IPR2017-01374
`
`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 PICKERING
`
`HALE AND DORR LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
`Adam R. Brausa (Reg. No.
`60,287)
`Daralyn J. Durie (Pro Hac
`Vice)
`DURIE TANGRI LLP
`217 Leidesdorff Street
`
`San Francisco, CA 9411 l
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`CELLTRION, INC,
`Petitioner,
`
`V.
`
`GENENTECH, INC,
`Patent Owner.
`
`
`Case 1PR2017-01374
`
`Patent 6,407,213
`
`
`PATENT OWNER’S RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`IPR2017-01374
`
`Patent Owner’s Response
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`TECHNOLOGY BACKGROUND ................................................................. 5
`
`A.
`
`Antibody “Variable” And “Constant” Domains ........................................ 5
`
`B.
`
`“Humanized” Antibodies ............................................................................ 6
`
`III.
`
`’213 PATENT .................................................................................................. 8
`
`A.
`
`Invention ..................................................................................................... 8
`
`B.
`
`C.
`
`Advantages Of’ 21 3 Invention .................................................................. 10
`
`Prosecution History .................................................................................. 11
`
`IV. ASSERTED REFERENCES ......................................................................... 11
`
`A.
`
`Kurrle ........................................................................................................ 1 1
`
`B.
`
`C.
`
`Queen-1990 .............................................................................................. 13
`
`Furey ......................................................................................................... 15
`
`D.
`
`Chothia & Lesk ......................................................................................... 16
`
`E.
`
`Chothia-I985 ............................................................................................ 17
`
`F.
`
`Hudziak ..................................................................................................... 17
`
`V.
`
`PERSON OF ORDINARY SKILL ............................................................... 17
`
`VI.
`
`CLAIM CONSTRUCTION .......................................................................... 18
`
`VII. SUMMARY OF ARGUMENT ..................................................................... 19
`
`VIII. ARGUMENT ................................................................................................. 22
`
`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`Grounds 1, 3—8: The Board Should Confirm The Patentability Of
`Claims 12, 42, 60, 65, 71, 73—74, And 79 Because Neither Kurrle
`Nor Queen-1990 Is Prior Art. ................................................................... 22
`
`The inventors made and tested HuMAb4D5-5 and HuMAb4D5-
`
`8 before July 26, 1990. ........................................................................ 23
`
`a)
`
`b)
`
`c)
`
`a)
`
`b)
`
`c)
`
`Consensus sequence ....................................................................... 23
`
`Humanized 4D5 antibody sequences ............................................. 25
`
`Production and testing of humanized 4D5 antibodies ................... 27
`
`(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 HuMAb4D5-8 demonstrate actual reduction
`
`to practice of claims 12, 42, 60, 65, 7 1, 73—74, and 79 before
`July 26, 1990. ...................................................................................... 34
`
`HuMAb4D5—5 and HuMAb4D5—8 embody claims 12, 42,
`60, 65, 71, 73-74, and 79 ................................................................ 35
`
`The inventors determined that HuMAb4D5-5 and
`HuMAb4D5-8 would work for the intended purpose of the
`claims before July 26, 1990. .......................................................... 39
`
`Contemporaneous records from non-inventors corroborate
`the inventor’s actual reduction to practice before July 26,
`1990. ............................................................................................... 40
