Trials@uspto.gov PARTIES AND BOARD ONLY Paper No. 86
`Tel: 571-272-7822
`Entered: November 29,2018
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01373
`Patent 6,407,213 B1
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
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`IPR2017-01373
`Patent 6,407,213 B1
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`
`
`
`ORDERS
`
`Denying-in-Part and Dismissing-in-Part Petitioner’s Motion to Exclude
`37 C.F.R. § 42.64(c)
`
`Denying Patent Owner’s Motion to Exclude
`37 C.F.R. § 42.64(c)
`
`Dismissing Patent Owner’s Motion to Strike
`37 C.F.R. § 42.5
`
`Denying Petitioner’s Motions to Seal without Prejudice to Patent Owner
`37 C.F.R. § 42.55
`
`Granting Patent Owner’s Motion to Seal
`37 C.F.R. § 42.55
`
`Modifying Previous Order Granting Patent Owner’s Motions to Seal
`37 C.F.R. § 42.55
`
`
`
`ii
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`IPR2017-01373
`Patent 6,407,213 B1
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`
`INTRODUCTION
`Celltrion, Inc. (“Petitioner”) filed a Petition for an inter partes review
`of claims 1, 2, 4, 12, 25, 29–31, 33, 42, 60, 62–67, 69, and 71–81 of U.S.
`Patent No. 6,407,213 B1 (“the ’213 patent,” Ex. 1001). Paper 2 (“Pet.”).
`Genentech, Inc. (“Patent Owner”) filed a Preliminary Response. Paper 9
`(“Prelim. Resp.”). We instituted trial to review patentability of the
`challenged claims. Paper 16 (“Dec.”).
`Thereafter, Patent Owner filed a Response to the Petition (Paper 38,
`“PO Resp.”), and Petitioner filed a Reply (Paper 54). The parties also
`briefed whether certain exhibits should be excluded from the record.
`Papers 61, 64, 68, 69, 72, 81. Patent Owner further sought to strike certain
`evidence and argument, and the parties briefed the issue. Papers 59, 71. In
`addition, Patent Owner filed a motion for observation on the cross-
`examination of Petitioner’s declarant (Paper 66), and Petitioner filed an
`opposition thereto (Paper 70).
`An oral hearing for this proceeding was held on July 16, 2018. See
`Paper 83.
`The Board has jurisdiction under 35 U.S.C. § 6 and issues this final
`written decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. For
`the reasons provided below, we conclude Petitioner has established by a
`preponderance of the evidence that claims 1, 2, 4, 12, 25, 29–31, 33, 42, 60,
`62–64, 66, 67, 69, 71, 73, 74, 78, 80, and 81 of the ’213 patent are
`unpatentable. Petitioner, however, has not met its burden to show the
`unpatentability of claims 65, 72, 75–77, and 79.
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`Patent 6,407,213 B1
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`Related Proceedings
`Petitioner also filed IPR2017-01374, challenging the same claims of
`the ’213 patent based on different prior art references. Concurrently with
`this Decision, we issue a final written decision in that case.
`The ’213 patent is also the subject of IPR2017-01488 (with
`IPR2017-02139 joined thereto) and IPR2017-01489 (with IPR2017-02140
`joined thereto). Concurrently with this Decision, we issue final written
`decision in those cases.
`Four other inter partes reviews involving the ’213 patent have been
`terminated. In IPR2016-01693 and IPR2016-01694, the parties settled
`before institution, whereas in IPR2017-02031 and IPR2017-02032,
`Petitioner sought adverse judgement after institution.
`The parties further identified several district court cases involving the
`’213 patent. Paper 84, 3–4; Paper 85, 2–3.
`The ’213 Patent and Relevant Background
`The ’213 patent issued from an application that is a
`continuation-in-part of an application filed on June 14, 1991. Ex. 1001, (63).
