Document:

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                                                                 EXHIBIT 10.26.1

                                November 13, 2001

Bay City Capital LLC
750 Battery Street, Suite 600
San Francisco, CA  94111
Attn: Sanford S. Zweifach

        Re:    Extension of Letter Agreement between Epoch Biosciences, Inc.
               and Bay City Capital BD LLC

Dear Mr. Zweifach:

        Reference is made to the Letter Agreement between Epoch Biosciences,
Inc. (the "Company") and Bay City Capital BD, LLC., (the "Advisor") dated
November 7, 2000 with respect to the engagement of Advisor by the Company (the
"Agreement").

        Pursuant to Paragraph 13 of the Agreement, the term of Advisor's
engagement ends effective November 7, 2001. This Letter is to document our
mutual agreement that the term of Advisor's engagement shall continue until May
7, 2002, pursuant to the terms of the Agreement. All other provisions of the
Agreement shall remain in full force and effect.

        If the foregoing correctly sets forth the understanding agreement
between Advisor and Company, please so indicate in the space provided below,
whereupon this letter shall constitute a binding amendment and extension of the
Agreement.

                                            Very truly yours,

                                            EPOCH BIOSCIENCES, INC.

                                            /s/ William G. Gerber
                                            ------------------------------------
                                            William G. Gerber, M.D.,
                                            Chief Executive Officer

Agreed to and accepted this 15th day of November, 2001

/s/ Sanford S. Zweifach
--------------------------------------
Bay City Capital BD LLC

By:   Sanford S. Zweifach
Its:  President<PAGE>

                                                                 EXHIBIT 10.27.1

                     FIRST AMENDMENT TO EMPLOYMENT AGREEMENT

        This FIRST AMENDMENT TO EMPLOYMENT AGREEMENT (the "Amendment") is made
and entered into this 12th day of February, 2002, by and between EPOCH
BIOSCIENCES, INC., a Delaware corporation (the "Employer"), and Merl Hoekstra,
an individual (the "Employee").

                                    RECITALS:

        A. Employee and Employer are parties to that certain Employment
Agreement dated as of March 8, 2001 (the "Employment Agreement"); and

        C. The parties desire to amend the Employment Agreement to correct and
clarify certain provisions relating to severance compensation in the event of
termination by Employee as a result of Employer's breach of its obligations
under the Employment Agreement.

                                   AGREEMENT:

        NOW, THEREFORE, in consideration of the foregoing premises and the
respective covenants and agreements of each party to the other set forth herein,
the parties hereto, intending to be legally bound, hereby agree as follows:

        1. Amendment to Section 4.3. The parties hereby amend, as of the
Effective Date of the Employment Agreement, the second sentence of Section 4.3
of the Employment Agreement, such that Section 4.3 of the Employment Agreement
shall read in its entirety as follows:

                        "4.3 TERMINATION BY EMPLOYEE FOR EMPLOYER BREACH. In the
                event of a breach by the Employer of any of its material
                obligations to Employee under this Agreement, then Employee
                shall be entitled (i) to give a written default notice to the
                Employer identifying, in reasonable detail, the nature of such
                breach and stating that Employee intends to terminate this
                Agreement and Employee's employment with the Employer if such
                breach is not cured within the succeeding thirty (30) days (the
                "Cure Period") and (ii) if the Employer fails to cure such
                breach in all material respects within the Cure Period, to
                terminate Employee's employment with the Employer by a written
                termination notice delivered to the Employer no later than the
                15th day after the end of such Cure Period. In the event of any
                such breach by the Employer and the termination by Employee of
                Employee's employment pursuant to this Subsection 4.3, the
                Employer's sole liability and obligation to Employee shall be to
                pay to Employee the same compensation, on the same payment
                schedule, that applies to a termination of Employee's employment
                without Cause, AS PROVIDED IN SUBSECTION 4.1(a), 4.1(b) AND
                4.1(c) HEREOF AND, IN THE EVENT THAT SUCH BREACH OCCURS UPON OR
                WITHIN TWELVE (12) MONTHS FOLLOWING A CHANGE IN CONTROL, THEN
                SECTION 4.1(d) HEREOF IN LIEU OF SECTION 4.1(c) HEREOF. If
                Employee fails to exercise Employee's right of termination
                hereunder within the 15 day period specified above, then,
                notwithstanding anything to the contrary contained herein, the
                Employer's breach and its failure to cure such breach shall be
                deemed to have been waived by Employee, Employee's employment
                shall continue hereunder and Employee shall not be entitled to
                terminate this Agreement or Employee's employment or to receive
                any amounts or other payments from

<PAGE>

                the Employer by reason of such breach and failure to cure on the
                part of the Employer."

        2. Defined Terms. Unless otherwise defined herein, all capitalized terms
in this Amendment shall have the respective meanings ascribed to them in the
Employment Agreement.

        3. Effect on Employment Agreement. Except as specifically amended in the
manner and to the extent provided in Section 1 above, the Employment Agreement
shall remain unchanged and the Employment Agreement shall continue, as and to
the extent amended by this Amendment, in full force and effect.

        4. Conflicts. This Amendment shall be governed by all the terms and
conditions of the Employment Agreement. In the event of any conflict between the
terms of the Employment Agreement and the terms of this Amendment, the terms of
this Amendment will control.

