IPR2017-01489
`
`Patent Owner’s Response
`
`Filed on behalf of Patent Owner Genentech, Inc. by:
`
`David L. Cavanaugh (Reg. No. 36,476)
`Robert J. Gunther, Jr. (Pro Hac Vice)
`
`Lisa J. Pirozzolo (Pro Hac Vice)
`Kevin S. Prussia (Pro Hac Vice)
`
`Andrew J. Danford (Pro Hac Vice)
`WILMER CUTLER PICKERIN G
`
`Adam R. Brausa (Reg. No.
`60,287)
`
`Daralyn J. Durie (Pro Hac
`Vice)
`
`DURIE TANGRI LLP
`217 Leidesdorff Street
`
`HALE AND DORR LLP
`
`San Francisco, CA 94111
`
`1875 Pennsylvania Ave, NW
`Washington, DC 20006
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PFIZER, INC., AND
`
`SAMSUNG BIOEPIS CO., LTD.
`
`Petitioners,
`
`v.
`
`GENENTECH, INC.,
`
`Patent Owner.
`
`Case IPR2017-01489
`
`Patent 6,407,213
`
`PATENT OWNER’S RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`IPR2017-01489
`
`Patent Owner’s Response
`
`Page
`
`INTRODUCTION ....................................................................................... 1
`
`II.
`
`TECHNOLOGY BACKGROUND .............................................................. 4
`
`Antibody “Variable” And “Constant” Domains ...................................... 4
`
`“Humanized” Antibodies ........................................................................ 6
`
`’213 PATENT .............................................................................................. 8
`
`Invention ................................................................................................. 8
`
`Advantages Of ’213 Invention ................................................................ 9
`
`0
`
`Prosecution History ................................................................................ 10
`
`IV.
`
`ASSERTED REFERENCES ...................................................................... 11
`
`rurnDOPU?
`
`Queen-1989 ........................................................................................... l 1
`
`Queen-1990 ........................................................................................... 12
`
`Protein Data Bank .................................................................................. 14
`
`Tramontano ............................................................................................ 15
`
`Kabat-1987 ............................................................................................ 16
`
`Hudziak ................................................................................................. 16
`
`PERSON OF ORDINARY SKILL ............................................................. 17
`
`VI.
`
`CLAIM CONSTRUCTION ........................................................................ 17
`
`VII.
`
`SUMMARY OF ARGUMENT .................................................................. 18
`
`VIII.
`
`ARGUMENT .............................................................................................. 22
`
`

`

`IPR2017-01489
`
`Patent Owner’s Response
`
`Grounds 2-4, 7: The Board Should Confirm The Patentability Of
`Claims 12, 42, 60, 65, 71, 73-74, And 79 Because Neither Queen—
`1990 Nor Tramontano 15 Prior Art. ........................................................ 22
`
`The inventors made and tested HuMAb4D5-5 and HuMAb4D5-
`
`8 before July 26, 1990. ...................................................................... 23
`
`a)
`
`b)
`
`c)
`
`Consensus sequence ..................................................................... 23
`
`Humanized 4D5 antibody sequences ............................................ 25
`
`Production and testing of humanized 4D5 antibodies ................... 28
`
`(i)
`
`First humanized 4D5 variable domain fragment...................... 29
`
`(ii)
`
`First humanized 4D5 full-length antibody ............................... 31
`
`(iii) Other humanized 4D5 variants ................................................ 32
`
`HuMAb4D5-5 and HuMAb4DS-8 demonstrate actual reduction
`
`to practice of claims 12, 42, 60, 65, 71, 73-74, and 79 before
`July 26, 1990. ................................................................................... 33
`
`a)
`
`HuMAb4D5-5 and HuMAb4D5-8 embody claims 12, 42,
`60, 65, 71, 73—74, and 79 .............................................................. 34
`
`b)
`
`The inventors determined that HuMAb4D5-5 and
`
`HuMAb4D5-8 would work for the intended purpose of the
`claims before July 26, 1990. ........................................................ 38
`
`c)
`
`Contemporaneous records from non-inventors corroborate
`the inventor’s actual reduction to practice before July 26,
`1990 ............................................................................................. 39
`
`Queen—1990 and Tramontano are not § 102(b) prior art. ................... 41
`
`Grounds 1, 3, 6: Petitioners’ obviousness theory for Queen-1989
`actually rests on Queen-1990, which is not prior art to claims 12,
`42, 60, 65, 71, 73-74, and 79 ..................................................................44
`
`ii
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`