`The ’213 patent relates to “methods for the preparation and use of variant
`antibodies and finds application particularly in the fields of immunology and
`cancer diagnosis and therapy.” Ex. 1001, 1:12–14.
`A naturally occurring antibody (immunoglobulin) comprises two
`heavy chains and two light chains. Id. at 1:18–20. Each heavy chain has a
`variable domain (VH) and a number of constant domains. Id. at 1:21–23.
`Each light chain has a variable domain (VL) and a constant domain. Id. at
`1:23–24.
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`
`The variable domains are involved directly in binding the antibody to
`the antigen. Id. at 1:36–38. Each variable domain “comprises four
`framework (FR) regions, whose sequences are somewhat conserved,
`connected by three hyper-variable or complementarity determining regions
`(CDRs).” Id. at 1:40–43. The constant domains are not involved directly in
`binding the antibody to an antigen, but are involved in various effector
`functions. Id. at 1:33–34.
`Before the ’213 patent, monoclonal antibodies targeting a specific
`antigen, obtained from animals, such as mice, had been shown to be
`antigenic in human clinical use. Id. at 1:51–53. The ’213 patent recognizes
`efforts to construct chimeric antibodies and humanized antibodies in the
`prior art. Id. at 1:59–2:52. According to the ’213 patent, chimeric
`antibodies are “antibodies in which an animal antigen-binding variable
`domain is coupled to a human constant domain” (id. at 1:60–62), whereas
`“humanized antibodies are typically human antibodies in which some CDR
`residues and possibly some FR residues are substituted by residues from
`analogous sites in rodent antibodies” (id. at 2:32–35).
`The ’213 patent also acknowledges the following as known in the
`prior art:
`In certain cases, in order to transfer high antigen binding
`1.
`affinity, it is necessary to not only substitute CDRs, but also replace one or
`several FR residues from rodent antibodies for the human CDRs in human
`frameworks. Id. at 2:53–61.
`“For a given antibody[,] a small number of FR residues are
`2.
`anticipated to be important for antigen binding” because they either directly
`
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`Patent 6,407,213 B1
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`contact antigen or “critically affect[] the conformation of particular CDRs
`and thus their contribution to antigen binding.” Id. at 2:62–3:8.
`In a few instances, a variable domain “may contain
`3.
`glycosylation sites, and that this glycosylation may improve or abolish
`antigen binding.” Id. at 3:9–12.
`The function of an antibody is dependent on its
`4.
`three-dimensional structure, and amino acid substitutions can change the
`three-dimensional structure of an antibody. Id. at 3:40–43.
`The antigen binding affinity of a humanized antibody can be
`5.
`increased by mutagenesis based upon molecular modelling. Id. at 3:44–46.
`Despite such knowledge in the field, according to the ’213 patent, at
`the time of its invention, humanizing an antibody with retention of high
`affinity for antigen and other desired biological activities was difficult to
`achieve using then available procedures. Id. at 3:50–52. The ’213 patent
`purportedly provides methods for rationalizing the selection of sites for
`substitution in preparing humanized antibodies and, thereby, increasing the
`efficiency of antibody humanization. Id. at 3:53–55.
`Illustrative Claim
`Among the challenged claims, claims 1, 30, 62–64, 66, 79, and 80 are
`independent. Claim 1 is illustrative and is reproduced below:
`1.
`A humanized antibody variable domain comprising non-
`human Complementarity Determining Region (CDR) amino acid
`residues which bind an antigen incorporated into a human
`antibody variable domain, and further comprising a Framework
`Region (FR) amino acid substitution at a site selected from the
`group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L,
`67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H,
`
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`Patent 6,407,213 B1
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`
`Claim(s)
`1, 2, 12, 25, 29, 63,
`651–67, and 71–81
`1, 2, 4, 12, 25, 29, 62–
`67, 69, and 71–81
`65, 75–77, and 79
`
`65, 75–77, and 79
`
`2
`
`3
`
`4
`
`69H, 70H, 74H, and 92H, utilizing the numbering system set
`forth in Kabat.
