EXHIBIT
      4.1

    


    AMENDMENT
      NUMBER TWO TO RIGHTS AGREEMENT

    BETWEEN

    SIRNA
      THERAPEUTICS, INC.

    AND

    AMERICAN
      STOCK TRANSFER AND TRUST COMPANY

    


    This
      Amendment Number Two to Rights Agreement (this “Second Amendment”), made as of
      this 30th day of October, 2006, between Sirna Therapeutics, Inc., a Delaware
      corporation (the “Company”), and American Stock Transfer & Trust Company, a
      New York banking corporation, as rights agent (the “Rights Agent”), amends the
      Rights Agreement dated as of November 22, 2000 between the Company and the
      Rights Agent (as amended to date, the “Rights Agreement”).

    


    RECITALS

    


    A.    Pursuant
      to the Rights Agreement, the Board of Directors of the Company authorized and
      declared a dividend distribution of one right (each a “Right” and collectively
      the “Rights”) for each share of the Common Stock (as defined in the Rights
      Agreement) of the Company outstanding at the close of business on December
      8,
      2000 (the “Record Date”), and authorized the issuance of one Right in respect of
      each share of common stock of the Company issued between the Record Date and
      the
      Distribution Date (as such term is defined in Section 3 of the Rights
      Agreement), each Right representing the right to purchase one one-hundredths
      of
      a share of Series AA Preferred Stock of the Company having the rights, powers
      and preferences set forth in the form of Certificate of Designation attached
      to
      the Rights Agreement as Exhibit A, upon the terms and subject to the conditions
      set forth in the Rights Agreement.

    


    B.    On
      February 11, 2003, the Company and the Rights Agent entered into an Amendment
      to
      Rights Agreement (the “First Amendment”) that amended the Rights Agreement to,
      among other matters, exempt the Investors (as defined in the First Amendment)
      from the definition of “Acquiring Person” under the Rights Agreement and to
      clarify that the announcement, approval, execution or delivery of the Stock
      Purchase Agreement (as defined in the First Amendment) shall not cause a
“Distribution Date” to have occurred under the Rights Agreement.

    


    C.    The
      Board
      of Directors of the Company has determined that it is in the best interests
      of
      the Company and its stockholders to further amend the Rights Agreement,
      including all applicable sections, to, among other things, revise the
      definitions of (i) “Acquiring Person” to exempt Merck & Co., Inc., a
      Delaware corporation (“Parent”), Spinnaker Acquisition Corp.,
      a
      Delaware corporation and a wholly-owned subsidiary of Parent (“Merger Sub”), and
      all of their respective affiliates therefrom,
      and (ii) “Expiration Date” to mean immediately prior to the Effective Time, as
      such term is defined in the Agreement and Plan of Merger, dated as of October
      30, 2006, by and among the Company, Parent and Merger
      Sub (the “Merger Agreement”), and to clarify that no “Shares Acquisition Date”
or “Distribution Date” will occur solely by reason of the approval, execution or
      delivery of the Merger Agreement or the Voting Agreements (as defined in the
      Merger Agreement) or the consummation of the transactions contemplated
      thereby.
      

    
      
         

      

      
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    D.    Pursuant
      to Section 27 of the Rights Agreement, the Board of Directors of the Company
      has
      determined that an amendment to the Rights Agreement as set forth herein is
      necessary and desirable in order to reflect the foregoing, and the Company
      and
      the Rights Agent desire to evidence such amendment in writing. 

    


    NOW
      THEREFORE, intending to be legally bound, the Company and the Rights Agent
      hereby agree that the Rights Agreement is hereby amended as set forth
      below:

    


    1.    Section
      1(a) of the Rights Agreement is amended to add the following sentence at the
      end
      thereof:

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, none of Parent, Merger
      Sub, or any of their respective Affiliates or Associates, individually
      or collectively, shall be deemed to be an Acquiring Person solely as a result
      of
      (i) the announcement, approval, execution or delivery of the Merger Agreement
      or
      the Voting Agreements or (ii) the consummation of the transactions contemplated
      by the Merger Agreement or the Voting Agreements.”

    


    2.    The
      following Section 1(k) is inserted into the Rights Agreement, and all subsequent
      subsections of Section 1 are renumbered accordingly, and all cross-references
      to
      such renumbered subsections are changed to refer to such subsections as if
      renumbered:

    


    “1(k)
      “Merger Agreement” shall mean the Agreement and Plan of Merger, dated as of
      October 30, 2006, by and among Merck & Co., Inc., a Delaware corporation,
      Spinnaker Acquisition Corp., a Delaware corporation and a wholly-owned
      subsidiary of Parent, and the Company, as it may be amended from time to time.
      The defined terms “Parent,” “Merger Sub,” “Effective Time” and “Voting
      Agreements” used herein shall have the meanings ascribed to such terms in the
      Merger Agreement.”

    


    3.    Section
      1(s) (after giving effect to the renumbering caused by this Second Amendment)
      of
      the Rights Agreement is hereby amended to add the following sentence at the
      end
      thereof:

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, a Stock Acquisition Date
      shall not be deemed to have occurred solely as a result of (i) the announcement,
      approval, execution or delivery of the Merger Agreement or the Voting Agreements
      or (ii) the consummation of the transactions contemplated by the Merger
      Agreement or the Voting Agreements.”

