`Attorney's Docket No. 22338-10230
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Control Nos.:
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`90/007,542
`... ~
`90/007,859 ~
`
`Group Art Unit:
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`3991
`
`Confirmation Nos.:
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`7585 ('542)
`6447 ('859)
`
`Filed:
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`13 May 2005
`23 December 2005
`
`('542)
`('859)
`
`Patent Owner:
`
`Genentech, Inc. and
`City of Hope
`
`Examiner:
`
`B.M. Celsa
`
`For:
`
`Merged Reexaminations of U.S. Patent No. 6,331,415 (Cabilly et al.)
`
`RESPONSE UNDER 37 C.F.R. § 1.550(b)
`
`Mail Stop Ex Parte Reexam
`COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`This communication timely responds to the final Office action mailed on February 25,
`
`2008. By petition granted on March 19, 2008, the original response date of April 25, 2008 was
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`extended until June 6, 2008.
`
`Patent Owners ("Owners") respectfully request reconsideration of the claims in view of
`
`the following remarks.
`
`Sanofi/Regeneron Ex. 1 023, pg 668
`
`Merck Ex. 1023, pg 694
`
`
`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230,10231
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`I.
`
`TABLE OF CONTENTS
`PRELIMINARY MATTERS .............................................................................................................................. 3
`INFORMATION DISCLOSURE STATEMENT ......................................................................................................... 3
`A.
`
`B.
`
`INTERVIEW SUMMARY ..................................................................................................................................... )
`
`C. STATUS OF LITIGATION INVOLVING THE '4 15 PATENT .................................................................................... 3
`D. ADDITIONAL EVIDENCE PROVIDED WITH THIS RESPONSE ................................................................................ 3
`
`II. RESPONSE TO REJECTIONS .......................................................................................................................... 4
`A. WITHDRAWN REJECTIONS ............................................................................................................................... 4
`B. SUMMARy OF THE REJECTIONS ........................................................................................................................ 5
`C. BRIEF SUMMARY OF WHY THE '415 CLAIMS ARE NOT OBVIOUS FROM THE '567 CLAIMS
`AND IN VIEW OF THE PRIOR ART ...................................................................................................................... 5
`I. The Cited Art Teaches Away from Expression of Heavy and Light Chain Polypeptides
`in a Single Transformed Host Cell ............................ ............................................................................. 6
`2. A Person of Ordinary Skill Would Not Have Viewed the Cited References as
`Making Achievement of the '415 inventions Predictable ......................................................................... 8
`3. There is Substantial Evidence of Secondary indicia of Non-Obviousness of the '415 Claimed
`inventions ................................................................... .......................................................................... 10
`D. DETAILED RESPONSE TO THE REJECTIONS ..................................................................................................... I 0
`I. The '567 Patent Claims Do Not Suggest Producing Heavy and Light Chains in
`One Transformed Host Cell .................. ............................................................................................. 12
`2. Co-Transformation of Host Cells with Two DNA Sequences is Not Equivalent
`to Co-Expression of Those Sequences .................................................................................................... 15
`(a) The Axel Patent Shows that Co-Transformation Was Not Equivalent to Co-expression ................................ 16
`(b) The Axel Patent and its Prosecution History Show No Production or Recovery of "DNA I Polypeptides" .... 16
`(c) Production of Heavy and Light Chains in One Host Cell is Not Required by Axel... ...................................... l9
`(d) Rice, Ochi and Oi Reinforce Unpredictability Shown in Axel ........................................................................ 22
`3. The Cited References Teach Away from Producing Two Immunoglobulin Polypeptides in One
`Transformed Host Cell ........................................................................................................................... 23
`(a) The Prevailing Mindset in April 1983 Was Production of One Eukaryotic Polypeptide at a Time in a