`Reviewed Grounds of Unpatentability
`We instituted inter partes review of the following grounds of
`unpatentability:
`Ground
`1
`
`§ 103
`
`Basis
`§ 103
`
`Reference(s)
`Queen 19892 and Protein
`Data Bank (PDB database)
`Queen 19903 and PDB
`database
`§ 103 Queen 1989, PDB database,
`and Tramontano4
`§ 103 Queen 1990, PDB database,
`and Tramontano
`
`
`1 In the Petition, the summary chart of the challenges does not include
`claim 65 in Ground 1. Pet. 4. As a result, we did not include claim 65 in
`Ground 1 in our Decision to Institute. Dec. 5, 22. Petitioner later stated that
`the omission was due to a “clerical error.” Tr. 5:10–12. Although Patent
`Owner correctly pointed out that the clerical error was “not on the Board’s
`part” (id. at 5:21–6:3), we ordered that the “the institution decision in
`IPR2017-01373 include Claim 65” (id. at 7:3–5) because Patent Owner
`addressed that claim in its Response, and “there appears to be no prejudice
`to Patent Owner” (id. at 5:15–18).
`2 Queen et al., A Humanized Antibody that Binds to the Interleukin 2
`Receptor, 86 PRO. NAT’L ACAD. SCI. 10029–33 (1989) (Ex. 1034).
`3 Queen et al., International Publication No. WO 90/07861 A1, published
`July 26, 1990 (Ex. 1050).
`4 Tramontano, A. et al., Framework Residue 71 is a Major Determinant of
`the Position and Conformation of the Second Hypervariable Region in the
`VH Domains of Immunoglobulins, 215 J. MOL. BIOL. 175–82 (1990)
`(Ex. 1051).
`
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`Patent 6,407,213 B1
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`
`Ground
`5
`
`Claim(s)
`4, 62, 64, and 69
`
`6
`
`7
`
`30, 31, 42, and 60
`
`30, 31, 33, 42, and 60
`
`Reference(s)
`Basis
`§ 103 Queen 1989, PDB database,
`and Kabat 19875
`§ 103 Queen 1989, PDB database,
`and Hudziak6
`§ 103 Queen 1990, PDB database,
`and Hudziak
`
`Pet. 4; Dec. 5, 22.
`In support of its patentability challenges, Petitioner relies on the
`Declarations of Dr. Lutz Riechmann (Exs. 1003, 1143) and Dr. Robert
`Charles Fredrick Leonard (Ex. 1004).
`Patent Owner relies on the Declarations of co-inventors Dr. Leonard
`G. Presta (Ex. 2016) and Dr. Paul J. Carter (Ex. 2017), research technician
`Mr. John Ridgway Brady (Ex. 2018), and expert witness Dr. Ian A. Wilson
`(Ex. 2041).
`
`ANALYSIS
`Principles of Law
`To prevail in this inter partes review of the challenged claims,
`Petitioner must prove unpatentability by a preponderance of the evidence.
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`
`
`5 Kabat, et al., Sequences of Proteins of Immunological Interest, Tabulation
`and Analysis of Amino Acid and Nucleic Acid Sequences of Precursors, V-
`Regions, C-Regions, J-Chain, T-Cell Receptor for Antigen, T-Cell Surface
`Antigens (National Institutes of Health, Bethesda, MD, 4th Ed. 1987)
`(Ex. 1052).
`6 Hudziak et al., p185HER2 Monoclonal Antibody Has Antiproliferative
`Effects In Vitro and Sensitizes Human Breast Tumor Cells to Tumor
`Necrosis Factor, 9 MOL. CELL BIOL. 1165–72 (1989) (Ex. 1021).
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`
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations, including (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of skill in the art; and (4) objective evidence of nonobviousness.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). The strength of each
`of the Graham factors must be weighed in every case and must be weighed
`en route to the final obviousness determination. See, e.g., Stratoflex, Inc. v.
