IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Attorney's Docket No. 22338-10230
`
`Patent
`
`Control Nos.:
`
`90/007,542
`90/007,859Z
`
`Group Art Unit:
`
`3991
`
`Confirmation Nos.:
`
`7585 (’542)
`6447 (’859)
`
`Examiner:
`
`B.M. Celsa
`
`Filed:
`
`13 May 2005
`23 December 2005
`
`(’542)
`(’859)
`
`Patent Owner:
`
`Genentech, Inc. and
`City of Hope
`
`For:
`
`Merged Reexaminations of U.S. Patent No. 6,331,415 (Cabilly et al.)
`
`RESPONSE UNDER 37 C.F.R. § l.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
`
`extended until June 6, 2008.
`
`Patent Owners (“Owners”) respectfully request reconsideration of the claims in view of
`
`the following remarks.
`
`
`
`Genzyme Ex. 1023, pg 671
`
`Genzyme Ex. 1023, pg 671
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`TABLE OF CONTENTS
`
`1.
`
`PRELIMINARY MATTERS ..............................................................................................
`
`........................... ..3
`
`A.
`
`B.
`
`C.
`
`INFORMATION DISCLOSURE STATEMENT ....................................................................................................... ..3
`
`INTERVIEW SUMMARY ................................................................................................................................... ..3
`
`STATUS OF LITIGATION INVOLVING THE ,4 I 5 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`A. WITHDRAWN REJECTIONS .............................................................................................................................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.
`
`2.
`
`3.
`
`The Cited Art Teaches A way from Expression ofHeavy and Light Chain Polypeptides
`in a Single Transformed Host Cell......................................................................................................... .. 6
`
`A Person of Ordinary Skill Would Not Have Viewed the Cited References as
`Making Achievement ofthe ’415 Inventions Predictable....................................................................... .. 8
`
`There is Substantial Evidence ofSecondary lndicia ofNon-Obviousness ofthe '4 I 5 Claimed
`Inventions ............................................................................................................................................. .. I 0
`
`D. DETAILED RESPONSE TO THE REJECTIONS ................................................................................................... .. I0
`
`I.
`
`The '5 6 7 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.................................................................................................. .. 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 Po|ypeptides”.... I6
`(c) Production of Heavy and Light Chains in One Host Cell is Not Required by Axel ....................................... .. I9
`(d) Rice, Ochi and Oi Reinforce Unpredictability Shown in Axel ...................................................................... ..22
`
`3.
`
`The Cited References Teach Away from Producing Two lmmunoglobulin Polypeptides in One
`Transformed Host Cell......................................................................................................................... .. 23
`(a) The Prevailing Mindset in April I983 Was Production of One Eukaryotic Polypeptide at a Time in a
`Transformed Host Cell .................................................................................................................................. ..24
`
`4.
`
`(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 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
`'4 I 5 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 ’4l 5 Patented Invention Must Be Considered ............................ ..32
`(c) A Hypothetical Doubly-Transformed B-Cell Cannot Establish Reasonable
`Expectations Relevant to the '4l5 Claims ..................................................................................................... ..35
`(d) The Xenopus 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
`
`D.
`
`E.
`
`STATUS OF DEPENDENT CLAIMS .................................................................................................................. ..42
`
`III. CONCLUSION ................................................................................................................................................. ..42
`
`ATTACHMENT A: OWNERS’ SUMMARY OF INTERVIEW HELD APRIL 2, 2008 ................................. ..44
`
`ATTACHMENT B: EXCERPTS FROM FILE HISTORIES CITED IN THE RESPONSE .......................... ..46
`
`REPLY
`
`6 JUNE 2008 — PAGE 2
`
`Genzyme Ex. 1023, pg 672
`
`
`Genzyme Ex. 1023, pg 672
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 1023]
`
`REMARKS
`
`1.
`
`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. 6,331,415 (“the ’415 patent”) has
`
`been the subject of litigation in the Central District of California. Owners now report that the
`
`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.