`
`Kurrle and Queen—1990 are not § 102(b) prior art. ............................. 41
`
`Grounds 1, 3: Claims 66—67, 71—72, 75—76, and 78 Are Not
`Anticipated Or Obvious Because The Asserted References Fail To
`Teach Non—Human CDRs “Which Bind Antigen Incorporated Into
`A Human Antibody Variable Domain.” ................................................... 44
`
`ii
`
`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`C.
`
`Grounds 2—3, 6: Claims 4, 33, 62, 64, and 69 Are Not Anticipated
`Or Obvious. .............................................................................................. 46
`
`l.
`
`The Asserted References Do Not Teach The Consensus
`
`Sequence Limitations. ......................................................................... 46
`
`2.
`
`Queen-1990 does not teach any antibody with the framework
`substitutions of claims 4, 33, 62, and 69 that incorporates non-
`human CDRs that bind antigen. .......................................................... 48
`
`D.
`
`E.
`
`F.
`
`Grounds 3—5, 7—8: Claims 12, 42, 60, 65, and 71—79 Would Not
`Have Been Obvious From The Broad Genus Of Potential
`
`Substitutions Allegedly Disclosed In The Asserted References. ............. 50
`
`Ground 5: Claim 65’s “Up To 3—Fold More” Binding Affinity
`Limitation Would Not Have Been Obvious. ............................................ 56
`
`Grounds 1-3: Claim 63’s “Lack Immunogenicity” Limitation Is
`Not Anticipated Or Obvious ..................................................................... 57
`
`G.
`
`Grounds 6-8:
`
`It Would Not Have Been Obvious That A
`
`Humanized Antibody With The Framework Substitutions Recited
`In Claims 30-31, 33,42, And 60 Would Bind p185lIER2 .......................... 60
`
`H.
`
`Objective Indicia Of Non—Obviousness Confirm The Patentability
`Of The Challenged Claims. ...................................................................... 62
`
`l.
`
`2.
`
`Unexpected results .............................................................................. 62
`
`Commercial success ............................................................................ 64
`
`I.
`
`Inter Partes Review Is Unconstitutional. .................................................. 65
`
`IX.
`
`CONCLUSION .............................................................................................. 66
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`
`IPR2017-01374
`
`Patent Owner’s Response
`
`Page(s)
`
`Federal Cases
`
`Brown & Williamson Tobacco Corp. v. I’hitip Morris Inc,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 65
`
`In re Clarke,
`
`356 F.2d 987 (C.C.P.A. 1966) ............................................................................ 38
`
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) .......................................................................... 40
`
`KSR International (To. v. Teleflex Inc,
`550 US. 398 (2007) ............................................................................................ 53
`
`Leo Pharm. Prods, Ltd. v. Rea,
`
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 54
`
`Markman v. Westview Instruments, Inc,
`517 U.S. 370 (1996) ............................................................................................ 65
`
`McCormick Harvesting Mach. (‘0. v. C. Aultman & (‘o.,
`169 US. 606 (1898) ............................................................................................ 65
`
`Medichem, SA. v. RoIabo, 8L,
`437 F.3d 1157 (Fed. Cir. 2006) .......................................................................... 41
`
`In re Merchant,
`575 F.2d 865 (C.C.P.A. 1978) ............................................................................ 64
`
`NFC Tech, LLC v. MataI,
`871 F.3d 1367 (Fed. Cir. 2017) .......................................................................... 35
`
`In re NTP, Inc,
`
`654 F.3d 1279 (Fed. Cir. 201 l) .......................................................................... 34
`
`Oil States Energy Services, LLC v. Greene ’5' Energy Group, IJIJC',
`No. 16-712 .......................................................................................................... 66
`
`iv
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`

