`
`Attorney's Docket No. 223 3 8-1023 0
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`Patent
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`Control Nos.:
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`90/007,542
`90/007,3595
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`Group Art Unit:
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`3991
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`Confirmation Nos.:
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`7585 (’542)
`6447 (’859)
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`Examiner:
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`B.M. Celsa
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`Filed:
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`13 May 2005
`23 December 2005
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`(’542)
`(’859)
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`Patent Owner:
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`Genentech, Inc. and
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`City of Hope
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`For:
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`Merged Reexaminations of U.S. Patent No. 6,331,415 (Cabilly et al.)
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`RESPONSE UNDER 37 C.F.R. § l.550(b[
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`Mail Stop Ex Parte Reexam
`COMMISSIONER FOR PATENTS
`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`Sir:
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`This communication timely responds to the final Office action mailed on February 25,
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`2008. By petition granted on March 19, 2008, the original response date of April 25, 2008 was
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`extended until J une 6, 2008.
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`Patent Owners (“Owners”) respectfully request reconsideration of the claims in view of
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`the following remarks.
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`Genzyme Ex. 1028, pg 781
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, I023l
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`TABLE OF CONTENTS
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`I.
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`........................... ..3
`PRELIMINARY MATTERS ..............................................................................................
`A.
`INFORMATION DISCLOSURE STATEMENT ....................................................................................................... ..3
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`B.
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`INTERVIEW SUMMARY .................................................................................. ..
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`STATUS OF LITIGATION INVOLVING THE ’4 I 5 PATENT .................................................................................. ..3
`C.
`D. ADDITIONAL EVIDENCE PROVIDED WITH THIS RESPONSE .............................................................................. ..3
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`II. RESPONSE TO REJECTIONS........................................................................................................................ ..4
`A. WITHDRAWN REJECTIONS ............................................................................................................................. ..4
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`SUMMARY OF THE REJECTIONS ...................................................................................................................... .. 5
`B.
`C. BRIEF SUMMARY OF WHY THE ’415 CLAIMS ARE NOT OBVIOUS FROM THE ’567 CLAIMS
`AND IN VIEw OF THE PRIOR ART .................................................................................................................... .. 5
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`2.
`
`I.
`
`The Cited Art Teaches Awayfrom Expression ofHeavy and Light Chain Polypeptides
`in a Single Transformed Host Cell......................................................................................................... .. 6
`A Person ofOrdinary Skill Would Not Have Viewed the Cited References as
`Making Achievement ofthe '4 I 5 Inventions Predictable....................................................................... .. 8
`There is Substantial Evidence ofSecondary lndicia ofNon-Obviousness ofthe '4 I 5 Claimed
`Inventions ............................................................................................................................................. .. I 0
`DETAILED RESPONSE TO THE REJECTIONS ................................................................................................... .. 10
`
`I.
`
`The ‘567 Patent Claims Do Not Suggest Producing Heavy and Light Chains in
`One Transformed Host Cell ................................................................................................................. .. I2
`2. Co-Transformation ofHost Cells with Two DNA Sequences Is Not Equivalent
`to Co-Expression of Those Sequences.................................................................................................. .. I 5
`(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”.... I6
`(c) Production OfHeaVy and Light Chains in One Host Cell is Not Required by Axel ....................................... .. I9
`(d) Rice, Ochi and Oi Reinforce Unpredictability Shown III Axel ...................................................................... ..22
`The Cited References Teach Away from Producing Two Immunoglobulin Polypeptides in One
`Transformed Host Cell......................................................................................................................... I. 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 Eukaryotie 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 I983 ............................................................................................................................................. ..27
`(e) Dallas Would Not Have Altered the “One Protein-One Host Cell” Mindset Established
`by the Other Cited References ....................................................................................................................... ..28
`The Cited References and General Knowledge in the Art Would Not Have Made the
`'4I5 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 Unpredictability ..................... ..30
`(b) The Predictability of Achieving the Entire ’4l5 Patented Invention Must Be Considered ............................ ..32
`(c) A Hypothetical Doubly-Transforrned B-Cell Cannot Establish Reasonable
`Expectations Relevant to the ‘M5 Claims ..................................................................................................... ..3S
`(d) The Xcnopus Oocyte Microinjection Experiments Do Not Establish that the
`’4l5 Claimed Invention Could Have Been Predictably Achieved in April 1983 ........................................... ..38
`STRONG EVIDENCE OF SECONDARY CONSIDERATIONS SUPPORTS THE CONCLUSION THAT THE ’4 I 5 PATENT
`CLAIMS ARE NOT OBVIOUS ........ ..