`Transformed Host Cell .................................................................................................................................... 24
`(b) Moore and Kaplan Expressly Call for Production of Only One Heavy or Light Chain at a Time in a
`Transformed Host Cell .................................................................................................................................... 25
`(c) Axel Reinforces the Mindset of Producing Only One Eukaryotic Polypeptide
`in a Transformed Host cell... ............................................................................................................................ 26
`(d) Rice, Ochi, and Oi Further Reinforce the "One Protein-One Host Cell" Mindset Prevalent
`in April of 1983 ............................................................................................................................................... 27
`(e) Dallas Would Not Have Altered the "One Protein-One Host Cell'' Mindset Established
`by the Other Cited References ......................................................................................................................... 28
`4. The Cited References and General Knowledge in the Art Would Not Have Made the
`'415 invention Reasonably Predictable to a Person of Ordinary Skill in the Art in 1983 .. .................. 30
`(a) The Cited References that Provide Experimental Results Report Significant Unpredietability ....................... 30
`(b) The Predictability of Achieving the Entire '415 Patented Invention Must Be Considered .............................. 32
`(c) A Hypothetical Doubly-Transformed B-Cell Cannot Establish Reasonable
`Expectations Relevant to the '415 Claims ....................................................................................................... 35
`(d) The Xenopus Oocyte Microinjection Experiments Do Not Establish that the
`'415 Claimed Invention Could Have Been Predictably Achieved in April 1983.. ........................................... 38
`D. STRONG EVIDENCE OF SECONDARY CONSIDERATIONS SUPPORTS THE CONCLUSION THAT THE '415 PATENT
`CLAIMS ARE NOT OBVIOUS ........................................................................................................................... 40
`E. STATUS OF DEPENDENT CLAIMS .................................................................................................................... 42
`
`Ill. CONCLUSION ................................................................................................................................................... 42
`ATTACHMENT A: OWNERS' SUMMARY OF INTERVIEW HELD APRIL 2, 2008 ................................... 44
`A TT ACHM ENT 8: EXCERPTS FROM FILE HISTORIES CITED IN THE RESPONSE ............................ 46
`
`REPLY
`
`6 JUNE 2008 - PAGE 2
`
`Sanofi/Regeneron Ex. 1 023, pg 669
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`Merck Ex. 1023, pg 695
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I 0231
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`REMARKS
`
`I.
`
`Preliminary Matters
`
`A.
`
`Information Disclosure Statement
`
`Owners thank the Office for the indication that all materials previously submitted to the
`
`Office have been fully considered. Owners respectfully request consideration of materials
`
`provided in the accompanying supplemental information disclosure statement.
`
`B.
`
`Interview Summary
`
`Owners thank Examiners Celsa, Jones and Padmashri for the courtesy of an interview
`
`held on April 2, 2008. Owners' summary of the interview is provided in Attachment A to this
`
`response, in compliance with 37 C.F.R. § 1.560(b).
`
`C.
`
`Status of Litigation Involving the '415 Patent
`
`Owners have previously indicated that U.S. Patent No. 6,3 31 ,415 ("the '415 patent") has
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`been the subject of litigation in the Central District of California. Owners now report that the
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`parties to that litigation have jointly requested dismissal of the action with prejudice pursuant to
`
`a settlement agreement between the parties, and that the dismissal was ordered on June 4, 2008.
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`Owners also report that on May 30, 2008, an action was filed in the Central District of California
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`by Centocor seeking, inter alia, a declaratory judgment that the '415 patent is invalid and not
`
`enforceable. A copy of the complaint is provided in the accompanying information disclosure
`
`statement.
`
`D.
`
`Additional Evidence Provided with this Response
`
`Owners submit and request favorable consideration of this response and the
`
`accompanying declarations under 37 C.F.R. § 1.132 of Dr. Steven McKnight and Dr. Finton
`
`Walton. Owners submit the declaration of Dr. McKnight in response to new scientific findings
`
`of the Office in the final Office action ("Final Action"). Owners submit the declaration of Dr.