`

`lPR2017-01374
`
`Patent Owner’s Response
`
`()rtho—McNei! Pharm, Inc. v. Mylar: Labs, Inc,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 54
`
`Sinorgehem (70. v. 11217 Trade Comm ’n,
`511 F.3d 1132 (Fed. Cir. 2007) .......................................................................... 18
`
`In re Sam,
`
`54 F.3d 746 (Fed. Cir. 1995) .............................................................................. 62
`
`In re Steed,
`
`802 F.3d 1311 (Fed- Cir. 2015) .......................................................................... 34
`
`Tokai (7(er. v. Easter: Balers, Inc,
`632 F.3d 1358 (Fed. Cir. 2011) .......................................................................... 64
`
`Patent Trial and Appeal Board Cases
`
`Greer: (.‘ross Corp. v. Shire Human Generic Therapies,
`lPR2016-00258, Paper 89 (Mar. 22, 2017) ........................................................ 40
`
`Nintendo ()fAm., Inc. v. iLife Tech, Inez,
`lPR2015-00109, 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
`
`Constitutional Provisions
`
`U.S. Const. Amendment VII .................................................................................... 65
`
`

`

`IPR2017-01374
`
`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 antibody—the
`
`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 ’2] 3 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
`
`Petitioner’s 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 Petitioner has failed to carry its burden for those claims. Patent
`
`Owner’s response is supported by new evidence obtained from cross-examination
`
`of Petitioner’s declarants, Dr. Lutz Riechmann (Ex—2039) and Dr. Robert Leonard
`
`(EX-2040), as well as the declaration of Dr. Ian Wilson (Ex-2041) submitted
`
`herewith.
`
`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`First, the Board should confirm the patentability of claims 12, 42, 60, 65,
`
`71, 73-74, and 791 because the inventors conceived and actually reduced to
`
`practice those claims prior to the publication of Kurrle and Queen—1990. 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.
`
`Second, the challenged claims require that resulting humanized antibodies
`
`bind an antigen. Petitioner has failed to offer any proof that this limitation is
`
`satisfied for antibodies having the substitutions recited in claims 66-67, 71-72, 75-
`
`76, and 78. Kurrle contains no binding data for the only antibody (EUCIV-4) that
`
`discloses the substitutions recited in claims 66—67, 71—72, 75—76, and 78. And
`
`Queen-1990 discloses no antibody sequence containing the claimed framework
`
`substitutions—let alone data showing that such an antibody binds antigen.
`
`Petitioner’s own declarant, Dr. Riechmann, confirmed at his deposition that the
`
`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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`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`only way to know whether a particular antibody has binding affinity at all is to test
`
`it—yet Petitioner has presented no evidence of such testing here.
`
`Third, Petitioner has failed to show that Queen—1990 teaches the
`
`“consensus” sequence limitations of claims 4, 33, 62, 64, and 69. As the Board
`
`recognized in its institution decision, the ’2] 3 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.
`
`Fourth, claims 12, 42, 60, 65—67, and 71—79 recite at least one and up to five
`
`specific framework substitutions. Petitioner asserts that these claims would have
`
`been obvious in view of the broad genus of potential framework substitutions
`
`purportedly disclosed in the asserted references—which essentially encompasses
`
`every framework position. Missing from the asserted references (or anywhere in
`
`the petition) is a reason why a person of ordinary skill would have chosen the
`
`specific framework substitutions recited in those claims. On the contrary, applying
`
`the same general criteria relied upon by Petitioner, Queen-1990 produced a
`
`humanized antibody with 15 substitutions—none of which correspond with the
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`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`claims. If Queen—1990 itself did not obtain any of the claimed substitutions, it
`
`surely would not have been obvious to a skilled artisan to do so applying those
`
`same rules. Nor would those specific claimed framework substitutions have been
`
`obvious to try. What Petitioner cites is not a “small” or “easily traversed” number
`
`of possibilities in the context of antibody humanization, particularly as of 1991
`
`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.
`
`Fiflh, claims 30—31, 33, 42, and 60 require an antibody with the recited
`
`substitutions that binds a specific antigen called “pl 85mm.” Petitioner have not
`
`shown that such an antibody would have been obvious. Petitioner merely cites the
`
`general disclosure of references involving humanized antibodies for different
`
`antigens and presents no evidence that those general techniques would result in the
`
`claimed substitutions when applied to an antibody that binds p185flfiR2.
`
`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. Petitioner presented no evidence
`
`of any antibody disclosed in Kurrle and/or Queen—1990 that has those properties.
`
`And the record now confirms that these properties are highly unpredictable and
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`

`

`IPR2017-01374
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`Patent Owner’s Response
`
`that a skilled artisan would not have had a reasonable expectation of success in
`
`achieving those specific claim limitations.
`
`[1.
`
`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
`
`1132; Ex—1082 at 160.) A typical antibody, or “immunoglobulin,” has two identical
`
`heavy chains and two identical light chains:
`
`
`
`(Ex—2041 1133; EX—2023 at 10 (annotated); Ex—lOOl, 1:17-20.) Each chain contains
`
`a “variable” domain (red box above) and “constant” domains (green box above).
`
`(Ex—2041 TBS; EX-lOOl, 1:20—27.) The heavy chain (V11) and light chain (VL)
`
`variable domains are illustrated above in blue and pink, respectively.
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`