`

`IPR2017-01489
`
`Patent Owner’s Response
`
`C.
`
`Grounds 1-4, 6-7: The Queen references combined with the PDB
`
`database would not have led to the invention of claims 12, 42, 60,
`
`65-67, and 71-79 with a reasonable expectation of success. ................... 45
`
`D.
`
`Grounds 1-2, 5, 7: Claims 4, 33, 62, 64, And 69 Would Not Have
`
`Been Obvious Because The Asserted References Do Not Teach
`
`The “Consensus” Sequence Limitations. ................................................ 51
`
`l.
`
`The asserted references do not teach the “consensus” sequence
`limitation. ......................................................................................... 51
`
`a)
`
`b)
`
`Queen-1990 (Grounds 2, 7) .......................................................... 52
`
`Queen-1989 (Grounds 1, 5) .......................................................... 53
`
`2.
`
`The asserted references do not teach any antibody with the
`framework substitutions of claims 4, 33, 62, 64, and 69 that
`
`incorporates non-human CDRs that bind antigen. ............................. 56
`
`E.
`
`Grounds 1-4: The Asserted References Do Not Render Obvious
`
`The “Up To 3-Fold More” Binding Affinity Limitation Of Claim
`65 ........................................................................................................... 57
`
`F.
`
`Grounds 1-2: Queen-1989 And Queen-1990 Do Not Render
`Obvious The “Lacks Immunogenicity” Limitation 0f Claim 63. ........... 60
`
`G.
`
`Grounds 6-7: Petitioners Have Not Shown That It Would Have
`
`Been Obvious That A Humanized Antibody With The Framework
`Substitutions Recited In Claims 30-31, 33, 42, And 60 Would Bind
`p185“ER2 ................................................................................................. 61
`
`H.
`
`Objective lndicia Of Non-Obviousness Confirm The Patentability
`Of The Challenged Claims ..................................................................... 64
`
`l.
`
`2.
`
`Unexpected results ............................................................................ 64
`
`Commercial success .......................................................................... 67
`
`l.
`
`Inter Partes Review Is Unconstitutional. ............................................... 68
`
`IX.
`
`CONCLUSION .......................................................................................... 68
`
`iii
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`

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`IPR2017-01489
`
`Patent Owner’s Response
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Federal Cases
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc,
`229 F.3d 1 120 (Fed. Cir. 2000) ........................................................................ 68
`
`In re Clarke,
`
`356 F.2d 987 (C.C.P.A. 1966) .......................................................................... 37
`
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ........................................................................ 40
`
`Flex-Rest, LLC v. Steelcase, Inc.,
`
`455 F.3d 1351 (Fed. Cir. 2006) ........................................................................ 64
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ......................................................................................... 50
`
`Leo Pharm. Prods., Ltd. v. Rea,
`
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................................ 50
`
`Markman v. Wesrview Instruments, Inc,
`
`517 U.S. 370 (1996) ......................................................................................... 68
`
`McCormick Harvesting Mach. Co. v. C. Aaltman & Co.,
`
`169 U.S. 606 (1898) ......................................................................................... 68
`
`Medichem, SA. 12. Rolabo, S.L.,
`
`437 F.3d 1157 (Fed. Cir. 2006) ........................................................................ 40
`
`In re Merchant,
`
`575 F.2d 865 (C.C.P.A. 1978) .......................................................................... 66
`
`NFC Tech, LLC v. Maral,
`
`871 F.3d 1367 (Fed. Cir. 2017) ........................................................................ 34
`
`In re NTP, Inc.,
`
`654 F.3d 1279 (Fed. Cir. 2011) ........................................................................ 34
`
`iV
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`

