IPR2017-01488
`
`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 IPR2017-01488
`
`Patent 6,407,213
`
`PATENT OWNER’S RESPONSE
`
`

`

`TABLE OF CONTENTS
`
`IPR2017-01488
`
`Patent Owner’s Response
`
`Page
`
`INTRODUCTION ....................................................................................... 1
`
`II.
`
`TECHNOLOGY BACKGROUND .............................................................. 5
`
`Antibody “Variable” And “Constant” Domains ...................................... 5
`
`“Humanized” Antibodies ........................................................................ 6
`
`’213 PATENT .............................................................................................. 8
`
`Invention ................................................................................................. 8
`
`Advantages Of The ’213 Invention ........................................................ 10
`
`0
`
`Prosecution History ................................................................................ II
`
`IV.
`
`ASSERTED REFERENCES ...................................................................... 12
`
`rurnDOPU?
`
`Kurrle .................................................................................................... 12
`
`Queen-1990 ........................................................................................... 13
`
`Furey ..................................................................................................... 15
`
`Chothia & Lesk ...................................................................................... 16
`
`Chothia—1985 ......................................................................................... 17
`
`Hudziak ................................................................................................. 17
`
`PERSON OF ORDINARY SKILL ............................................................. 18
`
`VI.
`
`CLAIM CONSTRUCTION ........................................................................ 18
`
`VII.
`
`SUMMARY OF ARGUMENT .................................................................. 19
`
`VIII.
`
`ARGUMENT .............................................................................................. 23
`
`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`Grounds 1, 3-10: 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. ................................................................. 23
`
`The inventors made and tested HuMAb4D5-5 and HuMAb4D5-
`
`8 before July 26, 1990. ...................................................................... 24
`
`a)
`
`b)
`
`c)
`
`Consensus sequence ..................................................................... 24
`
`Humanized 4D5 antibody sequences ............................................ 26
`
`Production and testing of humanized 4D5 antibodies ................... 29
`
`(i)
`
`First humanized 4D5 variable domain fragment...................... 30
`
`(ii)
`
`First humanized 4D5 full-length antibody ............................... 32
`
`(iii) Other humanized 4D5 variants ................................................ 33
`
`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. ................................................................................... 35
`
`a)
`
`HuMAb4D5-5 and HuMAb4D5-8 embody claims 12, 42,
`60, 65, 71, 73—74, and 79 .............................................................. 36
`
`b)
`
`The inventors determined that HuMAb4D5-5 and
`
`HuMAb4D5-8 would work for the intended purpose of the
`claims before July 26, 1990. ........................................................ 40
`
`c)
`
`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. ............................ 42
`
`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.” ................................................. 45
`
`ii
`
`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`C.
`
`Grounds 2-3, 8: Claims 4, 33, 62, 64, and 69 Are Not Anticipated
`Or Obvious. ........................................................................................... 47
`
`l.
`
`The Asserted References Do Not Teach The Consensus
`
`Sequence Limitations. ....................................................................... 47
`
`2.
`
`Queen-1990 does not teach any antibody with the framework
`substitutions of claims 4, 33, 62, 64, and 69 that incorporates
`non-human CDRs that bind antigen. ................................................. 49
`
`D.
`
`Grounds 3-10: Claims 12, 42, 60, 65-67, And 71-79 Would Not
`
`Have Been Obvious From The Broad Genus Of Potential
`
`Substitutions Allegedly Disclosed In The Asserted References .............. 50
`
`E.
`
`F.
`
`Ground 7: Claim 65’s “Up To 3—Fold More” Binding Affinity
`Limitation Would Not Have Been Obvious. .......................................... 56
`
`Grounds 1-3: Claim 63’s “Lacks Immunogenicity” Limitation Is
`Not Anticipated Or Obvious. ................................................................. 58
`
`G.
`
`Grounds 8-10: 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 p185HER2. ........................ 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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`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`Federal Cases
`
`Brown & Wifliamson Tobacco Corp. v. Philip Morris Inc,
`229 F.3d 1120 (Fed. Cir. 2000) ........................................................................ 68
`
`In re Ciarke,
`
`356 F.2d 987 (C.C.P.A. 1966) .......................................................................... 39
`
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ........................................................................ 41
`
`Flex-Rest, LLC v. Steelease, Inc.,
`
`455 F.3d 1351 (Fed. Cir. 2006) ........................................................................ 64
`
`KSR International Co. v. Teleflex Inc.,
`
`550 U.S. 398 (2007) ......................................................................................... 54
`
`Leo Pharm. Prods., Ltd. v. Rea,
`
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................................ 55
`
`Markman v. Wesm'ew Instruments, Inc.,
`
`517 U.S. 370 (1996) ......................................................................................... 68
`
`McCormick Harvesting Mach. Co. v. C. Aalnnan & Ca,
`169 U.S. 606 (1898) ......................................................................................... 68
`
`Medichem, SA. v. Rolabo, S.L.,
`
`437 F.3d 1 157 (Fed. Cir. 2006) ........................................................................ 41
`
`In re Merchant,
`
`575 F.2d 865 (C.C.P.A. 1978) .......................................................................... 66
`
`NFC Tech, LLC v. Mata},
`
`871 F.3d 1367 (Fed. Cir. 2017) ........................................................................ 35
`
`In re NTP, Inc.,
`
`654 F.3d 1279 (Fed. Cir. 2011) ........................................................................ 35
`
`iV
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`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`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) ........................................................................ 54
`
`Sinorgchem Co. v. Inr’l Trade Comm ’n,
`511 F.3d 1132 (Fed. Cir. 2007) ........................................................................ 19
`
`In re Soni,
`
`54 F.3d 746 (Fed. Cir. 1995) ............................................................................ 64
`
`In re Steed,
`
`802 F.3d 1311 (Fed. Cir. 2015) ........................................................................ 35
`
`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) ...................................................... 41
`
`Nintendo 0fAm., Inc. v. iLife Tech, Inc,
`IPR2015-00109, Paper 40 (Apr. 28, 2016) ....................................................... 41
`
`Federal Statutes
`
`35 U.S.C. § 102(a) .......................................................................................... 35, 42
`
`35 U.S.C. § 102(b) ................................................................................................ 42
`
`35 U.S.C. § 120 .................................................................................................... 42
`
`Constitutional Provisions
`
`US. Const. Amendment VII ................................................................................. 68
`
`