`....40
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`E.
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`STATUS OF DEPENDENT CLAIMS .................................................................................................................. ..42
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`Ill. CONCLUSION ................................................................................................................................................. ..42
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`ATTACHMENT A: OWNERS’ SUMMARY OF INTERVIEW HELD APRIL 2, 2008 ................................. ..44
`ATTACHMENT B: EXCERPTS FROM FILE HISTORIES CITED IN THE RESPONSE .......................... ..46
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`REPLY
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`6 JUNE 2008 - PAGE 2
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`Genzyme Ex. 1028, pg 782
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, 1023]
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`REMARKS
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`Preliminary Matters
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`A.
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`Information Disclosure Statement
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`Owners thank the Office for the indication that all materials previously submitted to the
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`Office have been fully considered. Owners respectfully request consideration of materials
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`provided in the accompanying supplemental information disclosure statement.
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`B.
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`Interview Summary
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`Owners thank Examiners Celsa, Jones and Padmashri for the courtesy of an interview
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`held on April 2, 2008. Owners’ summary of the interview is provided in Attachment A to this
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`response, in compliance with 37 C.F.R. § 1.560(b).
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`C.
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`Status of Litigation Involving the ’4l5 Patent
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`Owners have previously indicated that US. Patent No. 6,331,415 (“the ’41 5 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
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`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 ’41 5 patent is invalid and not
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`enforceable. A copy of the complaint is provided in the accompanying information disclosure
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`statement.
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`D.
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`Additional Evidence Provided with this Response
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`Owners submit and request favorable consideration of this response and the
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`accompanying declarations under 37 C.F.R. § 1.132 of Dr. Steven McKnight and Dr. Finton
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`Walton. Owners submit the declaration of Dr. McKnight in response to new scientific findings
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`of the Office in the final Office action (“Final Action”). Owners submit the declaration of Dr.
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`Walton in response to the Office’s observations about the legal significance of licensing of ALI
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`(U.S. Patent No. 4,399,216), and in support of the non-obviousness of the ’41 5 patent claims.
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`Owners submit that “good and sufficient reasons why the affidavit or other evidence is
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`necessary and was not earlier presented” exist pursuant to 37 C.F.R. § 1.116. Specifically, the
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`REPLY
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`6 JUNE 2008 - PAGE 3
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`Genzyme Ex. 1028, pg 783
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, 1023]
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`Office makes new factual determinations, and advances new or changed theories to support
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`rejections in the Final Action, particularly at pages 21-46. Examples include: use ofi (U.S.
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`Patent No. 5,840,545) to support findings of obviousness of co-expression despite a significantly
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`changed interpretation of the M1 prior art disclosure (Final Action at 5, 15-16); reliance on
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`Ax_d as teaching production of “functional proteins” (Final Action at 30); reliance on El (Ochi
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`§t_al.,J 302: 340-42 (1983)) and Q (Oi §t_al., Proc. Nat’l. Acad. Sci. (USA) 80: 825-29
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`(1983)) as providing additional motivation to co-transform host cells (Final Action at 38); use of
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`Elias (PCT Publication No. WO 82/03088) to modify the teachings in Mqfl (Final Action at
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`40); and references to licensing of Axel (Final Action at 46). Owners could not have reasonably
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`predicted that the Office would make these new or changed findings, or use them to support the
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`rejections set forth in the Final Action. The declarations of Drs. McKnight and Walton respond
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`to these new issues. Owners submit that presentation of the present declaration evidence is thus
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`appropriate under 37 C.F.R. § 1.116.
