIFICATION AGREEMENT

     This Loan Modification Agreement (this "Loan Modification Agreement") is
entered into as of January 25, 2004, by and between SILICON VALLEY BANK, a
California-chartered bank, with its principal place of business at 3003 Tasman
Drive, Santa Clara, California 95054 and with a loan production office located
at One Newton Executive Park, Suite 200, 2221 Washington Street, Newton,
Massachusetts 02462, doing business under the name "Silicon Valley East"
("Bank") and GTC BIOTHERAPEUTICS, INC., a Massachusetts corporation with its
chief executive office located at 175 Crossing Boulevard, Suite 410, Framingham,
Massachusetts 01702 ("Borrower").

1.   DESCRIPTION OF EXISTING INDEBTEDNESS AND OBLIGATIONS. Among other
indebtedness and obligations which may be owing by Borrower to Bank, Borrower is
indebted to Bank pursuant to a loan arrangement dated as of March 27, 2002,
evidenced by, among other documents, a certain Loan and Security Agreement dated
as of March 27, 2002, between Borrower and Bank, as amended by a Loan
Modification Agreement dated June 11, 2003, and by a Loan Modification Agreement
dated August 13, 2003 (as amended, the "Loan Agreement"). Capitalized terms used
but not otherwise defined herein shall have the same meaning as in the Loan
Agreement.

2.   DESCRIPTION OF COLLATERAL. Repayment of the Obligations is secured by the
Collateral as described in the Loan Agreement (together with any other
collateral security granted to Bank, the "Security Documents").

Hereinafter, the Security Documents, together with all other documents
evidencing or securing the Obligations shall be referred to as the "Existing
Loan Documents".

3.   DESCRIPTION OF CHANGE IN TERMS.

     A.   MODIFICATIONS TO LOAN AGREEMENT.

          1.   The Loan Agreement shall be amended by deleting the following
provision appearing in the first sentence of Section 2.1.6(a) thereof:

                         ""2.1.6. 2003 EQUIPMENT ADVANCES.

                                 (a)  Availability. Through December 31, 2003
                         (the "2003 Equipment Availability End Date"), Bank
                         shall make Equipment Advances under the 2003 Committed
                         Equipment not exceeding the 2003 Committed Equipment
                         Line."

               and inserting in lieu thereof the following:

                         ""2.1.6. 2003 EQUIPMENT ADVANCES.

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                                 (a)  Availability. Through June 30, 2004 (the
                         "2003 Equipment Availability End Date"), Bank shall
                         make Equipment Advances under the 2003 Committed
                         Equipment not exceeding the 2003 Committed Equipment
                         Line."

          2.   The Loan Agreement shall be amended by deleting the following,
appearing as Section 6.7(a) thereof, in its entirety:

                                 "(a) LIQUIDITY. Borrower and its Subsidiaries
                         shall maintain unrestricted cash and marketable
                         securities less outstanding Obligations under the
                         Committed Revolving Line, of not less than Twenty-Five
                         Million Dollars ($25,000,000.00). If, at any time, the
                         Borrower shall fail to satisfy the terms of this
                         Section 6.7(a), then the Borrower shall immediately
                         deposit with the Bank an amount of unrestricted cash
                         equal to the outstanding Obligations hereunder, and
                         shall thereafter maintain unrestricted cash with the
                         Bank equal to the outstanding Obligations, as such
                         amount may increase or decrease."

               and inserting in lieu thereof the following:

                                 "(a) LIQUIDITY. Borrower and its Subsidiaries
                         shall maintain unrestricted cash and marketable
                         securities less outstanding Obligations under the
                         Committed Revolving Line, of not less than Eighteen
                         Million Dollars ($18,000,000.00). If, at any time, the
                         Borrower shall fail to satisfy the terms of this
                         Section 6.7(a), then the Borrower shall immediately
                         deposit with the Bank an amount of unrestricted cash
                         equal to the outstanding Obligations hereunder, and
                         shall thereafter maintain unrestricted cash with the
                         Bank equal to the outstanding Obligations, as such
                         amount may increase or decrease."

          3.   The Loan Agreement shall be amended by inserting the following
provision to appear as Section 6.9 thereof:

                                 "6.9 MARKET APPROVAL. On or before February 28,
                         2004, the Borrower shall provide the Bank with a
                         evidence, acceptable to the Bank, in it reasonable
                         discretion, that the Borrower has submitted to the
                         European Medicines Evaluation Agency a market approval
                         application for its drug, rhATIII".

          4.   The Compliance Certificate appearing as EXHIBIT D to the Loan
Agreement is hereby replaced with the Compliance Certificate attached as EXHIBIT
A hereto.

4.   FEES. The Borrower shall pay to Bank a modification fee equal to Twenty
Thousand Dollars ($20,000.00), which modification fee shall be due and payable
on the date hereof and shall be deemed fully earned as of the date hereof. The
Borrower shall also reimburse Bank for

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all legal fees and expenses incurred in connection with this amendment to the
Existing Loan Documents.

5.   RATIFICATION OF PLEDGE AGREEMENT. Borrower hereby ratifies, confirms and
reaffirms, all and singular, the terms and conditions of a certain Pledge
Agreement dated as of March 27, 2002, between Borrower and Bank, and
acknowledges, confirms and agrees that said Pledge Agreement shall remain in
full force and effect and the Collateral defined therein shall continue to
secure the Obligations under the Loan Agreement, as amended hereby.

6.   RATIFICATION OF NEGATIVE PLEDGE. Borrower hereby ratifies, confirms and
reaffirms, all and singular, the terms and conditions of a certain Negative
Pledge Agreement dated as of March 27, 2002, between Borrower and Bank, and
acknowledges, confirms and agrees that said Negative Pledge Agreement shall
remain in full force and effect.

