Trials@uspto.gov
`571-272-7822
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`Paper No. 15
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` Entered: December 1 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01374
`Patent 6,407,213 B1
`____________
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`
`
`
`Paper No. 15
`
`
` Entered: December 1 2017
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-01374
`Patent 6,407,213 B1
`____________
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`IPR2017-01374
`Patent 6,407,213 B1
`
`
`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”) timely filed a Preliminary Response.
`Paper 7 (“Prelim. Resp.”). We review the Petition, Preliminary Response,
`and accompanying evidence under 35 U.S.C. § 314.
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Because
`Petitioner has established a reasonable likelihood that it would prevail in
`showing the unpatentability of at least one challenged claims, we institute an
`inter partes review of the challenged claims.
`Related Proceedings
`Petitioner has concurrently filed IPR2017-01373, challenging the
`same claims of the ’213 patent based on different prior art references. Paper
`3, 4.
`
`The ’213 patent is the subject of IPR2016-01693 and IPR2016-01694,
`filed by Mylan Pharmaceuticals Inc. Paper 3, 4. Those two proceedings
`were terminated before institution due to settlement. Mylan
`Pharmaceuticals Inc. v. Genentech, Inc., IPR2016-01693 (PTAB March 10,
`2017) (Paper 24); IPR2016-01694 (PTAB March 10, 2017) (Paper 23).
`The ’213 patent is also the subject of the following pending matters:
`IPR2017-01488 and IPR2017-01489, brought by Pfizer, Inc.; IPR2017-
`02031 and IPR2017-02032 brought by Boehringer Ingelheim
`Pharmaceuticals, Inc.; and IPR2017-02139 and IPR2017-02140, brought by
`Samsung Bioepis Co., Ltd.
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`IPR2017-01374
`Patent 6,407,213 B1
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`
`The parties have identified no district court cases involving the ’213
`patent. We note, however, that the petitioner in IPR2017-01488 represents
`that the ’213 Patent is at issue in Amgen Inc. v. Genentech, Inc., No. 2-17-
`cv-07349 (C.D. Cal.); Genentech, Inc. v. Amgen Inc., No. 1-17-cv-01407 (D.
`Del.); Genentech, Inc. v. Amgen Inc., No. 1-17-cv-01471 (D. Del.).
`IPR2017-01488, Paper 16, 1. The parties are encouraged to update their
`mandatory disclosures.
`The ’213 Patent and Relevant Background
`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.
`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 1:33–35.
`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
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`Patent 6,407,213 B1
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`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
`contact antigen or “critically affect[] the conformation of particular CDRs
`and thus their contribution to antigen binding.” Id. at 2:62–3:8.
`3.
`In a few instances, a variable domain “may contain glycosylation
`sites, and that this glycosylation may improve or abolish antigen binding.” Id.
`at 3:9–12.
`4.
`The function of an antibody is dependent on its three-dimensional
`structure, and amino acid substitutions can change the three-dimensional
`structure of an antibody. Id. at 3:40–43.
`5.
`The antigen binding affinity of a humanized antibody can be
`increased by mutagenesis based upon molecular modelling. Id. at 3:44–46.
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`4
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`Patent 6,407,213 B1
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`
`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, 69H, 70H, 74H, and 92H,
`utilizing the numbering system set forth in Kabat.
`Ex. 1001, 85:44–52.
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 4):
`Ground
`Claim(s)
`Basis
`Reference(s)
`1
`1, 2, 25, 29, 63, 66, 71,
`§ 102 Kurrle1
`75, 76, 78, 80, and 81
`1, 2, 4, 29, 62–64, 80,
`and 81
`
`2
`
`§ 102 Queen 19902
`
`
`1 Kurrle, et al., European Patent Application Publication No. 0403156,
`published December 19, 1990. Ex. 1071.
`2 Queen, et al., International Publication No. WO 1990/07861, published
`July 26, 1990. Ex. 1050.