`Aeroquip Corp., 713 F.2d 1530, 1538–39 (Fed. Cir. 1983) (instructing that
`evidence of secondary considerations, when present, must always be
`considered in determining obviousness).
`A party that asserts obviousness of a claim must show that “a skilled
`artisan would have been motivated to combine the teachings of the prior art
`references to achieve the claimed invention, and that the skilled artisan
`would have had a reasonable expectation of success in doing so.” In re
`Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016). An
`obviousness analysis, however, “need not seek out precise teachings directed
`to the specific subject matter of the challenged claim” because we “can take
`account of the inferences and creative steps that a person of ordinary skill in
`the art would employ.” KSR, 550 U.S. at 418. Moreover, “any need or
`problem known in the field of endeavor at the time of invention and
`
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`addressed by the patent can provide a reason for combining the elements in
`the manner claimed.” Id. at 420.
`We analyze the instituted grounds of unpatentability in accordance
`with these principles.
`Level of Ordinary Skill in the Art
`In the Decision to Institute, we found the parties’ proposed definitions
`of a person of ordinary skill for the ’213 patent are similar. Dec. 10 (citing
`Pet. 12; Prelim. Resp. 17). We adopted Patent Owner’s proposed definition
`that “[a] person of ordinary skill for the ’213 patent would have had a Ph.D.
`or equivalent in chemistry, biochemistry, structural biology, or a closely
`related field, and experience with antibody structural characterization,
`engineering, and/or biological testing, or an M.D. with practical academic or
`industrial experience in antibody development.” Id. at 10–11. During trial,
`the parties did not dispute this finding. Having considered the complete
`record developed at trial, we see no reason to change our assessment.
`We further note that, in this case, the prior art itself demonstrates the
`level of skill in the art at the time of the invention. See Okajima v.
`Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that specific
`findings regarding ordinary skill level are not required “where the prior art
`itself reflects an appropriate level and a need for testimony is not shown”)
`(quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158,
`163 (Fed. Cir. 1985)).
`
`Claim Construction
`In an inter partes review, the Board interprets a claim term in an
`unexpired patent according to its broadest reasonable construction in light of
`the specification of the patent in which it appears. 37 C.F.R. § 42.100(b)
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`(2017); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016).
`Under that standard, and absent any special definitions, we assign claim
`terms their ordinary and customary meaning, as would be understood by one
`of ordinary skill in the art at the time of the invention, in the context of the
`entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. In re Paulsen, 30
`F.3d 1475, 1480 (Fed. Cir. 1994).
`In the Decision to Institute, we agreed with Patent Owner that the
`’213 patent expressly defined “consensus human variable domain,” which
`appears in claims 4, 33, 62, and 69, to mean “a human variable domain
`which comprises the most frequently occurring amino acid residues at each
`location in all human immunoglobulins of any particular subclass or subunit
`structure.” Dec. 7; Ex. 1001, 11:32–38. During trial, the parties did not
`argue otherwise, and we see no reason to change our position as to claim
`construction.
`We, however, clarify that “all” in the consensus of “all human
`immunoglobulins” is not in the literal sense. Indeed, counsel for Patent
`Owner acknowledged that the term refers to “all reasonably available[,] all
`known at the time of the invention.” Tr. 47:21–48:5. Dr. Wilson, the expert
`witness for Patent Owner, testified that the consensus sequence of the
`’213 patent was “derived from ‘all’ known antibody sequences of any
`particular subclass or subunit structure.” Ex. 2041 ¶ 207 (emphasis added);
`see also PO Resp. 52 (arguing the same); Ex. 1140, 59:22–60:1 (Dr. Carter
`testifying that the consensus sequence, as defined in the ’213 patent, “only
`describes what was known at that time or it’s only available sequences at
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`that -- at that time”); Ex. 1142, 35:9–16 (Dr. Presta explaining that the
`consensus sequence of the ’213 patent had the most common residue at
`every position “for the sequences that were available”).