7.   RATIFICATION OF PERFECTION CERTIFICATE. Borrower hereby ratifies, confirms
and reaffirms, all and singular, the terms and disclosures contained in a
certain Perfection Certificate dated as of March 27, 2002, between Borrower and
Bank, and acknowledges, confirms and agrees the disclosures and information
above Borrower provided to Bank in the Perfection Certificate has not changed,
as of the date hereof.

8.   CONSISTENT CHANGES. The Existing Loan Documents are hereby amended wherever
necessary to reflect the changes described above.

9.   RATIFICATION OF LOAN DOCUMENTS. Borrower hereby ratifies, confirms, and
reaffirms all terms and conditions of all security or other collateral granted
to the Bank, and confirms that the indebtedness secured thereby includes,
without limitation, the Obligations.

10.  NO DEFENSES OF BORROWER. Borrower hereby acknowledges and agrees that
Borrower has no offsets, defenses, claims, or counterclaims against Bank with
respect to the Obligations, or otherwise, and that if Borrower now has, or ever
did have, any offsets, defenses, claims, or counterclaims against Bank, whether
known or unknown, at law or in equity, all of them are hereby expressly WAIVED
and Borrower hereby RELEASES Bank from any liability thereunder.

11.  CONTINUING VALIDITY. Borrower understands and agrees that in modifying the
existing Obligations, Bank is relying upon Borrower's representations,
warranties, and agreements, as set forth in the Existing Loan Documents. Except
as expressly modified pursuant to this Loan Modification Agreement, the terms of
the Existing Loan Documents remain unchanged and in full force and effect.
Bank's agreement to modifications to the existing Obligations pursuant to this
Loan Modification Agreement in no way shall obligate Bank to make any future
modifications to the Obligations. Nothing in this Loan Modification Agreement
shall constitute a satisfaction of the Obligations. It is the intention of Bank
and Borrower to retain as liable parties all makers of Existing Loan Documents,
unless the party is expressly released by Bank in writing. No maker will be
released by virtue of this Loan Modification Agreement.

12.  COUNTERSIGNATURE. This Loan Modification Agreement shall become effective
only when it shall have been executed by Borrower and Bank (provided, however,
in no event

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shall this Loan Modification Agreement become effective until signed by an
officer of Bank in California).


     This Loan Modification Agreement is executed as a sealed instrument under
the laws of the Commonwealth of Massachusetts as of the date first written
above.

<Table>
<S>                                                      <C>
BORROWER:                                                BANK:

GTC BIOTHERAPEUTICS, INC.,                               SILICON VALLEY BANK,
formerly known as Genzyme Transgenics Corporation        doing business as
                                                         SILICON VALLEY EAST


By:  /s/ John B. Green                                   By:  /s/ Pamela Aldsworth
    -------------------------------------                     --------------------------------------

Name: John B. Green                                      Name: Pamela Aldsworth
     ------------------------------------                     --------------------------------------

Title: Senior Vice President                             Title: SCO
      -----------------------------------                      -------------------------------------


                                                         SILICON VALLEY BANK

                                                         By:  /s/ Karen J. Berand
                                                            ----------------------------------------

                                                         Name:  Karen J. Berand
                                                              --------------------------------------

                                                         Title:  Division Manager
                                                               -------------------------------------
                                                               (signed in Santa Clara County, California)
</Table>

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                                    EXHIBIT A

                             COMPLIANCE CERTIFICATE

TO:      SILICON VALLEY BANK

FROM:    GTC BIOTHERAPEUTICS, INC.

     The undersigned authorized officer of GTC Biotherapeutics, Inc. certifies
that under the terms and conditions of the Loan and Security Agreement between
Borrower and Bank (the "Agreement"), (i) Borrower is in complete compliance for
the period ending ____________ with all required covenants except as noted below
and (ii) all representations and warranties in the Agreement are true and
correct in all material respects on this date. Attached are the required
documents supporting the certification. The Officer certifies that these are
prepared in accordance with Generally Accepted Accounting Principles (GAAP)
consistently applied from one period to the next except as explained in an
accompanying letter or footnotes. The Officer acknowledges that no borrowings
may be requested at any time or date of determination that Borrower is not in
compliance with any of the terms of the Agreement, and that compliance is
determined not just at the date this certificate is delivered.

     PLEASE INDICATE COMPLIANCE STATUS BY CIRCLING YES/NO UNDER "COMPLIES"
COLUMN.

<Table>
<Caption>
REPORTING COVENANT                             REQUIRED                                COMPLIES
------------------                             ------------------------------------------------
<S>                                            <C>                                     <C>
Quarterly financial statements with CC         Within 5 days after filing with SEC     Yes  No
Annual (CPA Audited)                           With 5 days after filing with SEC       Yes  No
Projects approved by Board of Directors        Annually, and as updated                Yes  No

<Caption>
FINANCIAL COVENANT                             REQUIRED                ACTUAL          COMPLIES
------------------                             --------                ------          --------
<S>                                            <C>                       <C>           <C>
MAINTAIN ON A QUARTERLY BASIS:
     Minimum Liquidity                         $  18,000,000.00          $ _______     Yes   No


<Caption>
<S>                                                                        <C>
COMMENTS REGARDING EXCEPTIONS:  See Attached.                                        BANK USE ONLY

Sincerely,
                                                                           Received by:
                                                                                       -----------------------
                                                                                       AUTHORIZED SIGNER
-----------------------
SIGNATURE
                                                                           Date:
                                                                                 -----------------------
-----------------------
TITLE                                                                      Verified:
                                                                                    --------------------
                                                                                    AUTHORIZED SIGNER
-----------------------
DATE                                                                       Date:
                                                                                -----------------------------
</Table>

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