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`Patent 6,407,213 B1
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`
`Ground
`3
`
`Reference(s)
`Basis
`§ 103 Queen 1990 and Kurrle
`
`Claim(s)
`1, 2, 4, 25, 29, 62–64,
`66, 67, 69, 71, 72, 75,
`76, 78, 80, and 81
`12
`
`4
`
`5
`
`6
`7
`
`8
`
`65, 73, 74, 77, 79
`
`60
`
`
`
`30, 31, and 33
`42
`
`§ 103 Queen 1990, Kurrle, and
`Furey 3
`§ 103 Queen 1990, Kurrle, and
`Chothia & Lesk,4 and
`Chothia 19855
`§ 103 Queen 1990 and Hudziak6
`
`Queen 1990, Kurrle,
`Hudziak and Furey
`Queen 1990, Hudziak, and
`Chothia & Lesk
`In support of its patentability challenges, Petitioner relies on the
`Declarations of its technical experts, Dr. Lutz Riechmann, Ph.D (Ex. 1003)
`and Dr. Robert Charles Fredrick Leonard, M.D. (Ex. 1004).
`Patent Owner relies on the Declarations of named inventors
`Dr. Leonard G. Presta (Ex. 2016) and Dr. Paul J. Carter (Ex. 2017), research
`technician Mr. John Ridgway Brady (Ex. 2018).
`
`
`
`
`3 Furey et al., Structure of a Novel Bence-Jones Protein (Rhe) Fragment at
`1.6 Å Resolution, 167 J. MOL. BIOL. 661–92 (1983). Ex. 1125.
`4 Chothia and Lesk, Canonical Structures for the Hypervariable Regions of
`Immunoglobulins, 196 J. MOL. BIOL. 901–17 (1987). Ex. 1062.
`5 Chothia et al., Domain Association in Immunoglobulin Molecules: The
`Packing of Variable Domains, 186 J. MOL. BIOL. 651–63 (1985). Ex. 1063.
`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.
`6
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`Patent 6,407,213 B1
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`
`ANALYSIS
`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);
`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).
`Petitioner proposes the construction of several claim terms. Pet. 13–
`15. Patent Owner states that “[n]o construction of those terms is necessary,
`but Patent Owner does not dispute Celltrion’s proposed constructions for
`purposes of this proceeding.” Prelim. Resp. 18. We agree with Patent
`Owner that those terms do not need express construction. See Wellman, Inc.
`v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (instructing
`that claim terms need only be construed to the extent necessary to resolve
`the controversy).
`Patent Owner proposes that we construe the term “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.” Prelim. Resp. 18–19. According to
`Patent Owner, “[t]hat construction comes directly from the definition
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`provided in the ’213 patent.” Id. at 18–19 (citing Ex. 1001, 11:32–38). For
`purposes of this Decision, we adopt Patent Owner’s proposed construction.
`Prior-Art Status of Kurrle and Queen 1990
`Petitioner asserts that Kurrle and Queen 1990 are prior art. See, e.g.,
`Pet. 1, 7. Patent Owner disagrees. Prelim. Resp. 2, 12, 13, 20–42.
`In an inter partes review, the burden of persuasion is on the petitioner
`to prove unpatentability by a preponderance of the evidence, and that burden
`never shifts to the patentee. Dynamic Drinkware, LLC v. Nat’l Graphics,
`Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015). The petitioner also has the
`initial burden of production to show that an asserted reference qualifies as
`prior art under 35 U.S.C. § 102. Id. at 1378–79. Once the petitioner has met
`that initial burden, the burden of production shifts to the patent owner to
`argue or produce evidence that either the asserted reference does not render
`the challenged claims unpatentable, or the reference is not prior art. Id.
`(citing Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed.
`Cir. 2008)).
`A threshold issue, then, is whether Petitioner has met its initial burden
`to show that Kurrle and Queen 1990 are prior art to the challenged claims.
`The ’213 patent issued from application number 08/146,206 (“the ’206
`application”), which is an application that entered the national stage on
`November 17, 1993, from a PCT application filed on June 15, 1992.
`Ex. 1001, (21), (22), (86). The ’206 application is also a continuation-in-
`part of application No. 07/715,272 (“the ’272 application”), filed on June 14,
`1991. Id. at (63). Kurrle was published on December 19, 1990 (Ex. 1071,
`(43)), and Queen 1990 was published on July 26, 1990 (Ex. 1050, (43)),
`both of which predate the earliest possible priority date shown on the face of
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`the ’213 patent. Thus, we determine that Petitioner has satisfied its initial
`burden of showing that Kurrle and Queen 1990 qualify as prior art to the
`challenged claims.