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`IPR2017-01489
`
`Patent Owner’s Response
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`Oil States Energy Services, LLC v. Greene ’5 Energy Group, LLC,
`No. 16—712 ....................................................................................................... 68
`
`Ortha-McNeil Pharm., Inc. v. Mylan Labs, Inc,
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................................ 50
`
`Sinorgchem Co. v. Inr’l Trade Comm ’n,
`511 F.3d 1132 (Fed. Cir. 2007) ........................................................................ 18
`
`In re Soni,
`
`54 F.3d 746 (Fed. Cir. 1995) ............................................................................ 64
`
`In re Steed,
`
`802 F.3d 1311 (Fed. Cir. 2015) .................................................................. 33, 34
`
`Tokai Corp. v. Easton Enters, Inc,
`
`632 F.3d 1358 (Fed. Cir. 201 l) ........................................................................ 67
`
`Patent Trial and Appeal Board Cases
`
`Green Cross Corp. v. Shire Human Generic Therapies,
`IPR2016—00258, Paper 89 (Mar. 22, 2017) ................................................ 40, 64
`
`Nintendo 0fAm., Inc. v. iLife Tech, Inc,
`IPR2015-00109, Paper 40 (Apr. 28, 2016) ....................................................... 40
`
`Federal Statutes
`
`35 U.S.C. § 102(a) .......................................................................................... 33, 41
`
`35 U.S.C. § 102(b) ................................................................................................ 41
`
`35 U.S.C. § 120 .............................................................................................. 41, 46
`
`Constitutional Provisions
`
`US. Const. Amendment VII ................................................................................. 68
`
`

`

`IPR2017-01489
`
`Patent Owner’s Response
`
`I.
`
`INTRODUCTION
`
`US. Patent No. 6,407,213 claims humanized antibodies with amino acid
`
`substitutions at specific positions. Unlike prior art humanized antibodies—which
`
`required handpicking a unique human framework sequence for each antibodymthe
`
`claimed antibodies could be produced from a single human “consensus” sequence,
`
`which is a composite of all human antibody framework sequences of a particular
`
`subclass or subtype. The ’213 invention thus provides a broadly-applicable
`
`humanization platform, which has produced numerous successful drugs, including
`
`treatments for cancer, asthma, and macular degeneration.
`
`In its preliminary response, Patent Owner identified several deficiencies in
`
`Petitioners’ proof for all challenged claims. However, to narrow the issues, Patent
`
`Owner now focuses on a subset of the challenged claims and presents specific
`
`reasons why Petitioners have failed to carry their burden for those claims. Patent
`
`Owner’s response is supported by new evidence obtained from cross-examination
`
`of Petitioners’ declarants Dr. Jefferson Foote (Ex-2039) and Mr. Timothy Buss
`
`(Ex-2040), as well as the declaration of Dr. Ian Wilson (EX—2041) submitted
`
`herewith.
`
`First, the Board should confirm the patentability of claims 12, 42, 60, 65,
`
`71, 73-74, and 79 because the inventors conceived and actually reduced to practice
`
`those claims prior to the publication of Queen—1990 and Tramontano (Grounds 2—4,
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`

`

`IPR2017-01489
`
`Patent Owner’s Response
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`7). That prior reduction to practice is corroborated by several non-inventors whose
`
`contemporaneous notebooks confirm that the inventors made humanized
`
`antibodies embodying the claims and verified that they would work for their
`
`intended purpose before July 26, 1990. In addition, although Petitioners’ purport
`
`to rely upon Queen—1989 for Grounds l, 3, and 6, Petitioners’ obviousness theory
`
`in those grounds actually rests on Queen-1990 (which Petitioners’ expert explicitly
`
`cites as the basis for his analysis). If the Board finds Queen-1990 antedated, then it
`
`should also reject Petitioners’ challenge to those claims in Grounds l, 3, and 6.
`
`Second, the Board should confirm the patentability of claims 12, 42, 60, 65-
`
`67, and 71-79.‘ Petitioners’ analysis of the Queen references combined with the
`
`PDB database discloses numerous potential framework substitutions.
`
`In fact, the
`
`record now shows that applying Petitioners’ own analysis of the PDB structures
`
`encompasses many more framework substitutions than the selective subset cited
`
`the petitions. That broad genus does not render obvious claims 12, 42, 60, 65-67,
`
`and 71-79, which narrowly recite at least one and up to five specific framework
`
`substitutions. Nor would those specific claimed framework substitutions have
`
`
`
`Many claims have been challenged in multiple grounds. Patent Owner
`
`explains below (§VII) how the issues summarized in this introductory section
`
`correspond with the instituted grounds.
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`