`
`Owners also report that on May 30, 2008, an action was filed in the Central District of California
`
`by Centocor seeking, inter alia, a declaratory judgment that the ’41 5 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 ’4l 5 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
`
`Genzyme Ex. 1023, pg 673
`
`
`
`Genzyme Ex. 1023, pg 673
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`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
`
`3.16:1 as teaching production of “functional proteins” (Final Action at 30); reliance on E1 (Ochi
`
`§t_al., Natgrg 302: 340-42 (1983)) and Qi (Oi egg, Proc. Nat’l. Acad. Sci. 1USA)80: 825-29
`
`(1983)) as providing additional motivation to co-transform host cells (Final Action at 38); use of
`
`figs (PCT Publication No. WO 82/03088) to modify the teachings in Mqg (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.F.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 § l02(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
`
`E. 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 @ heavy
`light chain domains .
`.
`. .” This appears to be an inadvertent error in view ofthe Office’s conclusions noted
`above.
`
`REPLY
`
`6 JUNE 2008 - PAGE 4
`
`Genzyme Ex. 1023, pg 674
`
`
`
`Genzyme Ex. 1023, pg 674
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`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 La], Proc. Nat’l. Acad. Sci. (USA) 79: 7862 (1982)) and
`
`Iggplfiln (European Patent No. 0044722), further in view of Dallas, and further in view of Qgflcm
`
`(Deacon gt_al., Biochem. Soc. Trans. 4: 818-20 (1976)), Valle 1981 (Valle etal, Nature 291:
`
`338-40 (1981)), or Ochi, alone or further in view of Moore. 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
`
`its rejections at pages 10 to 20 of the Final Action. At pages 21 to 46, the Office addresses issues
`
`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]
`
`patented invention in light of the prior art” (Final Action at 12); and (ii) “The prior art provides
`
`further motivation to make active antibody with a reasonable expectation of success” (Final
`
`Action at 14). Owners respectfully request withdrawal of the rejections because the Off1ce’s
`
`conclusions are inconsistent with the collective teachings and suggestions of the cited references,
`
`and with the beliefs and expectations of the person of ordinary skill in the art in early April 1983.
`
`Owners respectfully traverse the rejections set forth in the Final Action, and request
`
`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 ’41 5 patent claims require three
`
`separate steps: (i) a host cell must be transformed with immunoglobulin heavy chain an_d light
`
`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 2003 — PAGE 5
`
`Genzyme Ex. 1023, pg 675
`
`
`
`Genzyme Ex. 1023, pg 675
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`assembled to form an immunoglobulin molecule or an immunologically functional
`
`immunoglobulin fragment (“fragment”). _S_e§ McKnight 2nd Dec. 111] 4-5.
`
`The inventions of the ’41 5 and ’567 patents have distinct utilities and applications linked
`
`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
`
`fragments by expressing both chains in one host cell pursuant to the ’41 5 patented methods. S_eg
`
`ggu, ’415 patent, col. 14, lns. 20-49; col. 12, lns. 50-56. The evidence also establishes that the
`
`products made by each patented method are distinct, and have independent benefits and
`
`applications. S_e_e, e_.g,, McKnight 2nd Dec. 1] 15; Riggs Dec. 1111 19-29.
`
`The evidence of record demonstrates that the material distinctions between the ’41 5 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
`’4l 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
`
`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. _S_eg McKnight 2nd Dec. 111] 7-9. As he explains, the cited references all show the
`
`unpredictability of successfully expressing and recovering even one eukaryotic polypeptide from
`
`a host cell in April 1983.
`
`_SJe_e i_d. at 111] 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
`
`Genzyme Ex. 1023, pg 676
`
`
`
`Genzyme Ex. 1023, pg 676
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`production of a multimeric eukaryotic protein, into more manageable steps (e. g., produce each
`
`constituent polypeptide of the multimer in a separate host cell, as was proposed in Moore and
`
`Kaplang. fig i_c_l. at 1111 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.
`
`E Q. at. 111] 19, 27. Moreover, as he explains, while Axel shows successful cotransforrnation
`
`with a “DNA I” (gg_., a B-globin gene) and a “DNA II” (a marker gene such as thymidine
`
`kinase), it shows unsuccessful coexpression of both sequences. E Q. at 1111 20-22. Specifically,
`
`Qtgl reports incorrect transcription of the DNA I sequence and no production or recovery of the
`
`polypeptide encoded by it. S_e<_: Q. at 11 21. Axel thus does not show production of two
`
`“functional” polypeptides in a co-transformed cell.