`And evidence of record shows that at the priority date of the
`’213 patent, the sequences that were listed in Kabat 1987 “were the
`sequences available.” Ex. 1142, 35:9–20; see also Ex. 2016 ¶ 25 (Kabat
`1987 “collected known sequence data of antibodies”); Ex. 1140, 60:13–25
`(Dr. Carter explaining the consensus sequence was derived from
`Kabat 1987, which is what was available at the time of the ’213 patent);
`Ex. 1142, 27:19–25 (Dr. Presta stating that “Elvin Kabat had taken all
`known human/mouse/rabbit antibody sequences, published them in a
`government publication, and that there were human subgroups of sequences
`within the heavy and the light chains”).
`Thus, although we reiterate our previous construction of “consensus
`human variable domain,” we clarify that “all human immunoglobulins of
`any particular subclass or subunit structure” in the ’213 patent refers to those
`immunoglobulins set forth in Kabat 1987. 7
`In the institution decision of IPR2017-01488, the same panel stated
`that the term “lacks immunogenicity,” as recited in claim 63, refers to a
`humanized antibody having reduced immunogenicity in a human patient as
`compared to its non-humanized parent antibody. For the purpose of this
`
`
`7 Because an inter partes review is limited to challenges based “only on the
`basis of prior art consisting of patents or printed publications,” we do not
`address whether the challenged claims would satisfy the written description
`and/or enablement requirement under 35 U.S.C. § 112 if “all human
`immunoglobulins” were not limited as set forth in Kabat 1987.
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`Decision, we adopt the same interpretation, which neither party disputes.
`See PO Resp. 18; Reply 16.
`For the purpose of this Decision, we see no need to expressly construe
`any other claim terms. Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355,
`1361 (Fed. Cir. 2011) (stating claim terms need only be construed to the
`extent necessary to resolve the controversy).
`Disclosures of the Asserted Prior Art
`
`Queen 1989
`Queen 1989 teaches constructing a humanized antibody by combining
`the CDRs of a murine antibody with human framework and constant
`regions. Ex. 1034, Abstract, 3–4. According to Queen 1989, “[f]or the
`humanized antibody, sequence homology and molecular modeling were used
`to select a combination of mouse and human sequence elements that would
`reduce immunogenicity while retaining high binding affinity.” Id. at 1. In
`Queen 1989, the human framework regions were chosen to maximize
`homology with the murine antibody sequence. Id. at Abstract, 3. In
`addition, based on a computer model, Queen 1989 identified “several amino
`acids which, while outside the CDRs, are likely to interact with the CDRs or
`antigen. These mouse amino acids were also retained in the humanized
`antibody.” Id. at Abstract, 3. Further, Queen 1989 teaches substituting an
`unusual amino acid in the human framework region if the corresponding
`positions in the murine antibody “actually has a residue much more typical
`of human sequences.” Id. at 4.
`
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`Queen 1990
`Queen 1990 teaches the following four criteria for designing
`humanized antibodies that “have a very strong affinity for a desired
`antigen”:
`
`Criterion I: As acceptor, use a framework from a particular
`human immunoglobulin that is unusually homologous to the
`donor immunoglobulin to be humanized, or use a consensus
`framework from many human antibodies . . . .
`. . . .
`Criterion II: If an amino acid in the framework of the
`human acceptor immunoglobulin is unusual (i.e. “rare”, which as
`used herein indicates an amino acid occurring at that position in
`no more than about 10% of human heavy (respectively light)
`chain V region sequences in a representative data bank), and if
`the donor amino acid at that position is typical for human
`sequences (i.e. “common”, which as used herein indicates an
`amino acid occurring in at least about 25% of sequences in a
`representative data bank), then the donor amino acid rather than
`the acceptor may be selected . . . .