`Patent Owner attempts to disqualify Kurrle and Queen 1990 as prior
`art, arguing that the challenged claims were actually reduced to practice
`before either Kurrle or Queen 1990 was published, i.e., before the July 26,
`1990 publication of Queen 1990. Prelim. Resp. 20–43. As a preliminary
`matter, we note that this avenue of antedating a reference is unavailable if
`the reference qualifies as prior art under 35 U.S.C. § 102(b). See 37 C.F.R.
`§ 1.131(a)(2). Patent Owner argues that Queen 1990 and Tramontano do not
`qualify as prior art under § 102(b). Prelim. Resp. 40. According to Patent
`Owner, even though the ’213 patent issued from a continuation-in-part of the
`’272 application, the challenged claims are entitled to the priority date of
`June 14, 1991, the filing date of the ’272 application. Id. at 40–42. For
`purposes of this Decision, we assume, without deciding, that the challenged
`claims are entitled to the priority date of June 14, 1991.
`Reduction to practice is a question of law predicated on subsidiary
`factual findings. Brown v. Barbacid, 276 F.3d 1327, 1332 (Fed. Cir. 2002).
`To establish an actual reduction to practice, the inventor must prove that: (1)
`an embodiment of the invention was constructed that meets all the
`limitations of the claim-at-issue; and (2) the inventor appreciated that the
`invention would work for its intended purpose. Cooper v. Goldfarb, 154
`F.3d 1321, 1327 (Fed. Cir. 1998). A showing of prior invention requires
`corroboration. Mahurkar v. C.R. Bard, Inc., 79 F.3d 1572, 1577 (Fed. Cir.
`1996). Sufficiency of corroboration is determined by using a “rule of
`reason” analysis, under which all pertinent evidence is examined when
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`determining the credibility of an inventor’s testimony. Medichem, S.A. v.
`Rolabo, S.L., 437 F.3d 1157, 1170 (Fed. Cir. 2006). Corroboration may be
`testimony of a witness, other than the inventor, to the actual reduction to
`practice, or it may consist of evidence of surrounding facts and
`circumstances independent of information received from the inventor. Id. at
`1171.
`
`To support its argument of prior invention, Patent Owner relies on
`numerous confidential internal documents, including laboratory notebooks
`or excerpts of laboratory notebooks, and other documents relating to internal
`research. Prelim. Resp. 20–40 (citing Exs. 2001–2015); see also Paper 8
`(seeking to seal Exhibits 2001–2015). Patent Owner also relies on the
`Declarations of the inventors and another employee scientist. Id. (citing
`Exs. 2016–2018). These declarations, according to Patent Owner, “pertain[]
`to confidential research and development activities related to the invention
`described and claimed.” Paper 8, 3–4 (seeking to seal Exhibits 2016–2018).
`At this early stage of the proceeding, none of Patent Owner’s
`witnesses has been cross-examined regarding the antedating evidence. Thus,
`the better course of action is to permit the parties to fully develop the record
`during trial before determining whether Patent Owner’s evidence of prior
`invention is sufficient to disqualify Kurrle and Queen 1990 as prior art.
`Level of Ordinary Skill in the Art
`The parties propose similar definitions of a person of ordinary skill for
`the ’213 patent. See Pet. 12–13; Prelim. Resp. 17–18. For purposes of this
`Decision, we adopt 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
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`experience with antibody structural characterization, engineering, and/or
`biological testing, or an M.D. with practical academic or industrial
`experience in antibody development.” Prelim. Resp. 17–18.
`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)).
`
`Anticipation by Kurrle
`Kurrle discloses “humanised and civilised versions” of monoclonal
`antibodies against the human alpha/beta T-cell receptor. Ex. 1071, Abstract;
`see Ex. 1003 ¶ 111. In particular, Kurrle discloses the production of
`chimeric antibodies, i.e., those “having mixed murine and human
`characteristics in order to improve their effectiveness and/or lower their
`immunogenicity in patients.” Ex. 1071, 3:3–5. In one embodiment, “[o]nly
`the complementarity deter[min]ing regions and selected framework amino
`acids necessary for antigen binding are maintained murine. The remaining
`framework regions are converted to human sequences.” Id. at 3:9–11. Such
`alterations to the framework regions “can advantageously be made in the
`sequence immediately before and after the CDRs.” Id. at 8:25–26. In
`particular,
`Molecular models of antibodies have shown that the actual CDR
`loops can contain amino acids up to 4 amino acids away from the
`“Kabat” CDRs. Therefore, maintaining at least the major amino
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`acid differences (in size or charge) within 4 amino acids of the
`CDRs as murine may be beneficial.