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`II.
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`Response to Rejections
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`A.
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`Withdrawn Rejections
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`Owners appreciate withdrawal of rejections under 35 U.S.C. §§ 102 and 103, and for
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`double patenting, based on Moore, alone or in combination with the ’567 patent (U.S. Patent No.
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`4,816,567), Axel and Accolla (Accolla et al., Proc. Nat’l. Acad. Sci. (LISA) 77(1): 563-66
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`(1980)). The Office indicates that Moore is entitled to a § 102(e) effective date for “single host
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`expression of variable light and heavy chain for producing single-chain antibody” only as of “the
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`June 5 1995 date since the original 06/358,414 specification and claims 1-25 only disclose the
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`separate expression of the heavy and light chain antibody fragment in different host cells .
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`.
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`. .”
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`Final Action at 5 (emphasis original). The Office also indicates that Age does not have
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`support for “single host expression of variable light and heavy chains .
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`. .” prior to June 5, 1995.]
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`E. at 6.
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`At page 16 of the Final Action, the Office states that Moore “discloses a method of making ‘an
`immunologically functional fiagment’ comprising independently expressing in a host cell variable @ heavy
`light chain domains .
`.
`. 3’ This appears to be an inadvertent error in view ofthe Office’s conclusions noted
`above.
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`REPLY
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`6 JUNE 2008 - PAGE 4
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`Genzyme Ex. 1028, pg 784
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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, 1023]
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`B.
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`Summary of the Rejections
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`The Office rejects claims 1-36 for obviousness-type double patenting based on the ’567
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`patent, in view of Axel, Rice (Rice et al., Proc. Nat’l. Acad. Sci. (USA) 79: 7862 (1982)) and
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`Egglg (European Patent No. 0044722), further in view of Dallas, and further in view of Qgflm
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`(Deacon gt_al., Biochem. Soc. Trans. 4: 818-20 (1976)), Valle 1981 (Valle gal, Nature 291:
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`338-40 (1981)), or Ochi, alone or further in View ofL. Dependent claims 10 and 27-32 are
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`rejected when these references are further considered with fidgg (U.S. Patent No. 4,511,502),
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`and dependent claim 22 is further rejected in view of _Ac_<flla. 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.
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`The Office bases the final rejection on two conclusions, namely: (i) “One of ordinary
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`skill in the art would have been motivated to express, in a single host, light and heavy
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`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
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`Action at 14). Owners respectfully request withdrawal of the rejections because the Off1ce’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.
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`C.
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`Brief Summary of Why the ’415 Claims Are Not Obvious From the ’567
`Claims and in View of the Prior Art
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`Owners provide with this response a second declaration by Dr. Steven McKnight
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`responding to issues raised in the Final Action. Dr. McKnight accurately presents the views of a
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`person of ordinary skill in the art in April 1983, based on his relevant experience and training
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`from that time. He explains that, unlike the ’567 claims, the ’4l 5 patent claims require three
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`separate steps: (i) a host cell must be transformed with immunoglobulin heavy chain an_d light
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`chain DNA sequences; (ii) the DNA sequences must be independently expressed (transcribed
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`and translated) by the host cell to produce polypeptides; and (iii) the polypeptides must be
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`6 JUNE 2008 - PAGE 5
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`Genzyme Ex. 1028, pg 785
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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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`assembled to form an immunoglobulin molecule or an immunologically functional
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`immunoglobulin fragment (“fragment”). Effi McKnight 2nd Dec. 111] 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
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`of the patents identifies distinct benefits of producing immunoglobulin molecules and fragments
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`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 ’4l 5 patented methods. fig
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`ggu, ’415 patent, col. 14, lns. 20-49; col. 12, lns. 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
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`applications. fie, e.