`Criterion III: In the positions immediately adjacent to one
`or more of the 3 CDR[]s in the primary sequence of the
`humanized immunoglobulin chain, the donor amino acid(s)
`rather than acceptor amino acid may be selected. These amino
`acids are particularly likely to interact with the amino acids in
`the CDR[]s and, if chosen from the acceptor, distort the donor
`CDR[]s and reduce affinity. Moreover, the adjacent amino acids
`may interact directly with the antigen . . . and selecting these
`amino acids from the donor may be desirable to keep all the
`antigen contacts that provide affinity in the original antibody.
`Criterion IV: A 3-dimensional model, typically of the
`original donor antibody, shows that certain amino acids outside
`of the CDR[]s are close to the CDR[]s and have a good
`probability of interacting with amino acids in the CDR[]s by
`hydrogen bonding, Van der Waals forces, hydrophobic
`interactions, etc. At those amino acid positions, the donor amino
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`acid rather than the acceptor immunoglobulin amino acid may be
`selected. Amino acids according to this criterion will generally
`have a side chain atom within about 3 angstrom units of some
`site in the CDR[]s and must contain atoms that could interact
`with the CDR atoms according to established chemical forces,
`such as those listed above.
`Ex. 1050, 14:9–16:25. According to Queen 1990, “[w]hen combined into an
`intact antibody, the humanized light and heavy chains of the present
`invention will be substantially non-immunogenic in humans and retain
`substantially the same affinity as the donor immunoglobulin to the antigen.”
`Id. at 8:21–25.
`PDB Database
`According to Petitioner, the Protein Data Bank (PDB) database was
`established in 1971 as a computer archival service managed by the
`Brookhaven National Laboratory. Pet. 19–20; Ex. 1003 ¶ 129 (citing
`Ex. 1080). “The purpose of the Bank is to collect, standardize, and
`distribute atomic co-ordinates and other data from crystallographic studies.”
`Ex. 1080, 1. Dr. Riechmann testifies that the PDB database “is a repository
`of protein crystal atomic co-ordinates available to the public.” Ex. 1003
`¶ 129. “The information provided in the PDB database was only a list of
`residues and their coordinates, but this was computer-readable data that
`could be directly inputted into distance calculation and graphic programs . . .
`for use in visualization and comparison studies.” Id. According to
`Dr. Riechmann, in 1991, an ordinary artisan “relied on and contributed to the
`PDB database.” Id.
`Tramontano
`Tramontano teaches that “the major determinant of the position of H2
`[i.e., CDR2 of the heavy chain] is the size of the residue at site 71, a site that
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`is in the conserved framework of the VH domain.” Ex. 1051, Abstract.
`According to Tramontano, “[u]nderstanding the relationship between the
`residue at position 71 and the position and conformation of H2 has
`applications to the prediction and engineering of antigen-binding sites of
`immunoglobulins.” Id.
`Kabat 1987
`Kabat 1987 is a compilation of known antibody sequences. Ex. 1052.
`For a given type of immunoglobulin, Kabat 1987 identifies the most
`common amino acids occurring at each position. See, e.g., id. at 8. It also
`teaches the FR and CDR boundaries within the variable domains. See, e.g.,
`id. at 6–11.
`Hudziak
`Hudziak teaches p185HER2’s role in carcinoma development.
`Ex. 1021, Abstract. Hudziak shows that 4D5, “a monoclonal antibody
`directed against the extracellular domain of p185HER2 specifically inhibits the
`growth of breast tumor-derived cell lines overexpressing the HER2/c-erbB-2
`gene product.” Id. In addition, Hudziak reports that “resistance to the
`cytotoxic effect of tumor necrosis factor alpha, which has been shown to be
`a consequence of HER2/c-erbB-2 overexpression, is significantly reduced in
`the presence of this antibody.” Id. Hudziak states that “[m]onoclonal
`antibodies specific for p185HER2 may therefore be useful therapeutic agents
`for the treatment of human neoplasias.” Id. at 7.