`Id. at 8:27–29.
`Kurrle also discloses using “a simplified computer model . . . based on
`sequence homology to other antibodies with solved structures” to “judge
`proximity of framework amino acids to the CDRs.” Id. at 8:33–35. Kurrle
`further discloses changing existing framework residues in accord with the
`consensus sequences for particular human antibody subgroups. Id. at 8:36–
`47. Applying the subgroup consensus model, Kurrle discloses substitution
`of human framework residues for mouse residues, including at positions 4L,
`69H, 71H, 73H, and 76H. Id. at Tables 6A, 6B; See Pet. 17 & n.5; Ex. 1003
`¶¶ 111–113, 144–160, Exhibit C, 4–7.
`Relying on these disclosures, Petitioner asserts that Kurrle anticipates
`claims 1, 2, 25, 29, 63, 66, 71, 75, 76, 78, 80, and 81. Pet. 25–31. Patent
`Owner only challenges the merits of Petitioner’s assertion regarding claim
`63. Prelim. Resp. 45–47; see also id. at 2 (“[e]ven if Celltrion could rely on
`Kurrle . . . Celltrion has failed to demonstrate a reasonable likelihood of
`success for claim 63 in Ground 1”); Prelim. Resp. 45 n.8. Based on the
`current record, we determine Petitioner has established a reasonable
`likelihood that it would prevail in this assertion with respect to at least claim
`1.
`
`In sum, based on the current record, we are satisfied that Petitioner
`has shown a reasonable likelihood to prevail in its assertion that claim 1 is
`anticipated by Kurle. We, thus, institute an inter partes review of the claims
`challenged under this ground.
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`
`Obviousness over Queen 1990 and Kurrle
`Petitioner asserts that claims 1, 2, 4, 25, 29, 62–64, 66, 67, 69, 71, 72,
`75, 76, 78, 80 and 81 would have been obvious over the combination of
`Kurrle and Queen 1990. Pet. 38–49. Based on the current record, we
`determine Petitioner has established a reasonable likelihood that it would
`prevail in this assertion with respect to at least claim 1.
`Queen 1990 notes that humanization of framework amino acids
`frequently reduces the binding affinity of non-human (e.g., mouse)
`antibodies. Ex. 1050, 11:27–12:8. To account for this observation, Queen
`1990 suggests that human amino acids in the framework region close to the
`mouse CDRs may result in (1) distortions in the CDRs and (2) the loss of
`amino acids in framework regions that made contact with the antigen in the
`original mouse antibody. Id. Accordingly, Queen 1990 discloses methods
`for designing humanized immunoglobulins “hav[ing] a very strong affinity
`for a desired antigen,” by comparing amino acid sequences of a non-human
`“donor immunoglobulin to corresponding sequences in a collection of
`human immunoglobulin chains, and selecting as the human immunoglobulin
`one of the more homologous sequences from the collection.” Id. Abstract,
`12:9–15. Queen’s methods apply the following four criteria:
`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
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`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 the
`3 CDR[]s in the humanized immunoglobulin chain, the donor
`amino acid 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
`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.
`Id. at 12:17–14:25. 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 6:21–25.
`Petitioner asserts that Queen 1990 provided both “explicit motivation”
`and “a detailed roadmap with specific criteria used in designing humanized
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`immunoglobulins.” Pet. 31–32, 40 (citing Ex 1003 ¶¶ 162–71, 145–53, 197;
`Ex. 1050, 6:21–26, 12:9–15). Petitioner further asserts that “Kurrle
`employed a similarly detailed roadmap” to obtain a humanized antibody. Id.
`at 43 (citing Ex. 1071, 8:16–18, 8:25–40; Ex. 1003 ¶¶ 110–113, 198)).
`“Using these guidelines, Kurrle made a total of 13 substitutions in the light
`chain framework region and 18 substitutions in the heavy chain framework
`region,”7 including those at positions 4L, 69H, 71H, 73H, and 76H, as
`recited in the challenged claims. Id. at 41 (citing Ex. 1003 ¶¶ 144–147, 199,
`Exhibit C, 4–7); see Ex. 1003 ¶ 113.