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`., McKnight 2nd Dec. 1] 15; Riggs Dec. 1111 19-29.
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`The evidence of record demonstrates that the material distinctions between the ’41 5 and
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`’567 patent claims would not have been obvious to a person of ordinary skill in the art in April
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`1983. In particular, this evidence establishes that:
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`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;
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`a person of ordinary skill would not have believed that what was required by the
`’41 5 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
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`-
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`secondary considerations support the non-obviousness of the ’415 claims.
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`These findings establish that the ’4l5 claims would not have been considered obvious in April
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`1983 based on the ’567 claims in view of the cited art.
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`The Cited Art Teaches Away from Expression of Heavy and Light
`Chain Polypeptides in a Single Transformed Host Cell
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`Dr. McKnight explains that the cited references reflect the prevailing mind-set in April
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`1983 that only one eukaryotic polypeptide of interest should be produced in a recombinant host
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`cell. _S_e§ McKnight 2nd Dec.1111 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
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`a host cell in April 1983. _@ i_d. at 1111 8, 21-23, 30-34. He also explains that the prevailing
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`mindset would have led a person of ordinary skill to break down a complex project, such as
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`REPLY
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`6 JUNE 2008 - PAGE 6
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`Genzyme Ex. 1028, pg 786
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`REEXAM CONTROL NOS. 90/007,542, 90/007,859
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`ATTORNEY DOCKET NOS. 22338-10230, lO23l
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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). S_e§ ;g. at 1111 7-13.
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`Dr. McKnight explains that this mindset is reflected in Axel. He explains that a person of
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`ordinary skill in the art would have necessarily read the ALI DNA I + DNA 11 scheme as
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`suggesting production of only a single antibody polypeptide at a time in a co-transformed host.
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`E Q. at. 111] 19, 27. Moreover, as he explains, while Axel shows successful cotransformation
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`with a “DNA I” (g, a B-globin gene) and a “DNA II” (a marker gene such as thymidine
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`kinase), it shows unsuccessful coexpression of both sequences. E Q. at 111] 20-22. Specifically,
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`Q31 reports incorrect transcription of the DNA I sequence and no production or recovery of the
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`polypeptide encoded by it. S_e§ Q. at 11 21. Axel thus does not show production of two
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`“functional” polypeptides in a co-transformed cell.
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`The Axel prosecution history clearly supports Dr. McKnight’s analysis.
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`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
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`that deleted any reference to expression of a protein encoded by a “DNA I.” @ Application
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`Serial No. 06/124,513; Paper No. 9, dated February 8, 1982 at p. 2, 1[ 12; Paper No. 15, dated
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`January 12, 1983 at pp. 2-3, 6; and Paper No. 17, dated February 7, 1983.
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`Dr. McKnight explains that Qe, Ochi, and Qi reinforce the unpredictability shown in
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`Axel. §fi McKnight 2nd Dec. 1111 30-34. He points out that the three references describe
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`experiments where lymphoid cells were transformed with, and expressed, only a single foreign
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`immunoglobulin light chain gene. He explains how a person of skill would have interpreted the
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`experimental results reported in these papers, and, in particular, why such a person would have
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`found them to be reporting substantial unpredictability. E, g, i_d. at 111] 31-34; He also
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`explains why none of the publications describes or suggests expressing two different foreign
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`immunoglobulin genes in a single transformed host cell. E i_d_. at 11] 5, 34.
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`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
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`the approach of the ’4l5 patent. He explains that, instead, each reference expressly describes a
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`REPLY
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`6 JUNE 2008 - PAGE 7
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`Genzyme Ex. 1028, pg 787
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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. E Q. at 1111 12, 13.