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`IPR2017-01489
`
`Patent Owner’s Response
`
`been obvious to try. What Petitioners cite is not a “small” or “easily traversed”
`
`number of possibilities in the context of antibody humanization, particularly as of
`
`199] when the field was still nascent. And the record also confirms that the high
`
`degree of unpredictability of making framework substitutions, where even a single
`
`substitution can affect antigen binding in unpredictable ways.
`
`Third, Petitioners have failed to show that Queen-1990, or Queen-1989
`
`alone or combined with Kabat-l987, teaches the “consensus” sequence limitations
`
`of claims 4, 33, 62, 64, and 69. As the Board recognized in its institution decision,
`
`the ’213 patent expressly defines “consensus” sequence as a sequence generated
`
`from “all human immunoglobulins of any particular subclass or subunit structure.”
`
`Queen-1990, however, describes “a consensus framework from many human
`
`antibodies,” not “all." Dr. Wilson explains that a skilled artisan would understand
`
`that Queen-1990’s “consensus framework” is referring to a sequence generated
`
`from a subset of antibodies, which differs from what the ’213 patent requires.
`
`Queen-1989 does not even mention a consensus sequence, and Dr. Wilson explains
`
`that Petitioners” proposed combination with Kabat-l987 in Ground 5 would not
`
`have led to the consensus sequence of the ’213 patent.
`
`Fourth, claims 30—31, 33, 42, and 60 require an antibody with the recited
`
`substitutions that binds a specific antigen called “pISSHER2.” Petitioners have not
`
`shown that such an antibody would have been obvious. Petitioners merely cite the
`
`

`

`IPR2017-01489
`
`Patent Owner’s Response
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`general disclosure of references involving humanized antibodies for different
`
`antigens and present no evidence that those general techniques would result in the
`
`claimed substitutions when applied to an antibody that binds plSSHERZ.
`
`Finally, claims 63 and 65 contain additional limitations requiring that the
`
`antibody “lacks immunogenicity" or has “up to 3—fold more" binding affinity as
`
`compared with the parent non-human antibody. Petitioners presented no evidence
`
`of any antibody disclosed in the asserted references that has those properties. And
`
`the record now confirms that these properties are highly unpredictable and that a
`
`skilled artisan would not have had a reasonable expectation of success in achieving
`
`those specific claim limitations.
`
`11.
`
`TECHNOLOGY BACKGROUND
`
`A.
`
`Antibody “Variable” And “Constant” Domains
`
`The immune system defends against foreign substances, called “antigens,"
`
`by producing antibodies. Antibodies are proteins that bind to antigens. (Ex-2041
`
`‘][32; EX-l582 at 160.) A typical antibody, or “immunoglobulin,” has two identical
`
`heavy chains and two identical light chains:
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`

`

`IPR2017-01489
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`Patent Owner’s Response
`
` —_——-———l
`
`r————
`
`I
`
`(Ex—2041 c1133; Ex-2023 at 10 (annotated); Ex-lSOl, 1:17-20.) Each chain contains
`
`a “variable” domain (red box above) and “constant” domains (green box above).
`
`(Ex-2041 €135; Ex-lSOl, 1:20-27.) The heavy chain (VH) and light chain (VL)
`
`variable domains are illustrated above in blue and pink, respectively.
`
`Variable domains directly bind to the antigen.
`
`(Ex—2041 ‘][37; EX-lSOl,
`
`1:35-37.) Each variable domain contains three “complementarity determining
`
`regions,” or “CDRs,” (Ex-2041 L][38; Ex-lSOl, 1:35-50), shown as CDRl, CDRZ,
`
`and CDR3 in the enlarged portion above. Variable domains also contain four
`
`“framework regions,” or “FRs”—one on either side of each CDR—shown as FR 1,
`
`FR2, FR3, and FR4 in the same enlarged portion. The framework regions form a
`
`core structure from which the CDRs extend and form a binding site for the antigen.
`
`(Ex-2041 c1140; Ex-1501, 1:47-50.) Unlike the CDRs, which generally contain
`
`