`
`The Axel prosecution history clearly supports Dr. McKnight’s analysis. In particular, the
`
`Axel inventors conceded that the disclosure in their patent did not describe production and
`
`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 I.” E Application
`
`Serial No. 06/124,513; Paper No. 9, dated February 8, 1982 at p. 2, 1] 12; Paper No. 15, dated
`
`January 12, 1983 at pp. 2-3, 6; and Paper No. 17, dated February 7, 1983.
`
`Dr. McKnight explains that Rice, Ochi, and Qi reinforce the unpredictability shown in
`
`Axel. _Sg§ McKnight 2nd Dec. 1111 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. E, gg_., id, at 111] 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. E i_cl_. at 111] 5, 34.
`
`Dr. McKnight also discusses Moore and Kaplan, and demonstrates that these references
`
`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
`
`REPLY
`
`6 JUNE 2003 - PAGE 7
`
`Genzyme Ex. 1023, pg 677
`
`
`
`Genzyme Ex. 1023, pg 677
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`plan for producing an immunoglobulin molecule or fragment using heavy and light chain
`
`polypeptides that have been produced in separate host cells. fig Q. at 111] 12, 13.
`
`Dr. McKnight then explains why Dallas does not suggest modifying the ’567 claims or
`
`the teachings of other cited art to yield the ’4l5 claimed invention. Sfi Q. at 111] 38-48. He
`
`explains that Dallas describes experiments where L £1 genes encoding simple E C_0fl cell
`
`surface proteins are used to transform an Q Q1 host cell. E Q. at 1111 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 Qi, and
`
`the express teachings of Kaplan and Moore to express heavy and light chains polypeptides in
`
`separate host cells. S3 Q. at 1111 38-39, 47-48. He also explains why the Dallas L goli teachings
`
`would not be considered relevant to production of multimeric eukaryotic proteins. fie Q. at 1111
`
`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 cili host cells and Q §o_li 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
`
`host cell cultures.” E. at 1] 48.
`
`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
`
`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 _O_i each report experimental results that
`
`cumulatively show significant unpredictability in achieving successful expression of one
`
`recombinant DNA sequence encoding E foreign polypeptide. Axel reports experimental
`
`results showing only unsuccessful efforts to express a single DNA I sequence in a co-
`
`2
`
`gg file wrapper of U.S. Patent No. 5,137,721 (c;g,, Office action of October 28, 1982 (Paper No. 4) at 4; Office
`action of June 5, 1984 (Paper No. 1 1) at 3-4; Office action ofNovember 17, 1986 (Paper No. 17) at 3).
`
`REPLY
`
`6 JUNE 2008 — PAGE 8
`
`Genzyme Ex. 1023, pg 678
`
`
`
`Genzyme Ex. 1023, pg 678
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`transformed eukaryotic host cell. fige McKnight 2nd Dec. 11] 21-22. Similarly, Rice, Ochi, and
`
`Q report significant unpredictability in achieving successful expression of a single light chain
`
`immunoglobulin gene in various types of lymphoid cells.3 McKnight 2nd Dec. 1]1] 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 m
`
`light immunoglobulin chain polypeptides in E transformed host cell — a substantially more
`
`complex undertaking — could have been predictably achieved in April 1983. fie, gg, §§ id. at
`
`111] 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 Qi show, and each specifically directs the person
`
`of ordinary skill to produce heavy and light chain polypeptides in separate host cell cultures.
`
`§e_e_, gg, McKnight 2nd Dec. 1]1] 12-16.5 Similarly, Dallas would not have altered the
`
`expectations of a person of ordinary skill in the art attempting to achieve the ’4l 5 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
`
`eukaryotic proteins. fie, ggg McKnight 2nd Dec. 1]1] 39-40, 42-47; McKnight lst Dec. 11] 99-
`
`101; Harris 2nd Dec. 11] 72-76; Botchan Dec. 11] 79-82. Moreover, Dallas reports unpredictable
`
`results in far simpler experiments involving E. coli gene expression. E, gg” McKnight 2nd
`
`Dec. 1] 41; Harris 2nd Dec. 1] 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 of mRNA 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. fig Rice lst Dec. 1] 14.