`
`Walton in response to the Office's observations about the legal significance of licensing of Axel
`
`(U.S. Patent No. 4,399,216), and in support of the non-obviousness of the '415 patent claims.
`
`Owners submit that "good and sufficient reasons why the affidavit or other evidence is
`
`necessary and was not earlier presented" exist pursuant to 37 C.F.R. § 1.116. Specifically, the
`
`REPLY
`
`6 JUNE 2008- PAGE 3
`
`Sanofi/Regeneron Ex. 1 023, pg 670
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`Merck Ex. 1023, pg 696
`
`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`Office makes new factual determinations, and advances new or changed theories to support
`
`rejections in the Final Action, particularly at pages 21-46. Examples include: use of Moore (U.S.
`
`Patent No. 5,840,545) to support findings of obviousness of co-expression despite a significantly
`
`changed interpretation of the Moore prior art disclosure (Final Action at 5, 15-16); reliance on
`
`Axel as teaching production of "functional proteins" (Final Action at 30); reliance on Ochi (Ochi
`
`et al., Nature 302: 340-42 (1983)) and Oi (Oi et al., Proc. Nat' I. Acad. Sci. (USA) 80: 825-29
`
`(1983)) as providing additional motivation to co-transform host cells (Final Action at 38); use of
`
`Dallas (PCT Publication No. WO 82/03088) to modify the teachings in Moore (Final Action at
`
`40); and references to licensing of Axel (Final Action at 46). Owners could not have reasonably
`
`predicted that the Office would make these new or changed findings, or use them to support the
`
`rejections set forth in the Final Action. The declarations of Drs. McKnight and Walton respond
`
`to these new issues. Owners submit that presentation of the present declaration evidence is thus
`
`appropriate under 37 C.P.R. § 1.116.
`
`II.
`
`Response to Rejections
`
`A. Withdrawn Rejections
`
`Owners appreciate withdrawal of rejections under 35 U.S.C. §§ 102 and 103, and for
`
`double patenting, based on Moore, alone or in combination with the '567 patent (U.S. Patent No.
`
`4,816,567), Axel and Accolla (Accolla et al., Proc. Nat'l. Acad. Sci. (USA) 77(1): 563-66
`
`(1980)). The Office indicates that Moore is entitled to a§ 102(e) effective date for "single host
`
`expression of variable light and heavy chain for producing single-chain antibody" only as of "the
`
`June 5, 1995 date since the original 06/358,414 specification and claims 1-25 only disclose the
`
`separate expression of the heavy and light chain antibody fragment in different host cells .... "
`
`Final Action at 5 (emphasis original). The Office also indicates that Moore does not have
`support for "single host expression of variable light and heavy chains ... " prior to June 5, 1995. 1
`
`Id. at 6.
`
`At page 16 of the Final Action, the Office states that Moore "discloses a method of making 'an
`immunologically functional fragment' comprising independently expressing in a host cell variable and heavy
`light chain domains .... " This appears to be an inadvertent error in view of the Office's conclusions noted
`above.
`
`REPLY
`
`6JUNE 2008- PAGE 4
`
`Sanofi/Regeneron Ex. 1023, pg 671
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`Merck Ex. 1023, pg 697
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I 0231
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`B.
`
`Summary of the Rejections
`
`The Office rejects claims 1-36 for obviousness-type double patenting based on the '567
`
`patent, in view of Axel, Rice (Rice et al., Proc. Nat'l. Acad. Sci. (USA) 79: 7862 (1982)) and
`
`Kaplan (European Patent No. 0044722), further in view of Dallas, and further in view of Deacon
`
`(Deacon et al., Biochem. Soc. Trans. 4: 818-20 (1976)), Valle 1981 (Valle et al., Nature 291:
`
`338-40 (1981)), or Ochi, alone or further in view ofMoore. Dependent claims 10 and 27-32 are
`
`rejected when these references are further considered with Builder (U.S. Patent No. 4,511 ,502),
`
`and dependent claim 22 is further rejected in view of Accolla. The Office sets forth the basis of
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`its rejections at pages 10 to 20 of the Final Action. At pages 21 to 46, the Office addresses issues
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`raised by Owners in their previous responses.