`

`IPR2017-01374
`
`Patent Owner’s Response
`
`Variable domains directly bind to the antigen. (Ex-2041 1137; Ex—lOOl,
`
`1:35—37.) Each variable domain contains three “complementarity determining
`
`regions,” or “CDRs,” (Ex—204] 138; Ex—lOOl, 1:35-50), shown as CDRl, CDRZ,
`
`and CDR3 in the enlarged portion above. Variable domains also contain four
`
`“framework regions,” or “FRs”wne on either side of each CDRishown as FR],
`
`FRZ, 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 1140; Ex- 1001, 1:47—50.) Unlike the CDRs, which generally contain
`
`unique amino acids (or “residues”) for a particular antigen, the framework regions
`
`typically share more amino acid sequences in common (126., the same amino acids
`
`at the same positions) across other antibodies. (Ex-2041 1139; Err-1001, 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 136; Ex—2016 115.)
`
`B.
`
`“Humanized” Antibodies
`
`Before the ’213 patent, antibodies targeting a specific antigen could be
`
`obtained from animals (cg, mice).
`
`(EX—2041 1148; EX-lOOl, 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—2039, 159:5-1 l; EX-204l 1150; Ex-
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`

`

`IPR2017-01374
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`Patent Owner’s Response
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`1001, 1:55-58.) An immunogenic response had adverse clinical consequences,
`
`including diminished efiicacy and allergic reactions.
`
`(EX—2041 1151.)
`
`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 1]53; Ex-lOOl, 1:59-2:19.) However,
`
`immunogenicity could still result because chimeric antibodies retained a significant
`
`portion of the non—human antibody sequence.
`
`(Ex—2039, 24213—20; EX-2041 1]S4;
`
`Ex-1001, 2:12-19; EX-2022 at 2156.)
`
`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-1001, 2:20-52.) But that approach could reduce the antibody’s
`
`ability to bind to specific antigens.
`
`(Ex—2041 1]61; Ex—1034 at 10033.)
`
`Scientists pursued techniques for making humanized antibodies that
`
`balanced strong binding with low immunogenicity. (Ex-2041 1161.) For example,
`
`Queen-1989 (Ex-1034) 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-1034 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
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`

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`IPR2017-01374
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`Patent Owner’s Response
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`with the CDRS.” (1d) 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 1H56—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 WG-68;
`
`Ex-lOOl, 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 W85, 261—62.)
`
`[11.
`
`’2 13 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—1001, 11:32—38.) That
`
`“consensus” sequence provided a single human sequence for any humanized
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`

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`IPR2017-01374
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`Patent Owner’s Response
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`antibody of a particular subclass or subunit structure (eg, light chain Kl). (Id,
`
`54:66-56:57.)
`
`The ’213 inventors developed a multi-step process for their approach. First,
`
`they added the non-human CDRs t0 the human consensus sequence. (Id, 20:12-
`
`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
`
`whether the different non-human amino acid (i) “non-covalently binds antigen
`
`directly”; (ii) “interacts with a CDR”; (iii) “participates in the VL-VH interface,”
`
`£16., 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/or biological activity.” (Id, 20:32-21:36, 54:64-56:57.) The inventors
`
`believed that those positions were important to maintaining binding affinity. (Id,
`
`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 )
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`

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`IPR2017-01374
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`Patent Owner’s Response
`
`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 1B 1 .)
`
`B.
`
`Advantages 0f’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—1002 at 456—58, 1]1]2—9; EX-204l
`
`1183.) 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—1001, 4:24—28, 51:50—53; Ex—204l 1183.)
`
`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-1002 at 456—58, W29; Ex-
`
`2041 fl85.) 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-2041 1]85.) Genentech
`
`has used the ’213 invention to develop numerous drugs, including Herceptin®
`
`10
`
`