`According to Petitioner:
`A POSA would have been motivated to combine the teachings of
`Queen 1990 and Kurrle because of the similarity in the approaches
`implemented in these references and to improve on the successes
`of both. Ex. 1003 at ¶¶199–200. The combination of Queen 1990
`and Kurrle thus provided ample motivation and a reasonable
`expectation of success that a humanized monoclonal antibody
`could be obtained with “a much lower immunogenicity in patients”,
`Ex. 1071 at 3:11–12, while maintaining the binding affinity and
`specificity of the donor monoclonal antibody, and targeted the very
`species residues satisfying the claim 1 genus.
`Id. at 41.
`Patent Owner counters that Petitioner “never says what teaching
`absent from Queen 1990 is supposedly remedied by Kurrle, or vice versa—
`let alone explains how the skilled artisan would purportedly combine the
`teachings of these two references.” Prelim. Resp. 52. We are not persuaded
`by Patent Owner’s argument.
`
`7 We note that Petitioner’s expert identifies 13 human to mouse substitutions
`in the light chain framework region and 20 in the heavy chain framework
`region, defined as including a two-amino acid insertion between Kabat
`positions 103 and 104 of the heavy chain. See Ex. 1003 ¶ 199 & n.7.
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`Kurrle teaches methods of producing humanized antibodies.
`Ex. 1071, 8:27–47; Ex. 1003 ¶¶ 111–113, Exhibit C, 4–7. It explicitly
`discloses mouse for human substitution of framework residues at specific
`positions: 1L, 3L, 4L, 42L, 46L, 47L, 48L, 63L, 70L, 71L, 81L, 100L, 106L,
`27H, 28H, 30H, 38H, 40H, 48H, 66H, 67H, 69H, 71H, 73H, 76H, 83H,
`89H, 90H, 91H, 94H, 105H and 107H. Ex. 1071, Tables 6A, 6B; Ex. 1003
`¶¶ 113 & n.4, Exhibit C, 4–7.
`Queen 1990 similarly teaches methods of designing humanized
`antibodies. Ex. 1050, 14:14–17:2. As Patent Owner points out, “Celltrion
`does not point to any antibody sequence disclosed in Queen 1990 that
`contains the claimed framework substitutions.” Prelim. Resp. 50.
`Petitioner, instead, relies on Queen 1990 for teaching substitution of
`framework residues “immediately adjacent” to the CDRs as taught in Queen
`1990’s Criterion III. Pet. 31–33 (citing Ex. 1050, 14:1–12; Ex. 1003 ¶ 161–
`171, Exhibit C, 8–9). According to Petitioner’s expert, even taking into
`account the slightly different CDR boundaries assigned by Kabat as
`compared to Chothia and Lesk, only 24 amino acid residues are immediately
`adjacent to CDR regions: residues 23L, 35L, 49L, 57L, 88L, 98L, 30H, 36H,
`49H, 66H, 94H and 103H as according to Kabat, plus the addition of
`residues 25L, 33L, 49L, 53L, 90L, 97L, 25H, 33H, 52H, 56H, 95H and
`102H according to Chothia. Ex. 1003 ¶ 167.
`As Petitioner points out, before the ’213 patent, “[t]he field
`recognized that earlier efforts (e.g., chimeric antibodies, CDR grafting) often
`resulted in non-or poor binding, with immunogenicity remaining a concern.”
`Pet. 24 (citing Ex. 1050, 3:30–33; Ex. 1073, 9:12–19; Ex. 1003 ¶¶ 87–90;
`Ex. 1004 ¶¶ 33–34). Both Kurrle and Queen 1990 teach the design of
`
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`humanized antibodies with low immunogenicity (see Ex. 1050, 6:21–25
`(stating the resulting humanized antibody is “substantially non-immunogenic
`in humans and retain substantially the same affinity as the donor
`immunoglobulin to the antigen”); Ex. 1071, 3:11–12 (stating the resulting
`humanized antibody is “essentially a human antibody with a much lower
`immunogenicity in patients”)). Because Kurrle and Queen 1990 teach
`overlapping, and potentially complimentary, sets of candidate amino acids
`for mouse to human substitution, we agree with Petitioner that an ordinary
`artisan would have had a reason to combine the teachings of those
`references.