        5. Counterpart Execution. This Amendment may be executed by facsimile
and in counterparts, each of which shall be deemed an original and all of which
when taken together shall constitute but one and the same instrument.

        IN WITNESS WHEREOF, the parties have executed this First Amendment to
Employment Agreement as of the day and year set forth above.

                                            "EMPLOYER"

                                            EPOCH BIOSCIENCES, INC.,
                                            a Delaware corporation

                                            By: /s/ William G. Gerber
                                                --------------------------------
                                                William G. Gerber
                                                Its: Chief Executive Officer

                                            "EMPLOYEE"

                                                /s/ Merl Hoekstra
                                            ------------------------------------
                                            Merl Hoekstra

                                       2<PAGE>

                                                                 EXHIBIT 10.28.1

                     FIRST AMENDMENT TO EMPLOYMENT AGREEMENT

        This FIRST AMENDMENT TO EMPLOYMENT AGREEMENT (the "Amendment") is made
and entered into this 12th day of February, 2002, by and between EPOCH
BIOSCIENCES, INC., a Delaware corporation (the "Employer"), and Bert W. Hogue,
an individual (the "Employee").

                                    RECITALS:

        A. Employee and Employer are parties to that certain Employment
Agreement dated as of February 28, 2001 (the "Employment Agreement"); and

        C. The parties desire to amend the Employment Agreement to correct and
clarify certain provisions relating to severance compensation in the event of
termination by Employee as a result of Employer's breach of its obligations
under the Employment Agreement.

                                   AGREEMENT:

        NOW, THEREFORE, in consideration of the foregoing premises and the
respective covenants and agreements of each party to the other set forth herein,
the parties hereto, intending to be legally bound, hereby agree as follows:

        1. Amendment to Section 4.3. The parties hereby amend, as of the
Effective Date of the Employment Agreement, the second sentence of Section 4.3
of the Employment Agreement, such that Section 4.3 of the Employment Agreement
shall read in its entirety as follows:

                        "4.3 TERMINATION BY EMPLOYEE FOR EMPLOYER BREACH. In the
                event of a breach by the Employer of any of its material
                obligations to Employee under this Agreement, then Employee
                shall be entitled (i) to give a written default notice to the
                Employer identifying, in reasonable detail, the nature of such
                breach and stating that Employee intends to terminate this
                Agreement and Employee's employment with the Employer if such
                breach is not cured within the succeeding thirty (30) days (the
                "Cure Period") and (ii) if the Employer fails to cure such
                breach in all material respects within the Cure Period, to
                terminate Employee's employment with the Employer by a written
                termination notice delivered to the Employer no later than the
                15th day after the end of such Cure Period. In the event of any
                such breach by the Employer and the termination by Employee of
                Employee's employment pursuant to this Subsection 4.3, the
                Employer's sole liability and obligation to Employee shall be to
                pay to Employee the same compensation, on the same payment
                schedule, that applies to a termination of Employee's employment
                without Cause, AS PROVIDED IN SUBSECTION 4.1(a), 4.1(b) AND
                4.1(c) HEREOF AND, IN THE EVENT THAT SUCH BREACH OCCURS UPON OR
                WITHIN TWELVE (12) MONTHS FOLLOWING A CHANGE IN CONTROL, THEN
                SECTION 4.1(d) HEREOF IN LIEU OF SECTION 4.1(c) HEREOF. If
                Employee fails to exercise Employee's right of termination
                hereunder within the 15 day period specified above, then,
                notwithstanding anything to the contrary contained herein, the
                Employer's breach and its failure to cure such breach shall be
                deemed to have been waived by Employee, Employee's employment
                shall continue hereunder and Employee shall not be entitled to
                terminate this Agreement or Employee's employment or to receive
                any amounts or other payments from

<PAGE>

                the Employer by reason of such breach and failure to cure on the
                part of the Employer."

        2. Defined Terms. Unless otherwise defined herein, all capitalized terms
in this Amendment shall have the respective meanings ascribed to them in the
Employment Agreement.

        3. Effect on Employment Agreement. Except as specifically amended in the
manner and to the extent provided in Section 1 above, the Employment Agreement
shall remain unchanged and the Employment Agreement shall continue, as and to
the extent amended by this Amendment, in full force and effect.

        4. Conflicts. This Amendment shall be governed by all the terms and
conditions of the Employment Agreement. In the event of any conflict between the
terms of the Employment Agreement and the terms of this Amendment, the terms of
this Amendment will control.

        5. Counterpart Execution. This Amendment may be executed by facsimile
and in counterparts, each of which shall be deemed an original and all of which
when taken together shall constitute but one and the same instrument.

        IN WITNESS WHEREOF, the parties have executed this First Amendment to
Employment Agreement as of the day and year set forth above.

                                            "EMPLOYER"

                                            EPOCH BIOSCIENCES, INC.,
                                            a Delaware corporation

                                            By: /s/ William G. Gerber
                                                --------------------------------
                                                William G. Gerber
                                                Its: Chief Executive Officer

                                            "EMPLOYEE"

                                                /s/ Bert W. Hogue
                                            ------------------------------------
                                            Bert W. Hogue

                                       2

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