`

`IPR2017-01489
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`Patent Owner’s Response
`
`unique amino acids (or “residues”) for a particular antigen, the framework regions
`
`typically share more amino acid sequences in common (Len, the same amino acids
`
`at the same positions) across other antibodies. (Ex-2041 ‘][39; Ex—lSOl, 1:37-44.)
`
`The constant domains are not directly involved in antigen binding and
`
`typically have similar amino acid sequences across all antibodies within a subclass.
`
`(Ex-2041 (1136; Ex-2016 ‘][15.)
`
`B.
`
`“Humanized” Antibodies
`
`Before the ’2 l 3 patent, antibodies targeting a specific antigen could be
`
`obtained from animals (e.g., mice). (Ex-2041 ‘][48; Bit-1501, 1:52-58.) Those non-
`
`human antibodies, however, had limited use therapeutically because the human
`
`immune system would overtime identify them as antigens and attack them—
`
`known as an “immunogenic” response.
`
`(Ex-2041 ‘][50; Ex-lSOl, 1:55—58.) An
`
`immunogenic response had adverse clinical consequences, including diminished
`
`efficacy and allergic reactions.
`
`(Ex—2041 ‘][51; EX-2039, 190:25—191 :8.)
`
`Scientists developed several techniques seeking to address immunogenicity.
`
`One involved “chimeric" antibodies that combined a non-human variable domain
`
`with a human constant domain.
`
`(Ex-2041 ‘][53; Bit-1501, 1:59-2:19.) However,
`
`immunogenicity could still result because chimeric antibodies retained a significant
`
`portion of the non-human antibody sequence.
`
`(Ex-2041 ‘][54; Ex-lSOl, 2: 12-19;
`
`Bit-2022 at 2156.)
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`

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`IPR2017-01489
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`Patent Owner’s Response
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`Scientists also created “humanized” antibodies containing a human variable
`
`domain substituted with the amino acid sequence of the non—human CDRs.
`
`(Ex—
`
`2041 ‘][55; Ex-lSOl, 2:20—52.) But that approach could reduce the antibody’s
`
`ability to bind to specific antigens.
`
`(Ex-2041 ‘][61.)
`
`Scientists pursued techniques for making humanized antibodies that
`
`balanced strong binding with low immunogenicity.
`
`(Ex-2039, 5525-9; Ex-204l
`
`€161.) For example, Queen-1989 (Ex-1534) chose an existing human framework
`
`that was “as homologous as possible to the original mouse antibody to reduce any
`
`deformation of the mouse CDRS." (Ex- 1534 at 10033.) The humanized sequence
`
`was then further refined using computer modeling “to identify several framework
`
`amino acids in the mouse antibody that might interact with the CDRs or directly
`
`with antigen, and these amino acids were transferred to the human framework
`
`along with the CDRs.” (Id) That technique became known as the “best-fit”
`
`approach because it started from an existing human sequence with the closest
`
`match to the non—human antibody. (Ex-2041 ‘][‘][56-60; Ex-2024 at 4184.)
`
`Even using the best-fit approach, however, it still was difficult to produce an
`
`antibody with both strong binding and low immunogenicity. (Ex-2041 (“61-68;
`
`Ex-1501, 3:50-52.) The best-fit approach also was inefficient because it required
`
`identifying a new human framework sequence for each different humanized
`
`antibody. (Ex-2041 ‘fl‘llSS, 264-65)
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`