`

`(breast and gastric cancer), Perjeta® (breast cancer), Avastin® (colon, lung, ovarian,
`
`cervical, kidney, and brain cancer), Lucentis® (macular degeneration), and Xolair®
`
`IPR2017-01374
`
`Patent Owner’s Response
`
`(asthma). (Ex-2017 114; Err—2016 115.)
`
`C.
`
`Prosecution History
`
`The ’213 patent is a continuation-in-part of an application filed on June 14,
`
`1991. (Ex-1001 at l.) The challenged claims issued over hundreds of references
`
`considered during prosecution, including every reference in the instituted grounds.
`
`(Ex—1001 at 1-6.) The examiner did not make any rejection based upon any
`
`reference underlying the instituted grounds.
`
`During prosecution, the applicants successfully antedated US. Patent No.
`
`5,693,762, which had a filing date of September 28, 1990.
`
`(EX—1002 at 710—1 1,
`
`721.) As detailed below, the record in this proceeding further confirms that certain
`
`challenged claims were invented before the publication of either Kurrle (December
`
`19, 1990) or Queen-1990 (July 26, 1990).
`
`IV. ASSERTED REFERENCES
`
`A.
`
`Kurrle
`
`Kurrle is a European Patent Application published on December 19, 1990.
`
`Kurrle is not prior art to certain challenged claims. (Infra §VIII.A.)
`
`Unlike the ’213 patent’s consensus sequence approach, Kurrle used a best—fit
`
`approach for antibody humanization.
`
`(Ex—2041 fll26.) Starting from the murine
`
`11
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`