    


    4.    Section
      3(a) of the Rights Agreement is amended to add the following sentence at the
      end
      thereof: 

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, a Distribution Date shall
      not
      be deemed to have occurred solely as a result of (i) the announcement,
      approval, execution or delivery of the Merger Agreement or the Voting Agreements
      or (ii) the consummation of the transactions contemplated by the Merger
      Agreement or the Voting Agreements.”

    
      
         

      

      
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    5.    The
      second to last sentence of Section 7(a) of the Rights Agreement is deleted
      in
      its entirely and replaced with the following sentence: 

    


    “The
      “Expiration Date,” as used in this Rights Agreement, shall be the earliest of
      (i) the Final Expiration Date (as defined below), (ii) the time at which the
      Rights are redeemed as provided in Section 23 hereof, (iii) the time at which
      the Rights are exchanged as provided in Section 24 hereof or (iv) the time
      immediately prior to the Effective Time.”

    


    6.    Section
      11(b)(ii) of the Rights Agreement is amended to add the following sentence
      at
      the end thereof:

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, neither (i) the announcement,
      approval, execution or delivery of the Merger Agreement or the Voting Agreements
      nor (ii) the consummation of the transactions contemplated by the Merger
      Agreement or the Voting Agreements shall be deemed to be an event described
      in
      Section 11(b)(i) and shall not cause the Rights to be adjusted or exercisable
      in
      accordance with Section 11 or 12.”

    


    7.    Section
      13(a) of the Rights Agreement is amended to add the following sentence at the
      end thereof:

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, neither (i) the announcement,
      approval, execution or delivery of the Merger Agreement or the Voting Agreements
      nor (ii) the consummation of the transactions contemplated by the Merger
      Agreement or the Voting Agreements shall be deemed to be an event described
      in
      this Section 13(a) and shall not cause the Rights to be adjusted or exercisable
      in accordance with Section 12 or 13.”

    


    8.    Section
      13(b)(ii) of the Rights Agreement is amended to add the following at the end
      thereof:

    


    “Notwithstanding
      anything in this Rights Agreement to the contrary, none of Parent, Merger
      Sub, or any of their respective Affiliates or Associates, individually
      or collectively, shall be deemed to be a Principal Party solely as a result
      of
      (i) the announcement, approval, execution or delivery of the Merger Agreement
      or
      the Voting Agreements or (ii) the consummation of the transactions contemplated
      by the Merger Agreement or the Voting Agreements.”

    


    9.    The
      following Section 15 is inserted into the Rights Agreement, and all subsequent
      sections are renumbered accordingly, and all cross-references to such renumbered
      sections are changed to refer to such sections as if renumbered:

    
      
         

      

      
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    “15.
      TREATMENT OF MERGER AGREEMENT. Notwithstanding anything in this Rights Agreement
      to the contrary, neither (i) the announcement, approval, execution nor delivery
      of the Merger Agreement or the Voting Agreements or (ii) the consummation of
      the
      transactions contemplated by the Merger Agreement or the Voting Agreements,
      shall cause a Distribution Date, a Stock Acquisition Date, a Flip-In Event
      or a
      Flip-Over Event.”

    


    10.    EFFECTIVENESS.
      This Second Amendment shall be deemed effective immediately upon execution
      hereof by the Company and the Rights Agent. Except as amended hereby, the Rights
      Agreement shall remain in full force and effect and shall be otherwise
      unaffected hereby.

    


    11.    MISCELLANEOUS.
      This Second Amendment shall be deemed to be a contract made under the laws
      of
      the State of Colorado and for all purposes shall be governed by and construed
      in
      accordance with the laws of such state applicable to contracts made and
      performed entirely within such state. This Second Amendment may be executed
      in
      any number of counterparts, each of such counterparts shall for all purposes
      be
      deemed to be an original, and all such counterparts shall together constitute
      one and the same instrument. If any provision, covenant or restriction of this
      Second Amendment is held by a court of competent jurisdiction or other authority
      to be invalid, illegal or unenforceable, the remainder of the terms, provisions,
      covenants and restrictions of this Second Amendment shall remain in full force
      and effect and shall in no way be effected, impaired or invalidated. In the
      event of any conflict or inconsistency between this Second Amendment, on the
      one
      hand, and the First Amendment, on the other hand, this Second Amendment shall
      govern.

    


    


     

    [Signature
      Page Follows]

    
      
         

      

      
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    IN
      WITNESS WHEREOF, the parties hereto have executed this Second Amendment as
      of
      the date first set forth above.

     

    

      
        	
                SIRNA
                  THERAPEUTICS, INC.

              	 	
                AMERICAN
                  STOCK TRANSFER AND TRUST COMPANY

              
	 	 	 
	 	 	 
	
                By: 
                  /s/
                  Howard W. Robin

              	 	
                By: 
                  /s/
                  Wilbert Myles

              
	
                Name:
                  Howard W. Robin

              	 	
                Name:
                  Wilbert Myles

              
	
                Title:
                  President and Chief Executive Officer

              	 	
                Title:
                  Vice President

              


      

    

     

     

    
      
         

      

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