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`IPR2017-01489
`
`Patent Owner’s Response
`
`III.
`
`’213 PATENT
`
`A.
`
`Invention
`
`Beginning in the late 1980s, the inventors of the ’213 patent—Drs. Paul
`
`Carter and Leonard Presta at Genentech—developed a new approach to
`
`humanizing antibodies that solved the prior art binding and immunogenicity
`
`problems. Rather than starting from the most homologous human sequence of an
`
`actual antibody, the inventors developed an artificial “consensus human
`
`sequence”—i.e., “an amino acid sequence which comprises the most frequently
`
`occurring amino acid residues at each location in all human immunoglobulins of
`
`any particular subclass or subunit structure.” (Ex—1501, 11:32-38.) That
`
`“consensus” sequence provided a single human sequence for any humanized
`
`antibody of a particular subclass or subunit structure (e.g., light chain K1). (Id.,
`
`54:66-56:57.)
`
`The ’213 inventors developed a multi-step process for their approach. First,
`
`they added the non-human CDRs to the human consensus sequence. (Id, 20: l 2-
`
`31.) Next, they evaluated the differences between the framework regions of the
`
`non-human antibody and the human consensus sequence to determine whether
`
`further modifications to the consensus sequence were needed. (Id, 20:32-40.)
`
`Where the non-human antibody framework sequence differed from the
`
`human consensus sequence, the inventors used computer modeling to identify
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`IPR2017-01489
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`Patent Owner’s Response
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`whether the different non-human amino acid (1) “non-covalently binds antigen
`
`directly”; (ii) “interacts with a CDR"; (iii) “participates in the VL-VH interface,”
`
`i.e., the interface between variable domains of the heavy and light chains, or (iv) is
`
`a glycosylation site outside the CDRs that is likely to affect “antigen binding
`
`and/0r biological activity.” (Id, 20:32—21 :36, 54:64—56:57.) The inventors
`
`believed that those positions were important to maintaining binding affinity.
`
`(1d,,
`
`20:32-35.) If any of those requirements was met, that position in the consensus
`
`sequence could be substituted with the amino acid at the same position in the non-
`
`human antibody. Otherwise, the sequence of the human consensus sequence was
`
`retained.
`
`(1d,, 20:66-21 :8.)
`
`The ’213 claims reflect the inventors’ novel consensus sequence approach.
`
`They require a “humanized” antibody or variable domain that contains non-human
`
`CDRs that bind antigen when incorporated into the human framework sequence
`
`and certain specified framework substitutions that the inventors determined were
`
`important to antibody binding in their consensus sequence. (Ex-2016 ‘][31.)
`
`B.
`
`Advantages Of ’213 Invention
`
`Antibodies containing the ”213 patent’s consensus sequence were a
`
`significant advance over the prior art.
`
`First, the ’213 patent’s consensus sequence addressed the immunogenicity
`
`problems of other humanization techniques.
`
`(Ex-1502 at 3439-41, ‘][‘l[2—9; EX-204l
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`IPR2017-01489
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`Patent 0wner”s Response
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`H183.) At the same time, humanized antibodies embodying the ”213 invention
`
`retained strong binding affinity, or even have improved binding over the original
`
`non-human antibody.
`
`(Ex-1501, 4:24-28, 51:50—53; Ex-204l ‘][83.)
`
`Second, unlike the prior art best-fit approach that used a unique human
`
`sequence for each antibody, the ”213 patent provided a single human sequence that
`
`could be applied to a wide variety of antibodies.
`
`(Ex-1502 at 3439-41, ‘][‘][2-9; Ex-
`
`2041 ‘][85.) That broadly-applicable platform is reflected in the ”213 patent”s
`
`claims that specifically require a consensus sequence or that recite framework
`
`substitutions derived from that consensus sequence. (Ex-204i ‘][85.) Genentech
`
`has used the ”213 invention to develop numerous drugs, including l-lerceptin®
`
`(breast and gastric cancer), Perjeta® (breast cancer), Avastin® (colon, lung, ovarian,
`
`cervical, kidney, and brain cancer), Lucentis® (macular degeneration), and Xolair®
`
`(asthma). (Ex-2017 (114; EEK-2016 ‘][5.)
`
`C.
`
`Prosecution History
`
`The ”213 patent is a continuation-in-part of an application filed on June 14,
`
`1991.
`
`(Ex-1501 at l.) The challenged claims issued over hundreds of references
`
`considered during prosecution, including every reference in the instituted
`
`grounds. (Ex-1501 at 1-6.) Petitioners assert that the PDB database was not
`
`considered during prosecution.
`
`(Paper 1 at 14.) That is incorrect. The ”213
`
`specification repeatedly cites the PDB. (Ex-1501, 16:31-34, 19:35-41, 48:13-17.)
`
`10
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`