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`Dr. McKnight then explains why Di does not suggest modifying the ’567 claims or
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`the teachings of other cited art to yield the ’415 claimed invention. Sfi Q. at 1111 38-48. He
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`explains that Dallas describes experiments where l_3_. @ genes encoding simple L c_0fl cell
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`surface proteins are used to transform an Q fll host cell. E Q. at 1111 39-41. He explains that a
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`person of ordinary skill would have evaluated Dallas in conjunction with what is reported in the
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`other cited references, in particular, the unpredictability reported in ALI, Q, Ochi and Q1, and
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`the express teachings ofEap£1_n andJ to express heavy and light chains polypeptides in
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`separate host cells. 53 Q. at 1111 38-39, 47-48. He also explains why the Dallas L gcfi teachings
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`would not be considered relevant to production of multimeric eukaryotic proteins. fie Q. at 1111
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`42-47. Indeed, Owners note that during examination of the U.S. counterpart to J, the Office
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`limited the Dallas claims to the specific transformed L go_li host cells and Q go_li genes described
`in the Dallas examples.2 As Dr. McKnight concludes after reading Dallas with the teachings of
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`the other references, “a person of ordinary skill would have simply avoided all these problems
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`and uncertainties by producing the heavy and light immunoglobulin chains in separate bacterial
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`host cell cultures.” Q. at 11 48.
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`A Person of Ordinary Skill Would Not Have Viewed the Cited
`References as Making Achievement of the ’415 Inventions Predictable
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`A person of ordinary skill in the art would not have had a reasonable basis for believing
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`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
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`knowledge in the art.
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`As Dr. McKnight explains, Axel, Rice, Ochi, and _O_i 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 E foreign polypeptide. Axel reports experimental
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`results showing only unsuccessful efforts to express a single DNA 1 sequence in a co-
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`2
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`gg file wrapper of U.S. Patent No. 5,137,721 (§_.g,, Office action of October 28, 1982 (Paper No. 4) at 4; Office
`action oflune 5, 1984 (Paper No. 11) at 3-4; Office action ofNovember 17, 1986 (Paper No. 17) at 3).
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`REPLY
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`6 JUNE 2008 - PAGE 8
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`Genzyme Ex. 1028, pg 788
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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. §g=, McKnight 2nd Dec. 111] 21-22. Similarly, @, Ochi, and
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`Q report significant unpredictability in achieving successfiil expression of a single light chain
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`immunoglobulin gene in various types of lymphoid cells.3 McKnight 2nd Dec. 111] 30-34. These
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`reports of inconsistent and unpredictable experimental results would not have led a person of
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`ordinary skill to believe that independent expression of DNA sequences encoding heavy @
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`light immunoglobulin chain polypeptides in E transformed host cell — a substantially more
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`complex undertaking — could have been predictably achieved in April 1983. fig, gg_., §e_e Q. at
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`111] 5-8, 50.4
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`NeitherM nor Qplfi would have changed the expectations of the person of
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`ordinary skill when considered with the other references. Neither includes experimental results
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`that would counter what ALI, Rice, Ochi and Qi show, and each specifically directs the person
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`of ordinary skill to produce heavy and light chain polypeptides in gym host cell cultures.
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`§e_e_, gg,, McKnight 2nd Dec. 111] 12-165 Similarly, gag; would not have altered the
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`expectations of a person of ordinary skill in the art attempting to achieve the ’4l 5 patented
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`invention because of a person of ordinary skill would not find that its teachings would answer
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`questions raised by the other publications or provide guidance relevant to production of
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`eukaryotic proteins. fig, gg, McKnight 2nd Dec. 111] 39-40, 42-47; McKnight lst Dec. 111] 99-
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`101; Harris 2nd Dec. 111] 72-76; Botchan Dec. 111] 79-82. Moreover, Dallas reports unpredictable
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`results in far simpler experiments involving E. coli gene expression. See, gg, McKnight 2nd
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`Dec. 1] 41; Harris 2nd Dec. 1] 77.
