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                                                               EXHIBIT 10.21.1

                     CONFIDENTIAL PORTIONS HAVE BEEN OMITTED
                 BASED UPON A REQUEST FOR CONFIDENTIAL TREATMENT
        PURSUANT TO RULE 24B-2 OF THE SECURITIES EXCHANGE ACT OF 1934 AND
                 HAVE BEEN SEPARATELY FILED WITH THE COMMISSION

               FIRST AMENDMENT TO THE LICENSE AND SUPPLY AGREEMENT
             BETWEEN EPOCH AND PERKIN-ELMER HAVING AN EFFECTIVE DATE
                               OF JANUARY 5, 1999

This First Amendment to the License and Supply Agreement ("First Amendment")
dated as of the 30th day of June, 1999 ("Effective Date of First Amendment") is
between EPOCH PHARMACEUTICALS, INC., 12277 134th Court NE, Suite 100, Redmond,
WA ("Epoch") and THE PERKIN-ELMER CORPORATION, having its PE Biosystems Division
at 850 Lincoln Centre Drive, Foster City, CA 94404 ("Perkin-Elmer").

WHEREAS, Epoch and Perkin-Elmer have entered into a License and Supply Agreement
having an Effective Date of January 5, 1999 ("License and Supply Agreement").

WHEREAS, both Epoch and Perkin-Elmer desire to amend the License and Supply
Agreement so as to provide for the transfer of certain know-how relating to the
prediction of the melting temperature of MGB Oligonucleotides from Epoch to
Perkin-Elmer for the purpose of incorporating such know how into certain
Perkin-Elmer software products. e.g., Perkin-Elmer's Primer Express software
product.

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this First Amendment, the Parties agree as follows:

1.       Unless otherwise defined herein, capitalized terms will have the
         meaning ascribed to them in the License and Supply Agreement.

2.       DELETE existing Section 2.21 (Licensed Know-How) of the License and
         Supply Agreement and REPLACE with the following amended Section 2.21:

         2.21     "Licensed Know-How" means trade secrets, technical
                  information, experimental data, software and other knowledge
                  now existing and controlled by Epoch relating to (1) the
                  chemical synthesis and purification of MGB Oligonucleotide
                  using MGB Intermediate, and (2) algorithms and related
                  software for determining the melting temperature of MGB
                  Oligonucleotide, as described in Section 5.04 and Exhibit C,
                  to the extent that such technical information, experimental
                  data, software and other knowledge is not publicly available.


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3.       ADD the following to the end of existing Section 3.04 (Restrictions) of
         the License and Supply Agreement:

                  Licensed Products comprising Licensed Know-How in the form of
                  software embodying algorithms for determining the melting
                  temperature of MGB Oligonucleotide, as described in Section
                  5.04 and Exhibit C, will only be sold or marketed pursuant to
                  a limited-use non-exclusive license agreement consistent with
                  Perkin-Elmer's normal practice for the sale and marketing of
                  like software products.

4.       ADD the following to the table of existing Section 4.02 (Royalties) of
         the License and Supply Agreement:

                           software                  [*]

5.       ADD the following to existing Section 4.03 (Payment for Know-How) of
         the License and Supply Agreement:

                  Perkin-Elmer will pay to Epoch, as additional consideration
                  for the transfer of and license under Licensed Know-How, [*]
                  per month for the period between June 15, 1999 and the first
                  New Product Release of a Licensed Product provided that Epoch
                  makes available at least source code embodying algorithms for
                  determining the melting temperature of MGB Oligonucleotide as
                  described in Subsection 3 of amended Exhibit C within ten (10)
                  days of the Effective Date of First Amendment; where as used
                  herein, the term "New Product Release" means that point in a
                  Perkin-Elmer product development program at which a product is
                  released for unrestricted manufacture and sale to customers
                  under PE Biosystems ISO 9001 Product Development Procedures.
                  In the event that the period between June 15, 1999 and the
                  first New Product Release includes a fractional month,
                  payments due for that fractional month will be determined on a
                  pro rata basis. As yet additional consideration for the
                  transfer of and license under Licensed Know-How, Perkin-Elmer
                  will give to Epoch an ABI PRISM(TM) Model 7700 Sequence
                  Detection System instrument (p/n 7700-01-200/208) [*]. The
                  instrument provided hereunder will include all installation
                  services and warranties typically provided to customers in
                  connection with the purchase of such instrument. However,
                  Perkin-Elmer will not provide an optional service contract
                  covering the instrument. All reagents will be purchased by
                  Epoch using conventional retail distribution channels.

*    CONFIDENTIAL PORTIONS OMITTED AND FILED SEPARATELY WITH COMMISSION.


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6.       DELETE existing Section 5.04 (Transfer of Know-How) of the License and
         Supply Agreement and REPLACE with the following amended Section 5.04:

         5.04     Epoch will transfer Licensed Know-How to Perkin-Elmer to the
                  extent necessary for Perkin-Elmer to make full use of MGB
                  Intermediates and MGB Oligonucleotides. Such Licensed Know-How
                  will include, but not be limited to, that information
                  specified in Exhibit C. All Licensed Know-How is considered
                  Confidential Information and will only be used by Perkin-Elmer
                  in connection with the exploitation of the license rights
                  granted in Article III. All Licensed Know-How will remain
                  owned by Epoch.

7.       ADD the following to Exhibit C (Licensed Know-How) of the License and
         Supply Agreement:

         3.       Algorithms, object code, source code and any other embodiments
                  of methods or processes useful for predicting the melting
                  temperature of MGB Oligonucleotides, whether patented,
                  copyrighted or not.

IN WITNESS WHEREOF, the Parties, through their authorized officers, have
executed this First Amendment as of the Effective Date of First Amendment.

EPOCH PHARMACEUTICALS, INC.                 THE PERKIN-ELMER CORPORATION,
                                            THROUGH ITS PE BIOSYSTEMS DIVISION


By:    /s/  Sanford S. Zweifach             By:    /s/  Elaine Heron
   ---------------------------------           ---------------------------------
Name:  Sanford S. Zweifach                  Name:  Elaine Heron
     -------------------------------             -------------------------------
Title: President                            Title: Vice President
      ------------------------------               The Perkin-Elmer Corporation
Date:  July 1, 1999                               ------------------------------
     -------------------------------        Date:  June 30, 1999
                                                 -------------------------------



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