`Patent Owner does not dispute Petitioner’s assertion that the
`combination of Kurrle and Queen 1990 teaches or suggests all limitations in
`each of claims 1, 2, 25, 29, 66, 71, 75, 76, 78, 80, and 81. See Prelim.
`Resp. 45 n.8. After reviewing the record, we are satisfied that Petitioner has
`met its burden at this stage with regard to these claims. See Pet. 38–49
`We acknowledge the evidence of secondary considerations and Patent
`Owner’s argument that such evidence establishes the non-obviousness of the
`challenged claims. Prelim. Resp. 63–65. Indeed, evidence of secondary
`considerations, when present, “must always . . . be considered en route to a
`determination of obviousness.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d
`1530, 1538–39 (Fed. Cir. 1983). Here, the secondary-considerations
`evidence Patent Owner relies on is first presented together with the
`Preliminary Response, and Petitioner has not yet had an opportunity to
`respond to the evidence and arguments. Thus, in this case, a better course of
`action is to permit the parties to fully develop the record during trial before
`further weighing the alleged evidence of secondary considerations.
`
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`Based on the current record, we are satisfied that Petitioner has shown
`a reasonable likelihood to prevail in its assertion that claim 1 would have
`been obvious over the combination of Queen 1989 and Kurrle. We, thus,
`institute an inter partes review of the claims challenged under this ground.
`Anticipation by Queen 1990
`Petitioner asserts that 1, 2, 4, 29, 62–64, 80, 81 are anticipated by
`Queen 1990. Pet. 31–38. Patent Owner disagrees. Prelim. Resp. 50–54.
` With respect to claim 1, Petitioner argues that Criterion III of Queen
`1990 explicitly taught the substitution of framework residues immediately
`adjacent to CDR, thus encompassing the claimed framework residues 98L
`and 36H. Pet. 31–33 (citing Ex. 1050, 14:1–12; Ex. 1003 ¶¶ 145–153, 161–
`171, Exhibit C, 8–9). Patent Owner responds that Criterion III of Queen
`1990 is a “broad rule encompass[ing] substitutions at any of 23 different
`positions (Ex. 1003 ¶ 167)—literally thousands of different combinations
`and permutations of possible substitutions, only a small fraction of which
`overlap with the challenged claims.” Prelim. Resp. 50–51. On this record,
`we do not find Patent Owner’s argument persuasive.
`Claim 1 recites “[a] humanized antibody variable domain . . . further
`comprising a Framework Region (FR) amino acid substitution at a site
`selected from the group consisting of: . . . 98L . . . 36H.” On the present
`record, we accept Dr. Riechmann’s testimony that one of ordinary skill in
`the art would understand Queen 1990 to disclose 24 positions “immediately
`adjacent to CDR regions” including 98L and 36H. See Ex. 1003 ¶ 167.
`Because the Markush group of claim 1 is introduced with open-ended
`‘comprising” language, it is irrelevant whether these 24 positions may be
`
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`selected in “literally thousands” of multi-substitution combinations as Patent
`Owner suggests on pages 50–51 of the Preliminary Response.
`In sum, based on the current record, we are satisfied that Petitioner
`has shown a reasonable likelihood to prevail in its assertion that claim 1 is
`anticipated by Queen 1990. We, thus, institute an inter partes review of the
`claims challenged under this ground.
`Obviousness over Queen 1990, Kurrle, and Furey
`Claim 12 depends on claim 1 and further recites “wherein the residue
`at site 66L has been substituted.” Ex. 1001, 86:50–51. Petitioner argues that
`claim 12 would have been obvious over the combination of Kurrle, Queen
`1990, and Furey. Pet. 49–50. We find Petitioner’s argument persuasive and
`adopt it for purposes of this Decision.
`Furey teaches the structural importance of framework residues that
`established hydrogen bonding with CDR residues. Ex. 1125, Abstract, 673–
`674; Ex. 1003 ¶ 128. In particular, Furey reports 66L as a residue for
`interacting with CDR2 of the light chain. Id. at Table 4; Ex. 1003 ¶¶ 205–
`206. Petitioner argues that Kurrle and Queen 1990 provide an ordinary
`artisan the motivation to substitute framework region positions that are close
`enough to either influence CDR conformation or to interact directly with
`antigen. Pet. 49–50 (citing Ex. 1003
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