`
`4
`
`5
`
`See also Harris lst Dec. 11 22-28, 57-59, 62-63, 80-86; Botchan Dec. 1]1] 63-66, 97-103.
`
`See also McKnight lst Dec. 11] 14-18, 26-39, 92-96; Harris 2nd Dec. 11 68-70; Botchan Dec. 1]1] 38, 75-77;
`Altman Dec. 1] 15
`
`REPLY
`
`6 JUNE 2008 - PAGE 9
`
`Genzyme Ex. 1023, pg 679
`
`
`
`Genzyme Ex. 1023, pg 679
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 10231
`
`E, g, McKnight 2nd Dec. 111] 51-54; Harris 2nd Dec. 1111 91-97; Botchan Dec. 111] 86-94;
`
`Colman Dec.1]1] 15, 30, 32, 36.
`
`3.
`
`There is Substantial Evidence of Secondary Indicia of Non-
`Obviousness of the ’415 Claimed Inventions
`
`As Dr. Walton explains, the ’41 5 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 ’41 5 licenses are
`
`independent of payments made for licenses under the ’567 patent. Walton Dec. 111] 25-27. The
`
`licensing of the ’4l 5 patent by many sophisticated biotechnology and pharmaceutical companies
`
`shows recognition of the merits of the ’4l 5 patent claims independent of the ’567 patent claims.
`
`Q The royalty payments made by licensees attributable only to the ’4l 5 patent over many years
`
`also show commercial success of the ’4l 5 patented inventions, and that this is independent of the
`
`commercial success of the ’567 patent. Walton Dec. 1111 34-37, 44-46.
`
`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 of the earlier patent is used as the
`
`reference point and n_ot as prior art. SE, gg_., M.P.E.P. § 804(II)(B)(1).6 Obviousness
`
`determinations, in turn, 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 §e_e KSR Int’l Co. v. Teleflex Inc., 127
`
`S.Ct. 1727, 1734, 82 U.S.P.Q.2d 1385, 1391 (2007) (“Ifa court, or patent examiner, conducts
`
`this [glahi] analysis and concludes the claimed subject matter was obvious, the claim is
`
`invalid under § 103.”).
`
`gggflg General Foods Corp. v. Studiengesellschafi 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 ofthe prior art, the level of ordinary skill in the art, and
`secondary evidence of non-obviousness are all required factual determinations. $3 Studiengesellschafi Kohle
`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
`
`Genzyme Ex. 1023, pg 680
`
`
`
`Genzyme Ex. 1023, pg 680
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 1023]
`
`In KSR, the Court emphasized the important role that predictability in the field of the
`
`invention plays in an obviousness determinations 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. _K_S3, 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”);
`
`S_ee_ 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
`
`(Fed. Cir. 1991). And where the path taken by the patent owner was contrary to what was
`
`suggested in the prior art (gg, 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. SE S, 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) E fig Takeda Chem. Indus. v. Al ha harm Pt Ltd., 492
`
`F.3d 1350, 1358-1359, 83 U.S.P.Q.2d 1169, 1175-76 (Fed. Cir. 2007) (affirrning 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. &, ggg 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
`
`Genzyme Ex. 1023, pg 681
`
`
`
`Genzyme Ex. 1023, pg 681
`
`

`
`REEXAM CONTROL NOS. 90/007,542, 90/007,859
`
`ATTORNEY DOCKET NOS. 22338-10230, 1023]
`
`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 n_ot 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 cited references and the general knowledge and
`experience that person would have had at that time; and
`
`(iii)
`
`substantial evidence of secondary indicia of nonobviousness exists for the ’41 5
`patent claims.
`
`As a result, a person of ordinary skill in the art would not have considered the ’41 5 claims to
`
`have been obvious over the ’567 claims in conjunction with the cited references.
`
`1.
`
`The ’567 Patent Claims Do Not Suggest Producing Heavy a