`
`The Office bases the final rejection on two conclusions, namely: (i) "One of ordinary
`
`skill in the art would have been motivated to express, in a single host, light and heavy
`
`immunoglobulin chains (using one or two vectors) when viewing the reference Cabilly 1 ['567]
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`patented invention in light of the prior art" (Final Action at 12); and (ii) "The prior art provides
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`further motivation to make active antibody with a reasonable expectation of success" (Final
`
`Action at 14). Owners respectfully request withdrawal ofthe rejections because the Office's
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`conclusions are inconsistent with the collective teachings and suggestions of the cited references,
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`and with the beliefs and expectations of the person of ordinary skill in the art in early April 1983.
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`Owners respectfully traverse the rejections set forth in the Final Action, and request
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`withdrawal of rejections of claims 1-36.
`
`C.
`
`Brief Summary of Why the '415 Claims Are Not Obvious From the '567
`Claims and in View of the Prior Art
`
`Owners provide with this response a second declaration by Dr. Steven McKnight
`
`responding to issues raised in the Final Action. Dr. McKnight accurately presents the views of a
`
`person of ordinary skill in the art in April 1983, based on his relevant experience and training
`
`from that time. He explains that, unlike the '567 claims, the '415 patent claims require three
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`separate steps: (i) a host cell must be transformed with immunoglobulin heavy chain and light
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`chain DNA sequences; (ii) the DNA sequences must be independently expressed (transcribed
`
`and translated) by the host cell to produce polypeptides; and (iii) the polypeptides must be
`
`REPLY
`
`6 JUNE 2008- PAGE 5
`
`Sanofi/Regeneron Ex. 1 023, pg 672
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`Merck Ex. 1023, pg 698
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I 0231
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`assembled to form an immunoglobulin molecule or an immunologically functional
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`immunoglobulin fragment ("fragment"). See McKnight 2nd Dec. ~~ 4-5.
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`The inventions of the '415 and '567 patents have distinct utilities and applications linked
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`to the distinct methods and results each patent requires. For example, the common specification
`
`of the patents identifies distinct benefits of producing immunoglobulin molecules and fragments
`
`using individually produced chains, relative to the benefits of making such molecules or
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`fragments by expressing both chains in one host cell pursuant to the '415 patented methods. See,
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`~. '415 patent, col. 14, Ins. 20-49; col. 12, Ins. 50-56. The evidence also establishes that the
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`products made by each patented method are distinct, and have independent benefits and
`
`applications. See,~. McKnight 2nd Dec.~ 15; Riggs Dec.~~ 19-29.
`
`The evidence of record demonstrates that the material distinctions between the '415 and
`
`'567 patent claims would not have been obvious to a person of ordinary skill in the art in April
`
`1983. In particular, this evidence establishes that:
`
`the cited references do not suggest expressing heavy and light chain polypeptides
`in a single transformed host cell, but instead teach away from doing this;
`
`a person of ordinary skill would not have believed that what was required by the
`'415 patent claims could have been predictably achieved in April 1983 based on
`the '567 claims, and from what is disclosed in the cited references and generally
`known in the field at that time; and
`
`secondary considerations support the non-obviousness of the '415 claims.
`
`These findings establish that the '415 claims would not have been considered obvious in April
`
`1983 based on the '567 claims in view of the cited art.
`
`1.