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`Deacon and Valle 1981 also would not have changed the reasonable expectations of a
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`person of ordinary skill in April 1983 about predictably achieving the ’415 invention as a whole.
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`These references do not describe experiments that involve successful transformation, correct
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`transcription of foreign DNA, and successful translation of mRNA in the transformed host cells.
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`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. fig Rice lst Dec. 1] 14.
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`See also Harris lst Dec. 111122-28, 57-59, 62-63, 80-86; Botchan Dec. 111163-66, 97-I03.
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`See also McKnight lst Dec. 111] 14-18, 26-39, 92-96; Harris 2nd Dec. 111168-70; Botchan Dec. 111] 38, 75-77;
`Altman Dec. 1] l5
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`REPLY
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`6 JUNE 2008 - PAGE 9
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`Genzyme Ex. 1028, pg 789
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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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`E, gg,, McKnight 2nd Dec. 111] 51-54; Harris 2nd Dec. 111] 91-97; Botchan Dec. 111] 86-94;
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`Colman Dec.1]1] 15,30, 32, 36.
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`There is Substantial Evidence of Secondary Indicia of Non-
`Obviousness of the ’415 Claimed Inventions
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`As Dr. Walton explains, the ’4l 5 patent has been extensively licensed to third parties for
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`production of antibodies according to its claimed methods, including companies that have also
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`licensed the Ax_e_l patent. He analyzes and explains the significance of the substantial royalty
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`payments for these licenses. He observes that payments made under ’41 5 licenses are
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`independent of payments made for licenses under the ’567 patent. Walton Dec. 111] 25-27. The
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`licensing of the ’4l5 patent by many sophisticated biotechnology and pharmaceutical companies
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`shows recognition of the merits of the ’4l 5 patent claims independent of the ’567 patent claims.
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`Q The royalty payments made by licensees attributable only to the ’41 5 patent over many years
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`also show commercial success of the ’4l 5 patented inventions, and that this is independent of the
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`commercial success of the ’567 patent. Walton Dec. 1111 34-37, 44-46.
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`D.
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`Detailed Response to the Rejections
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`Obviousness—type double patenting analyses are made using the same obviousness
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`framework required by 35 U.S.C. § 103, except that the claim of the earlier patent is used as the
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`reference point and n_ot as prior art. Sg, ggu, M.P.E.P. § 804(II)(B)(1).6 Obviousness
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`determinations, in turn, are made on the basis of factual determinations pursuant to Graham V.
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`John Deere Co., 383 U.S. 1, 148 U.S.P.Q. 459 (1966).7 $3 KSR Int’l Co. V. Teleflex Inc., 127
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`S.Ct. 1727, 1734, 82 U.S.P.Q.2d 1385, 1391 (2007) (“Ifa court, or patent examiner, conducts
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`this |Graham] analysis and concludes the claimed subject matter was obvious, the claim is
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`invalid under § 103.”).
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`See also General Foods Corp_. v. Studiengesellschafl Kohle mbH, 972 F.2d I272, 128], 23 U.S.P.Q.2d I839,
`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 ofthe prior art, the level of ordinary skill in the art, and
`secondary evidence of non-obviousness are all required factual determinations. fifi Studiengesellschafi Kohle
`mbH v. Northern Petrochemical C0,, 784 F.2d 351, 355,228 U.S.P.Q. 837, 840 (Fed. Cir. 1986).