`Unpatentability of Claims 1, 2, 25, 29, 80, and 81
`Petitioner challenges claims 1, 2, 25, 29, 80, and 81 as obvious over
`the combination of the PDB database with either Queen 1989 or
`Queen 1990. Pet. 26–36, 48–49. Patent Owner states it “does not defend
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`the patentability of” those claims. PO Resp. 19–20. We adopt Petitioner’s
`obviousness analysis of claims 1, 2, 25, 29, 80, and 81 (Pet. 26–36, 48–49),
`and conclude Petitioner has shown by a preponderance of the evidence that
`those claims are unpatentable.
`Alternatively, we interpret Patent Owner’s express decision not to
`defend the patentability of claims 1, 2, 25, 29, 80, and 81 as a request for
`adverse judgment as to those claims. A party may request judgment against
`itself at any time during a proceeding. 37 C.F.R. § 42.73(b). Thus, we enter
`judgment adverse to Patent Owner with respect to those claims.
`Ground 1: Obviousness over Queen 1989 and PDB Database
`Petitioner argues that claims 1, 2, 12, 25, 29, 63, 65–67, and 71–81
`would have been obvious over the combination of Queen 1989 and the PDB
`database. Pet. 26–49. Because we dispose of claims 1, 2, 25, 29, 80, and 81
`above, we only need to address the patentability of claims 12, 63, 65–67, and
`71–79 as challenged under this ground. After reviewing the entire record,
`we determine that Petitioner has established by a preponderance of the
`evidence that claims 12, 63, 66, 67, 71, 73, 74, and 78 are unpatentable. We,
`however, conclude that Petitioner has not met its burden to show the
`unpatentability of claims 64, 65, 72, 75–77, and 79.
`Relying on the Declaration of Dr. Riechmann, Petitioner asserts that
`Queen 1989 taught that framework residues that (1) are close
`enough to influence CDR conformation; (2) interact directly with
`the antigen; and/or (3) are more ‘human’ in the mouse or donor
`immunoglobulin than the residue at the same position in human
`antibody variable domain (i.e., conserved) are candidates for
`substitution with the donor antibody residue in the humanization
`process.
`
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`Pet. 27 (citing Ex. 1034, 3–4; Ex. 1003 ¶ 247). According to Petitioner, an
`ordinary artisan “would have used those simple rules to determine which
`residues in a human FR region could be switched back to mouse.” Id.
`(citing Ex. 1003 ¶¶ 247–250).
`“[F]ollowing the teaching of Queen 1989” and using antibodies well-
`known prior to the ’213 patent, Petitioner continues, Dr. Riechmann was
`able to confirm the CDR-contacting framework residues that were targets for
`substitution. Pet. 30 (citing Ex. 1003 ¶¶ 254–258). These include residues
`4L, 58L, 62L, 66L, 67L, 69L, 8 73L, 85L, and 105L in the light chain, and
`residues 2H, 24H, 39H, 45H, 69H, 71H, 73H, 76H, 78H, 93H, and 103H in
`the heavy chain. Id.
`Of the ’213 patent, claims 12, 71, 73, and 74 recite a substitution at
`66L, 73H, 78H, and 93H, respectively; claim 63 recites a substitution at 4L,
`58L, 62L, 66L, 67L, 69L, 73L, 85L, 2H, 39H, 45H, or 69H; each of claims
`66, 67, and 78 recites a substitution at 24H, 73H, 78H, or 93H. Thus,
`Petitioner argues these claims would have been obvious over the
`combination of Queen 1989 and the PDB database. Pet. 35–47.
`Claims 12, 71, 73, and 74
`Patent Owner argues that Queen 1989 does not disclose a 3.3
`angstrom cutoff, the distance Petitioner relies on to identify CDR-contacting
`framework residues. PO Resp. 44–45. According to Patent Owner,
`Petitioner’s obviousness analysis under this Ground in fact relies on the
`
`
`8 Even though the Petition states that Dr. Riechmann found “8 light (L)
`chain” residues and does not list 69L (Pet. 30), Dr. Riechmann actually
`testifies he found nine residues, including 69L, in the light chain (Ex. 1003
`¶ 255).