`
`The Cited Art Teaches Away from Expression of Heavy and Light
`Chain Polypeptides in a Single Transformed Host Cell
`
`Dr. McKnight explains that the cited references reflect the prevailing mind-set in April
`
`1983 that only one eukaryotic polypeptide of interest should be produced in a recombinant host
`
`cell. See McKnight 2nd Dec.~~ 7-9. As he explains, the cited references all show the
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`unpredictability of successfully expressing and recovering even one eukaryotic polypeptide from
`
`a host cell in April 1983. See id. at~~ 8, 21-23, 30-34. He also explains that the prevailing
`
`mindset would have led a person of ordinary skill to break down a complex project, such as
`
`REPLY
`
`6 JUNE 2008- PAGE 6
`
`Sanofi/Regeneron Ex. 1 023, pg 673
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`Merck Ex. 1023, pg 699
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`
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`REEXAM CONTROL NOS. 90/007,542,90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I 0231
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`production of a multimeric eukaryotic protein, into more manageable steps (e.g., produce each
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`constituent polypeptide of the multimer in a separate host cell, as was proposed in Moore and
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`Kaplan). See id. at~~ 7-13.
`
`Dr. McKnight explains that this mindset is reflected in Axel. He explains that a person of
`
`ordinary skill in the art would have necessarily read the Axel DNA I +DNA II scheme as
`
`suggesting production of only a single antibody polypeptide at a time in a co-transformed host.
`
`See id. at. ~~ 19, 27. Moreover, as he explains, while Axel shows successful cotransformation
`
`with a "DNA I"(~, a ~-globin gene) and a "DNA II" (a marker gene such as thymidine
`
`kinase), it shows unsuccessful coexpression of both sequences. See id. at~~ 20-22. Specifically,
`
`Axel reports incorrect transcription of the DNA I sequence and no production or recovery of the
`
`polypeptide encoded by it. See id. at ~ 21. Axel thus does not show production of two
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`"functional" polypeptides in a co-transformed cell.
`
`The Axel prosecution history clearly supports Dr. McKnight's analysis. In particular, the
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`Axel inventors conceded that the disclosure in their patent did not describe production and
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`recovery of functional proteins encoded by a DNA I sequence, and eventually accepted claims
`
`that deleted any reference to expression of a protein encoded by a "DNA 1." See Application
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`Serial No. 06/124,513; PaperNo. 9, dated February 8, 1982 atp. 2, ~ 12; PaperNo. 15, dated
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`January 12, 1983 at pp. 2-3, 6; and Paper No. 17, dated February 7, 1983.
`
`Dr. McKnight explains that Rice, Ochi, and Oi reinforce the unpredictability shown in
`
`Axel. See McKnight 2nd Dec. ~~ 30-34. He points out that the three references describe
`
`experiments where lymphoid cells were transformed with, and expressed, only a single foreign
`
`immunoglobulin light chain gene. He explains how a person of skill would have interpreted the
`
`experimental results reported in these papers, and, in particular, why such a person would have
`
`found them to be reporting substantial unpredictability. See,~. id. at~~ 31-34; He also
`
`explains why none of the publications describes or suggests expressing two different foreign
`
`immunoglobulin genes in a single transformed host cell. See id. at~~ 5, 34.
`
`Dr. McKnight also discusses Moore and Kaplan, and demonstrates that these references
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`actually teach away producing immunoglobulins and fragments in a single host cell according to
`
`the approach of the '415 patent. He explains that, instead, each reference expressly describes a
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`REPLY
`
`6 JUNE 2008 - PAGE 7
`
`Sanofi/Regeneron Ex. 1 023, pg 67 4
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`Merck Ex. 1023, pg 700
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, 10231
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`plan for producing an immunoglobulin molecule or fragment using heavy and light chain
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`polypeptides that have been produced in separate host cells. See id. at~~ 12, 13.