`

`IPR2017-01489
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`Patent Owner’s Response
`
`During prosecution, the applicants successfully antedated U.S. Patent No.
`
`5,693,762, which had a filing date of September 28, 1990. (Ex-1502 at 4432-33,
`
`4443.) As detailed below, the record in this proceeding further confirms that
`
`certain challenged claims were also invented before the publication of either
`
`Queen—1990 (July 26, 1990) or Tramontano (September 5, 1990).
`
`IV. ASSERTED REFERENCES
`
`A.
`
`Queen-1989
`
`Queen-1989 describes the humanization of a murine anti-Tac antibody.
`
`(Ex-
`
`1534 at 10029.) Unlike the ’213 patent, Queen-1989 does not disclose or suggest
`
`the use of a generalized “consensus” sequence.
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`(Ex-2041 ‘][112.) Instead, Queen-
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`1989 used a best-fit approach, which involved (i) identifying a framework
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`sequence of an actual human antibody that was “as homologous as possible to the
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`original mouse antibody” (Ex-1534 at 10033); and (ii) incorporating the murine
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`CDRs into that human sequence (Ex-1534 at 10031). (Ex-2041 ‘j[‘][l 10-1 1.)
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`Queen-1989 then identified additional locations in the human framework to
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`substitute with murine residues. If the human framework contained “atypical”
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`residues, Queen—1989 substituted them with more commonly—occurring residues
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`from the murine antibody.
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`(Ex-1534 at 10032.) Queen-1989 also used a computer
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`model of the murine antibody “to identify several amino acids which, while outside
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`the CDRs, are likely to interact with the CDRs or antigen.” (Ex-1534 at 10029.)
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`IPR2017-01489
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`Using those techniques, Queen-1989 made a humanized antibody with 15
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`framework substitutions—none of which fall within the scope of the challenged
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`claims. (Ex-1534 at 10031; Ex-2041 ‘][112.)
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`B.
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`Queen- 1990
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`Queen-1990 is a PCT application published July 26, 1990.
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`It is not prior art
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`to certain challenged claims. (Infra §VIII.A.)
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`Queen-1990 used a best-fit approach to produce a humanized antibody. (Ex-
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`1550, 265-3325; Ex-2041 t][‘][1 13—14.) Queen-1990 identified four general criteria
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`for designing humanized antibodies.
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`(Ex-2041 ‘1[‘][1 14-22.)
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`Criterion I: Queen-1990 emphasized the importance of choosing the human
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`sequence most similar to the non-human antibody to reduce the possibility of
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`distorting the binding site formed by the CDRs.
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`(Ex—1550, 12: 17-35.) Queen-
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`1990 mentioned “a consensus framework from many human antibodies” (iii,
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`12:19—20), but included no details of what that “consensus framework” might be or
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`how it might be used to make a humanized antibody.
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`(Ex-2041 ‘ll‘fll 15-16.)
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`Criterion II: After selecting a best-fit human framework sequence, Queen—
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`1990 provided that “unusual” or “rare” amino acids could be replaced with more
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`common amino acids from the non-human sequence. (Ex-1550, 13:22-32.) This
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`step was intended to eliminate residues that may “disrupt the antibody structure”
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`by replacing them with non-human residues commonly found in other human
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`antibody sequences. (Iii, 13:32-37.)
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`Criterion HI: Queen-1990 disclosed that non-human residues may be used
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`immediately adjacent to CDRs to help maintain binding affinity.
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`(1d, 14:1-12.)
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`But as Petitioners’ expert Dr. Foote confirmed, substituting residues at these
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`positions is optional, “not obligatory.” (Ex-2039, 23824-23934.) Queen-1990
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`“doesn’t specify
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`a certain method for choosing these [residues]” and “does not
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`prioritize any particular one.” (Ex-2039, 246:3-12, 24625-247 :4.)
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`Criterion IV: Queen-1990 used computer modeling, “typically of the
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`original donor antibody,” to identify other residues that “have a good probability of
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`interacting with amino acids in the CDR’s [sic] by hydrogen bonding, Van der
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`Waals forces, hydrophobic interactions, etc.” (Ex-1050, 14:14-19.) Non-human
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`residues may be substituted at those positions that may interact with CDRs. (Ex-
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`1050, 14:19-21.) Amino acids satisfying this criterion “generally have a side chain
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`atom within about 3 angstrom units of some site in the CDR’s [sic].” (Ex- 1050,
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`14:22-25.) But Dr. Foote admitted that Criterion IV “doesn’t give a formula for
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`when or when not to replace them.