`

`IPR2017-01488
`
`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.
`
`

`

`IPR2017-01488
`
`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. Petitioners have 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. At their
`
`depositions, Petitioners’ declarants confirmed that the only way to know whether a
`
`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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`

`

`IPR2017-01488
`
`Patent Owner’s Response
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`particular humanized antibody has binding affinity at all is to test it—yet
`
`Petitioners have presented no evidence of such testing here.
`
`Third, Petitioners have 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 ’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.
`
`Fourth, claims 12, 42, 60, 65-67, and 71-79 recite at least one and up to five
`
`specific framework substitutions. Petitioners assert 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 Petitioners, Queen-1990 produced a
`
`humanized antibody with 15 substitutions—none of which correspond with the
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`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`claims.
`
`[f 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 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.
`
`Fifth, 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
`
`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 pISSHERZ.
`
`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 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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`

`

`lPR2017-01488
`
`Patent Owner’s Response
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`that a skilled artisan would not have had a reasonable expectation of success in
`
`achieving those specific claim limitations.
`
`II.
`
`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; Bit—1082 at 160.) A typical antibody, or “immunoglobulin,” has two identical
`
`heavy chains and two identical light chains:
`
`
`—_-_____4 D a I-————————__—.In
`
`i...’
`
`p h
`
`r——— I
`
`::
`
`(Ex-2041 ‘1133; EX-2023 at 10 (annotated); Err-1001, 1:17-20.) Each chain contains
`
`a “variable” domain (red box above) and “constant” domains (green box above).
`
`(Ex-2041 €135; Ex-lOOl, 1:20-27.) The heavy chain (VH) and light chain (VL)
`
`variable domains are illustrated above in blue and pink, respectively.
`
`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`Variable domains directly bind to the antigen.
`
`(Ex-2041 ‘][37; [ix-1001,
`
`1:35-37.) Each variable domain contains three “complementarity determining
`
`regions,” or “CDRs,” (Ex-2041 ‘][38; 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”—one on either side of each CDR—shown as FRI,
`
`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 LH40; Ex-lOOl, 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 ‘][39; Ex-lOOl, 1:37-44.)
`
`The constant domains are not direcdy involved in antigen binding and
`
`typically have similar amino acid sequences across all antibodies within a subclass.
`
`(Ex-2041 ‘1136; Bit-2016 t][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; Ex-1001, 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-lOOl, 1:55-58.) An
`
`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`immunogenic response had adverse clinical consequences, including diminished
`
`efficacy and allergic reactions. (Ex-2041 ‘][51; Err-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—1001, 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; Bit-1001, 2: 12-19;
`
`Bit-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 155; Ex-lOOl, 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, 55:5-9; Err-204]
`
`(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
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`

`

`IPR2017-01488
`
`Patent Owner’s Response
`
`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-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 ‘~][‘][85, 264-65.)
`
`III.
`
`’213 PATENT
`
`A.
`
`Invention
`
`Beginning in the late 19803, 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, 1 1:32-38.) That
`
`“consensus” sequence provided a single human sequence for any humanized
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`

`

`IPR2017-01488
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`Patent Owner’s Response
`
`antibody of a particular subclass or subunit structure (e.g., 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 to the human consensus sequence.
`
`(1d., 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,”
`
`i.€.,
`
`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.” (101, 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.)
`
`