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`Dr. McKnight then explains why Dallas does not suggest modifying the '567 claims or
`
`the teachings of other cited art to yield the '415 claimed invention. See id. at ~~ 3 8-48. He
`
`explains that Dallas describes experiments where E. coli genes encoding simple E. coli cell
`
`surface proteins are used to transform an E. coli host cell. See id. at ~~ 39-41. He explains that a
`
`person of ordinary skill would have evaluated Dallas in conjunction with what is reported in the
`
`other cited references, in particular, the unpredictability reported in Axel, Rice, Ochi and Oi, and
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`the express teachings of Kaplan and Moore to express heavy and light chains polypeptides in
`
`separate host cells. See id. at~~ 38-39, 47-48. He also explains why the Dallas E. coli teachings
`
`would not be considered relevant to production of multimeric eukaryotic proteins. See id. at ~~
`
`42-47. Indeed, Owners note that during examination of the U.S. counterpart to Dallas, the Office
`
`limited the Dallas claims to the specific transformed E. coli host cells and E. coli genes described
`in the Dallas examples.2 As Dr. McKnight concludes after reading Dallas with the teachings of
`
`the other references, "a person of ordinary skill would have simply avoided all these problems
`
`and uncertainties by producing the heavy and light immunoglobulin chains in separate bacterial
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`host cell cultures." Id. at~ 48.
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`2.
`
`A Person of Ordinary Skill Would Not Have Viewed the Cited
`References as Making Achievement of the '415 Inventions Predictable
`
`A person of ordinary skill in the art would not have had a reasonable basis for believing
`
`the '415 patented invention as a whole could have been predictably achieved based on the '567
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`patent claims, when considered with the teachings of the cited references and the general
`
`knowledge in the art.
`
`As Dr. McKnight explains, Axel, Rice, Ochi, and Oi each report experimental results that
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`cumulatively show significant unpredictability in achieving successful expression of one
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`recombinant DNA sequence encoding one foreign polypeptide. Axel reports experimental
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`results showing only unsuccessful efforts to express a single DNA I sequence in a co-
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`See file wrapper of U.S. Patent No. 5,137,721 ~.Office action of October 28, 1982 (Paper No.4) at 4; Office
`action of June 5, 1984 (Paper No. II) at 3-4; Office action of November 17, 1986 (Paper No. 17) at 3).
`
`REPLY
`
`6 JUNE 2008- PAGE 8
`
`Sanofi/Regeneron Ex. 1023, pg 675
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`Merck Ex. 1023, pg 701
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, 10231
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`transformed eukaryotic host cell. See McKnight 2nd Dec.~~ 21-22. Similarly, Rice, Ochi, and
`
`Oi report significant unpredictability in achieving successful expression of a single light chain
`immunoglobulin gene in various types oflymphoid cells. 3 McKnight 2nd Dec.~~ 30-34. These
`reports of inconsistent and unpredictable experimental results would not have led a person of
`
`ordinary skill to believe that independent expression of DNA sequences encoding heavy and
`
`light immunoglobulin chain polypeptides in one transformed host cell - a substantially more
`
`complex undertaking - could have been predictably achieved in April 1983. See, ~. See id. at
`~~5-8, 50. 4
`
`Neither Moore nor Kaplan would have changed the expectations of the person of
`
`ordinary skill when considered with the other references. Neither includes experimental results
`
`that would counter what Axel, Rice, Ochi and Oi show, and each specifically directs the person
`
`of ordinary skill to produce heavy and light chain polypeptides in separate host cell cultures.
`See, ~. McKnight 2nd Dec. ~~ 12-16.5 Similarly, Dallas would not have altered the
`expectations of a person of ordinary skill in the art attempting to achieve the '415 patented
`
`invention because of a person of ordinary skill would not find that its teachings would answer
`
`questions raised by the other publications or provide guidance relevant to production of
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`eukaryotic proteins. See,~. McKnight 2nd Dec.~~ 39-40, 42-47; McKnight 1st Dec.~~ 99-
`
`101; Harris 2nd Dec.~~ 72-76; Botchan Dec.~~ 79-82. Moreover, Dallas reports unpredictable
`
`results in far simpler experiments involving E. coli gene expression. See, ~. McKnight 2nd
`
`Dec. ~ 41; Harris 2nd Dec. ~ 77.
`
`Deacon and Valle 1981 also would not have changed the reasonable expectations of a
`
`person of ordinary skill in April 1983 about predictably achieving the '415 invention as a whole.