`
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`teachings of Queen 1990, which is not prior art to claims 12, 42, 60, 65, 71,
`73, 74, and 79. Id. (citing Ex. 1003 ¶ 263 & n.17). We are not persuaded.
`Dr. Riechmann testified that, in his opinion, an ordinary artisan
`“would have been motivated by Queen 1989 to substitute framework
`residues that contacted CDRs or antigen during antibody humanization in
`order to maintain conformation in the CDR/antigen binding regions.”
`Ex. 1003 ¶ 250. He noted that Dr. Eduardo A. Padlan, an expert witness for
`the petitioner in IPR2016-01693 and IPR2016-01694, “used known variable
`domain structures that were published in the PDB database to demonstrate
`the roadmap set forth in Queen 1989.” Id. ¶ 253. Dr. Riechmann stated that
`he agreed with Dr. Padlan’s analysis9 and had used the same procedure to
`humanize antibodies. Id. For the analysis,
`First, the atomic coordinates on the PDB database for each
`antibody above were extracted, each of the atoms of the main and
`side chains of each amino acid in the framework region was
`evaluated, and the Euclidean distance to the atoms of the main
`and side chain of the contacted CDR amino acid residue was
`calculated.
`
`
`9 Patent Owner argues that Dr. Riechmann “simply adopted” the opinion of
`Dr. Padlan without confirming the calculations. PO Resp. 46 (citing
`Ex. 2039, 313:5–314:6, 318:16–319:1, 320:11–321:2). Dr. Riechmann,
`however, testified that he independently analyzed the validity of the ’213
`patent and identified prior art before reviewing Dr. Padlan’s declaration.
`Ex. 2039, 32:4–16. He stated that he agreed with Dr. Padlan’s analysis and
`found the information therein “accurate and useful” in support of his own
`opinion. Ex. 1003 ¶¶ 10, 253; see also Ex. 2039, 314:14–317:22. In
`addition, Dr. Wilson, Patent Owner’s expert, agreed that Dr. Padlan “was
`certainly . . . an expert in antibody structures” with “a good reputation.”
`Ex. 1138, 236:13–237:1. Under these circumstances, we find it reasonable
`for Dr. Riechmann to rely on Dr. Padlan’s opinion.
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`Id. ¶ 255. The interatomic distance calculations are summarized in
`Exhibit O, and the “identity of framework residue atoms which contact the
`respective CDRs as demonstrated by their proximity (i.e., within about 3 Å
`in one or more known antibody structures) for each known and solved
`antibody structure available prior to June 1991” is listed in Exhibit Q. Id.
`(footnote omitted).
`In a footnote, Dr. Riechmann explained the 3 Å cutoff:
`As noted above, a person of ordinary skill in the art in 1991
`would have understood 3 Å to be the closest two atoms can be
`without a covalent or hydrogen bond between them. Thus, a
`person of ordinary skill in the art would have interpreted these
`residues to be in contact. See also, e.g., Queen 1990 at 14:21–25
`[Ex. 1050 at 16] (“Amino acids according to this criterion will
`generally have a side chain atom within about 3 angstrom units
`of some site in the CDR’s and must contain atoms that could
`interact with the CDR atoms according to established chemical
`forces, such as those listed above.”). In my experience, the term
`“about” generally means a +/– 10% variance from the claimed
`value. Accordingly, any distance of 3.3 Å or less will fall under
`this distance threshold set by Queen 1990 [Ex. 1050]. Even
`without the language in Queen 1990, however, a person of
`ordinary skill in the art would have identified residues closer than
`about 3 Å.
`Id. n.17.
`Patent Owner takes issue with the citation to Q