`
`REPLY
`
`6 JUNE 2008 - PAGE 10
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`Genzyme Ex. 1028, pg 790
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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, 1023]
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`In KSR, the Court emphasized the important role that predictability in the field of the
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`invention plays in an obviousness determinations One must consider whether uncertainty or
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`unpredictability in the field of the invention would have led a person of ordinary skill in the art to
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`conclude that a proposed invention was not obvious, even if there is some general suggestion or
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`desire to attempt to produce the invention. Ki, 127 S.Ct. at 1731, 82 U.S.P.Q.2d at 1396 (“a
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`court must ask whether the improvement is more than the predictable use of prior art elements”);
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`E al_s_o M.P.E.P. § 2145(X)(B); In re Vaeck, 947 F.2d 488, 495, 20 U.S.P.Q.2d 1438, 1444
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`(Fed. Cir. 1991). And where the path taken by the patent owner was contrary to what was
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`suggested in the prior art (gg, because it was believed the patented result could not be
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`predictably achieved), that prior art can be said to teach away from the invention. Where this
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`occurs, the invention is less likely to be obvious. _S;@ E, 127 S.Ct. at 1739-40, 82 U.S.P.Q.2d
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`at 1395 (noting the principle that “when the prior art teaches away from a combination, that
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`combination is more likely to be nonobvious”).
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`Indeed, it is well settled law that “[a] reference may be said to teach away when a person
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`of ordinary skill, upon reading the reference, would be discouraged from following the path set
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`out in the reference, or would be led in a direction divergent from the path that was taken by the
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`applicant.” In re ICON Health and Fitness Inc., 496 F.3d 1374, 1381; 83 U.S.P.Q.2d 1746,
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`1751 (Fed. Cir. 2007) (quoting In re Gurley, 27 F.3d 551, 553; 31 U.S.P.Q.2d 1130, 1131
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`(Fed.Cir. 1994)). (emphasis added) 3 fig Takeda Chem. Indus. v. Al ha hann Pt Ltd., 492
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`F.3d 1350, 1358-1359, 83 U.S.P.Q.2d 1169, 1175-76 (Fed. Cir. 2007) (affirrning the district
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`court’s finding of nonobviousness based, in part, on a finding that the prior art taught away from
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`the compound selected by patentee); In re Omeprazole Patent Litigation, 490 F. Supp. 2d 381,
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`531 (S.D.N.Y. 2007) (finding nonobviousness, in part based on conclusion that “[b]ecause the
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`goals of these [prior art] patents and the claimed inventions diverge, they teach away .
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`.
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`. .”).
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`Owners submit that this is precisely what is shown by the cited references and the evidence of
`record in this case.
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`Predictability in the result of assembling “known” components was a critical factor in KSR. S_t§, ggp, 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 11
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`Genzyme Ex. 1028, pg 791
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`
`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 1023!
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`As explained below, the substantial evidence of record establishes that:
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`(i)
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`the teachings of the cited references collectively teach away from the ’415
`claimed inventions because they direct the person of ordinary skill to n_ot produce
`more than one immunoglobulin polypeptide at a time in a recombinant host cell;
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`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 cited references and the general knowledge and
`experience that person would have had at that time; and
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`(iii)
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`substantial evidence of secondary indicia of nonobviousness exists for the ’4l 5
`patent claims.
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`As a result, a person of ordinary skill in the art would not have considered the ’4l 5 claims to
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`have been obvious over the ’567 claims in conjunction with the cited references.
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`The ’567 Patent Claims Do Not Suggest Producing Heavy and Light
`Chains in One Transformed Host Cell
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`The claims of the “reference” patent are the starting point of an obviousness-type double
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`patenting analysis.
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`In this case, the ’567 claims require production of only one chimeric heavy
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`or light chain polypeptide in a transformed host cell. The ’41 5 patent, by contrast, requires
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`production of an immunoglobulin molecule or fragment by a process in which DNA sequences
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`encoding both the heavy and light chain polypeptides are independently expressed in one host
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`cell. S_e§, gg, McKnight 2nd Dec. 111] 7, 17-34 ; Harris 2nd Dec. 111] 21-33; Botchan Dec. 111] 62,
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`67, 69-72; s§_e al