`
`These references do not describe experiments that involve successful transformation, correct
`
`transcription of foreign DNA, and successful translation ofmRNA in the transformed host cells.
`
`Moreover, as Dr. Rice explained, using the techniques described in the Rice paper, he attempted to introduce
`and express single immunoglobulin genes into lymphoid cell lines other than those described in the Rice paper,
`and in most of the experiments he could not produce stable transfectants. See Rice I st Dec.~ 14.
`
`See also Harris 1st Dec.~~ 22-28, 57-59,62-63, 80-86; Botchan Dec.~~ 63-66,97-103.
`
`See also McKnight I st Dec. ~~ 14-18, 26-39, 92-96; Harris 2nd Dec.~~ 68-70; Botch an Dec. ~~ 38, 75-77;
`Altman Dec. ~ 15
`
`REPLY
`
`6 JUNE 2008- PAGE 9
`
`Sanofi/Regeneron Ex. 1 023, pg 676
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`Merck Ex. 1023, pg 702
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`
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I 0231
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`See,~. McKnight 2nd Dec.~~ 51-54; Harris 2nd Dec.~~ 91-97; Botchan Dec.~~ 86-94;
`
`Colman Dec.~~ 15, 30, 32, 36.
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`3.
`
`There is Substantial Evidence of Secondary Indicia of Non(cid:173)
`Obviousness of the '415 Claimed Inventions
`
`As Dr. Walton explains, the '415 patent has been extensively licensed to third parties for
`
`production of antibodies according to its claimed methods, including companies that have also
`
`licensed the Axel patent. He analyzes and explains the significance of the substantial royalty
`
`payments for these licenses. He observes that payments made under '415 licenses are
`
`independent of payments made for licenses under the '567 patent. Walton Dec.~~ 25-27. The
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`licensing of the '415 patent by many sophisticated biotechnology and pharmaceutical companies
`
`shows recognition of the merits of the '415 patent claims independent of the '567 patent claims.
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`I d. The royalty payments made by licensees attributable only to the '415 patent over many years
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`also show commercial success of the '415 patented inventions, and that this is independent of the
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`commercial success ofthe '567 patent. Walton Dec. 1~ 34-37,44-46.
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`D.
`
`Detailed Response to the Rejections
`
`Obviousness-type double patenting analyses are made using the same obviousness
`
`framework required by 35 U.S.C. § 103, except that the claim ofthe earlier patent is used as the
`reference point and not as prior art. See,~. M.P.E.P. § 804(II)(B)(1). 6 Obviousness
`determinations, in tum, are made on the basis of factual determinations pursuant to Graham v.
`John Deere Co., 383 U.S. 1, 148 U.S.P.Q. 459 (1966). 7 See KSR Int'l Co. v. Teleflex Inc., 127
`
`S.Ct. 1727, 1734, 82 U.S.P.Q.2d 1385, 1391 (2007) ("If a court, or patent examiner, conducts
`
`this [Graham] analysis and concludes the claimed subject matter was obvious, the claim is
`
`invalid under§ 103.").
`
`6
`
`See also General Foods Com. v. Studiengesellschaft Kohle mbH, 972 F.2d 1272, 1281, 23 U.S.P.Q.2d 1839,
`1846 (Fed. Cir. 1992); In re Longi. 759 F.2d 887, 892, 225 U.S.P.Q. 645, 648 (Fed. Cir. 1985).
`
`The distinctions between the claims, the teachings of the prior art, the level of ordinary skill in the art, and
`secondary evidence of non-obviousness are all required factual determinations. See Studiengesellschaft Kahle
`mbH v. Northern Petrochemical Co., 784 F.2d 351,355,228 U.S.P.Q. 837, 840 (Fed. Cir. 1986).