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`[It] mainly givles] the list that you would
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`consider replacing.” (Ex-2039, 253:9—16.)
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`Queen-1990 disclosed a humanized antibody sequence produced using its
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`technique.
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`(Ex-1050, Fig. 2.) That antibody contained 15 framework
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`substitutions—none of which correspond with the ’213 claims. (Ex-2041 ‘][125.)
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`Queen-1990 states that the antibody produced using its technique had a binding
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`affinity within about 3- to 4-fold of the parent murine antibody, but does not
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`indicate any improvement in binding affinity for the humanized antibody. (Ex-
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`2041 ‘j[126; Ex—ISSO, 31:33—37.) Queen—1990 does not describe or report any
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`testing of immunogenicity for this humanized antibody.
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`(Ex-2041 ‘][126.)
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`C.
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`Protein Data Bank
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`The Protein Data Bank (“PDB”) is “a computer-based archival file for
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`macromolecular structures.”
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`(Ex-1580 at 535.) As of 1991, the PDB included
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`structural information for only a small number of antibodies or antibody fragments,
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`whose crystal structure had been solved—a process that at the time could take
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`several years for a single antibody.
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`(Ex. 2039, 67:13-13; Ex—204l ‘][157.) As a
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`database, the PDB does not describe the humanization of antibodies, let alone what
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`substitutions may be relevant for any particular antibody.
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`(EX—2041 ‘][158; EX-
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`2039, 258:23-260:6.)
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`Petitioners cite data from nine antibody crystal structures available in the
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`PDB database prior to August 1989. (Ex-1503C, Exs. F—N.) As discussed below,
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`Petitioners contend that those crystal structures would have supposedly led to
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`numerous possible framework substitutions.
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`D.
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`Tramontano
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`Tramontano (Ex-1551) was published on September 5, 1990. (Ex-2027
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`(showing date).) Tramontano is not prior art to certain challenged claims. (Infra
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`§VIII.A.)
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`Tramontano analyzed several antibody structures and found that “the major
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`determinant” of the position of one of the CDRs “is the size of the residue at
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`[heavy chain] site 71.” (Ex-1551 at 175.) Tramontano discussed potential
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`“applications to antibody engineering,” explaining that “[f]or the binding site of
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`the synthetic product to be the same as that in the original antibody, the
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`frameworks should have the same residues at those sites important for the positions
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`and conformations of the hypervariable regions.” (Ex-1551 at 182.) Tramontano,
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`however, never suggested that substitutions at position 71 H were desirable. (Ex-
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`2041 ‘J[152.)
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`Instead, Tramontano discussed humanized antibodies reported in Jones (Ex—
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`1533), Verhoeyen (Ex-1568), and Riechmann (Ex-1569).
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`(Ex—1551 at 181; Ex—
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`204] ‘1[153.) Jones had the same residue at 71H as the parent antibody and “had the
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`same affinity
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`as the original mouse antibody.” (Ex-1551 at 181; Ex-2041
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`111153.) By contrast, Verhoeyen (Ex-1568) included a different residue at 71H than
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`the murine antibody and saw a 10-fold reduction in binding affinity.
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`(Ex-1551 at
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`181; Bit-2041 ‘][153.) Finally, Riechmann (Ex-1569) had a different residue at 71H,
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`but maintained a binding affinity “close to that of the rat original.” (Ex—1551 at
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`181; EX-2041 ‘][154.) Tramontano offered no explanation for those divergent
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`results.
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`(Ex-1551 at 181; Ex-204l ‘][‘][153-54.)
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`E.
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`Kabat- 1987
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`Kabat-1987 (Ex-1552) is a reference book of antibody sequences that
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`includes statistics on the most common amino acids for a given type of
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`immunoglobulin.
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`(Id. at 8; Bit-2041 ‘][159.)
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`Kabat-1987 does not describe antibody humanization or discuss
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`substitutions that may be beneficial when humanizing an antibody.
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`(Ex—2041
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`(11160.) Rather, Kabat- 1 987’s tabulation of the “mo