`

`IPR2017-01488
`
`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 ‘][31.)
`
`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 3439-41, ‘][‘][2-9; Ex-2041
`
`‘][83.) 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; Err-2041 ‘][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-1002 at 3439-41, ‘][‘][2—9; Ex-
`
`204] ‘][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-2041 ‘][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®
`
`IPR2017-01488
`
`Patent Owner’s Response
`
`(asthma). (Ex-2017 ‘114; Ex-20l6 ‘][5.)
`
`C.
`
`Prosecution History
`
`The ’213 patent is a continuation-in-part of an application filed on June 14,
`
`199].
`
`(Ex-100] 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.
`
`Petitioners assert that Kurrle (Ex-1071), Chothia & Lesk (Ex-1062), and
`
`Chothia-1985 (Ex-1063) were not considered during prosecution. (Paper 1 at 14.)
`
`That is incorrect. Each is cited on the face of the patent.
`
`(See Ex- 1001 at l
`
`(Kurrle: “EP 403156”); id. at 2 (Chothia & Lesk: right column, ninth from top);
`
`id. (Chothia—1985: right column, twelfth from top).) And Chothia & Lesk and
`
`Chothia-1985 are discussed in the ’213 specification.
`
`(1d., 1:27-30 (Chothia-
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`1985); id, 3:1-3, 3:32, 7:7—8, 7:45, 10:38, 20:22-23, 20:29—30, 47:42-43, 48:66-67
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`(Chothia & Lesk).)
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`During prosecution, the applicants successfully antedated U.S. Patent No.
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`5,693,762, which had a filing date of September 28, 1990. (Ex-1002 at 4432-33,
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`4443.) As detailed below, the record in this proceeding further confirms that
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`certain challenged claims were also invented before the publication of either Kurrle
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`(December 19, 1990) or Queen-1990 (July 26, 1990).
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`IV. ASSERTED REFERENCES
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`A.
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`Kurrle
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`Kurrle is a European Patent Application published on December 19, 1990.
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`Kurrle is not prior art to certain challenged claims. (Infra §VIII.A.)
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`Unlike the ”213 patent’s consensus sequence approach, Kurrle used a best-fit
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`approach for antibody humanization.
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`(Ex—2041 ‘][129.) Starting from the murine
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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, 3:8-11), 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—i.e., 4 amino acids on either side of the 3
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`CDRs—or 48 potential substitutions in total. (Ex-2041 ‘][131; Ex-2039, 298:25-
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`299:5.) Kurrle provided no guidance on which substitutions may be beneficial for
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`any given antibody. (Ex-2041 ‘][l33.) Kurrle also highlighted the unpredictable
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`and “potential[ly] adverse consequences” of modifying the human antibody
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`sequence to incorporate amino acids from the murine antibody.
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`(Ex-1071, 8:40-43
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`(“[E]xtreme caution must be exercised to limit the number of changes.").)
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`Kurrle disclosed the sequence for four humanized antibodies: EUCIV],
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`EUCIVZ, EUCIV3, and EUCIV4. (Id, Tables 6A-B; Bit-2041 ‘][134 (identifying
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`substitutions in Kurrle’s antibodies).) EUCIVl and EUCIV2 lacked binding
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`affinity to the target antigen. (Ex-1071, 9:1-14; Ex-2041 ‘][l35.) EUCIV3 had
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`binding affinity for the target antigen, but it was less than the murine parent
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`antibody. (Ex- 1071, Table 7; EX-204l ‘][135.) EUCIV4 is the only antibody
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`sequence reported in Kurrle with substitutions at 71H, 73H, and/or 76H. (Ex-2041
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`‘][136.) However, Kurrle provides no binding affinity data for EUCIV4, and the
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`corresponding scientific publication to Kurrle makes no mention of EUCIV4. (Ex-
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`204] 1136; E's-2033.)
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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, 26:5-33z25; EX-204l t][‘][1 13-14.) Queen-1990 identified four general criteria
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`for designing humanized antibodies.
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`(Ex-2041 ‘][‘][114-122.)
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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.
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`(Ex-2041 ‘][‘][1 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-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 III: Queen-1990 disclosed that non-human residues may be used
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`immediately adjacent to CDRs to help maintain binding affinity. (Id, 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, 238:24-239:4.) 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, 246:25-247:4.)
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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 giv[es] the list that you would
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`consider replacing.” (Ex-2039, 253 :9- l 6.)
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`Queen-1990 disclosed a humanized antibody sequence produced using its
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`technique. (Ex-1050, Fig. 2.) That antibody contained 15 framework
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`substitutions—none of which correspond with the ’2 l 3 claims.
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`(Ex—2041 ‘][l 25.)
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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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`204] ‘][126; Ex-IOSO, 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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`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.
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`It consists of two antibody light chains, instead of two light
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`chains and two heavy chains. (Ex-2041 ‘][125.) 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 ‘][l47.)
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`Furey identified “1 1 side chain—side Chain hydrogen bonds” of which 6 “may
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`be common to all VL 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).
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`(1d,; Ex-2041 ‘][146.)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 ‘][14l.)
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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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`2
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`This shorthand follows Kabat’s convention, wh