`
`REPLY
`
`6 JUNE 2008- PAGE 10
`
`Sanofi/Regeneron Ex. 1 023, pg 677
`
`Merck Ex. 1023, pg 703
`
`
`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, I 0231
`
`In KSR, the Court emphasized the important role that predictability in the field of the
`invention plays in an obviousness determination. 8 One must consider whether uncertainty or
`
`unpredictability in the field of the invention would have led a person of ordinary skill in the art to
`
`conclude that a proposed invention was not obvious, even if there is some general suggestion or
`
`desire to attempt to produce the invention. KSR, 127 S.Ct. at 1731, 82 U.S.P.Q.2d at 1396 ("a
`
`court must ask whether the improvement is more than the predictable use of prior art elements");
`
`See also M.P.E.P. § 2145(X)(B); In re Vaeck, 947 F.2d 488,495,20 U.S.P.Q.2d 1438, 1444
`
`(Fed. Cir. 1991). And where the path taken by the patent owner was contrary to what was
`
`suggested in the prior art (~, because it was believed the patented result could not be
`
`predictably achieved), that prior art can be said to teach away from the invention. Where this
`
`occurs, the invention is less likely to be obvious. See KSR, 127 S.Ct. at 1739-40, 82 U.S.P.Q.2d
`
`at 1395 (noting the principle that "when the prior art teaches away from a combination, that
`
`combination is more likely to be nonobvious").
`
`Indeed, it is well settled law that "[a] reference may be said to teach away when a person
`
`of ordinary skill, upon reading the reference, would be discouraged from following the path set
`
`out in the reference, or would be led in a direction divergent from the path that was taken by the
`
`applicant." In re ICON Health and Fitness, Inc., 496 F.3d 1374, 1381; 83 U.S.P.Q.2d 1746,
`
`1751 (Fed. Cir. 2007) (quoting In re Gurley, 27 F.3d 551, 553; 31 U.S.P.Q.2d 1130, 1131
`
`(Fed.Cir. 1994)). (emphasis added) See also Takeda Chern. Indus. v. Alphapharm Pty, Ltd., 492
`
`F.3d 1350, 1358-1359, 83 U.S.P.Q.2d 1169, 1175-76 (Fed. Cir. 2007) (affirming the district
`
`court's finding of nonobviousness based, in part, on a finding that the prior art taught away from
`
`the compound selected by patentee); In re Omeprazole Patent Litigation, 490 F. Supp. 2d 381,
`
`531 (S.D.N.Y. 2007) (finding nonobviousness, in part based on conclusion that "[b]ecause the
`
`goals of these [prior art] patents and the claimed inventions diverge, they teach away .... ").
`
`Owners submit that this is precisely what is shown by the cited references and the evidence of
`
`record in this case.
`
`Predictability in the result of assembling "known" components was a critical factor in KSR. See,~. KSR,
`127 S.Ct. at 1742; 82 U.S.P.Q.2d at 1397 ("When there is a design need or market pressure to solve a problem
`and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to
`pursue the known options within his or her technical grasp." (emphasis added)). Central to the KSR holding
`was the determination that there was no doubt that the combination would work as expected, and that nothing
`taught away from the combination. KSR, 127 S.Ct. at 1744, 82 U.S.P.Q.2d at 1399.
`
`REPLY
`
`6 JUNE 2008- PAGE II
`
`Sanofi/Regeneron Ex. 1 023, pg 678
`
`Merck Ex. 1023, pg 704
`
`
`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`As explained below, the substantial evidence of record establishes that:
`
`(i)
`
`(ii)
`
`the teachings of the cited references collectively teach away from the '415
`claimed inventions because they direct the person of ordinary skill to not produce
`more than one immunoglobulin polypeptide at a time in a recombinant host cell;
`
`a person of ordinary skill would not have believed recombinant production of two
`different immunoglobulin polypeptides in a single transformed host cell could
`have been predictably achieved in April 1983 based on the methodologies and
`results described in the ci~ed references and the general knowledge and
`experience that person would have had at that time; and
`
`(iii)
`
`substantial evidence of