`IPR2017-01374
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`Patent Owner’s Response
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`antibody sequence, Kurrle searched for “the most homologous human antibody” to
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`provide the variable domain.
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`(Ex—1071, 8:16—18.) Kurrle incorporated the CDRs
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`from the mouse antibody into the human antibody sequence (id, 328—11), and then
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`made further substitutions of murine residues “in the sequence immediately before
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`and after the CDRs” and “up to 4 amino acids away” (id, 8:25-29).
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`Kurrle’s technique thus involved making substitutions in any of up to 24
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`different positions per antibody chain—£16., 4 amino acids on either side of the 3
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`CDRs—or 48 potential substitutions in total.
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`(Ex—2041 11128.) Kurrle provided no
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`guidance on which substitutions may be beneficial for any given antibody.
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`(Ex—
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`2041 11130.) Kurrle also highlighted the unpredictable and “p0tential[ly] adverse
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`consequences” of modifying the human antibody sequence to incorporate amino
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`acids from the murine antibody.
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`(Ex—1071, 8:40—43 (“[E1xtreme caution must be
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`exercised to limit the number of changes.”).)
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`Kurrle disclosed the sequence for four humanized antibodies: EUCIV],
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`EUCIV2, EUCIV3, and EUCIV4. (1d, Tables 6A-B; Ex-204l 11131 (identifying
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`substitutions in Kurrle’s antibodies).) EUCIV] and EUC1V2 lacked binding
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`affinity to the target antigen (Ex-1071, 9:17; Ex-204l 11132.) EUClV3 had binding
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`affinity for the target antigen, but it was less than the murine parent antibody.
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`(Ex—
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`1071, Fig. 7; Ex-204l 11132.) EUCIV4 is the only antibody sequence reported in
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`Kurrle with substitutions at 71H, 73H, and/or 76H. (Ex-2041 1133.) However,
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`Kurrle provides no binding affinity data for EUCIV4, and the corresponding
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`scientific publication to Kurrle makes no mention of EUC1V4.
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`(EX—2041 11133;
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`Ex-1072.)
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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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`1050, 265—3325; Bit—2041 11110—11.) Queen—1990 identified four general criteria
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`for designing humanized antibodies. (Ex-2041 '|]'|]1 1 1-19.)
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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. (Ex-1050, 12:17-35.) Queen-
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`1990 mentioned “a consensus framework from many human antibodies” (id,
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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. (Ex-2041 'fl'fll 12-13.)
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`Indeed, Petitioner’s expert, Dr- Riechmann conceded that the term as used in
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`Queen—1990 was “ambiguous.” (Ex—2039, 284: 10—13.)
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`Criterion H: 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.
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`(Ex—1050, 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.
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`(Ex—1050, 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. (Ex-1050, 14:1-
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`12.) But as Petitioner’s expert Dr. Riechmann confirmed, substituting residues at
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`these positions is “optional, not mandatory.” (Ex-2039, 289220—22.) Queen—1990
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`provides no guidance on which of these residues should be substituted for any
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`given antibody.
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`Indeed, as Dr. Riechmann noted, “[t]hat would not be a sensible
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`thing to do” because substitutions would vary according to the particular antibody
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`to be humanized, and “the structural components in each case are different.” (Ex-
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`2039, 29122—292110.)
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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 [or] may not” be substituted at those positions that may interact with
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`CDRs “depending on the particular antibody that you’re trying to humanize.” (Ex—
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`2039, 29425-8; Ex-lOSO, 14:19-21.) Amino acids satisfying this criterion
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`“generally have a side chain atom within about 3 angstrom units of some site in the
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`CDR’s [sic].” (Ex—1050, 14:22—25.)
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`Queen—1990 disclosed a humanized antibody sequence produced using its
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`technique. (Id, Fig. 2.) That antibody contained 15 framework substitutions—
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`none of which correspond with the “213 claims. (Ex-2041 fl 122.) Queen-1990
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`states that the antibody produced using its technique had a binding affinity within
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`about 3- to 4—fold of the parent murine antibody, but does not indicate any
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`improvement in binding affinity for the humanized antibody.
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`(Ex—2041 11123; Ex-
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`1050, 31 :33-37.) Queen—1990 does not describe or report any testing of
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`immunogenicity for this humanized antibody.
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`(EX-2041 11123.)
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`C.
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`Furey
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`Furey (Ex-l 125) is a 1983 publication describing the crystal structure of a
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`Bence—Jones protein fragment. A Bence—Jones fragment is different from a typical
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`antibody structure. It consists of two antibody light chains, instead of two light
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`chains and two heavy chains. (Ex-2041 11142.) Furey does not describe antibody
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`humanization or discuss substitutions beneficial when humanizing an antibody, let
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`alone describe how its analysis of a Bence—Jones fragment would be applicable to
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`typical antibody structures. (Ex-2041 11144.)
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`Furey identified “11 side chain—side chain hydrogen bonds” of which 6 “may
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`be common to all V1. domains-” (Ex—1125 at 673—74.) According to Furey, the
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`“most important” of those six hydrogen bonds “seem to be the two involved in the
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`salt-bridge” between 61L (Arg62) and 82L (Asp83). (Id; Ex-204l 11143.)2
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`D.
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`Chothia & Lesk
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`Chothia & Lesk (Ex—1062) is a 1987 publication that analyzed known
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`antibody structures to identify positions “primarily responsible for the main-chain
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`conformations observed in the hypervariable regions.” (Ex-1062 at 902.) Chothia
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`& Lesk does not describe antibody humanization or discuss substitutions beneficial
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`when humanizing an antibody.
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`(Ex—2041 11138.)
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`Chothia & Lesk noted that “[t]he major determinants of the tertiary structure
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`of the frameworks are the residues buried within and between the domains.” (Ex—
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`1062 at 903.) Table 4 identifies 50 positions “commonly buried within VL and Vi!
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`domains”—26 from the light chain and 24 from the heavy chain.
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`(1d. at 906.)
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`Chothia & Lesk does not indicate that any of those 50 positions has more
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`importance than any other to determine antibody structure.
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`(EX-2041 111137-38.)
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`This shorthand follows Kabat’s convention, which assigns standardized
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`numbers to the amino acid positions in antibody heavy (“H”) and light (“L”)
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`chains. (Ex-1001, 10:46-57; see EX-2041 1133.) For ex