Trials@uspto.gov
`571-272-7822
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` Paper No. 19
`Entered: March 29, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-02031
`Patent 6,407,213 B1
`____________
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
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`
`571-272-7822
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`
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`
`
`
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` Paper No. 19
`Entered: March 29, 2018
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC.,
`Patent Owner.
`____________
`
`Case IPR2017-02031
`Patent 6,407,213 B1
`____________
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`
`IPR2017-02031
`Patent 6,407,213 B1
`
`
`INTRODUCTION
`I.
`Boehringer Ingelheim Pharmaceuticals, Inc. (“Petitioner” or
`“Boehringer”) filed a Petition for an inter partes review of claims 1, 2, 4, 25,
`29, 62–64, 66, 67, 71, 69, 71–73, 75–78, 80, and 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 11 (“Prelim. Resp.”).
`Our authority to institute an inter partes review is derived ultimately
`from 35 U.S.C. § 314, which provides that an inter partes review may not be
`instituted unless the information presented in the Petition shows “there is a
`reasonable likelihood that the petitioner would prevail with respect to at least
`1 of the claims challenged in the petition.” Upon consideration of the
`Petition and Preliminary Response, we determine that Petitioner has shown a
`reasonable likelihood that it would prevail in showing the unpatentability of
`at least one challenged claim. Accordingly, and for the reasons set forth
`below, we institute inter partes review of claims 1, 2, 4, 25, 29, 62–64, 66,
`69, 71, 73, 75–78, 80, and 81 of the ’213 patent. As also discussed below,
`we decline to institute inter partes review of claims 67 and 72 of the ’213
`patent.
`
`A. 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,
`§ 102 Kurrle1
`71, 75, 76, 78, 80, and
`81
`
`1 Kurrle, et al., European Patent Application Publication No. 0403156,
`published December 19, 1990. Ex. 1071.
`2
`
`
`
`Reference(s)
`Basis
`§ 102 Queen 19902
`
`§ 103 Kurrle and Queen 1990
`
`§ 102
`
`Jones3
`
`Claim(s)
`1, 2, 4, 29, 62–64, 80,
`and 81
`1, 2, 4, 25, 29, 62–64,
`66, 67, 69, 71, 72, 75,
`76, 78, 80, and 81
`1, 2, 4, 25, 29, 62, 64,
`66, 69, 71, 73, 75–78,
`80, and 81
`73 and 77
`
`IPR2017-02031
`Patent 6,407,213 B1
`
`
`Ground
`2
`
`3
`
`4
`
`5
`
`§ 103 Kurrle, Queen 1990, and
`Chothia & Lesk4
`Jones and Riechmann5
`§ 103
`63
`6
`In support of its patentability challenges, Petitioner relies on the
`Declaration of Geoffrey Hale, PhD. Ex. 1003.
`
`The ’213 Patent and Relevant Background
`B.
`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
`
`
`2 Queen, et al., International Publication No. WO 90/07861, published July
`26, 1990. Ex. 1050.
`3 Jones et al., Replacing the complementarity-determining regions in a
`human antibody with those from a mouse, 321 Nature 522–525 (1986). Ex.
`1033.
`4 Chothia and Lesk, Canonical Structures for the Hypervariable Regions of
`Immunoglobulins, 196 J. MOL. BIOL. 901–17 (1987). Ex. 1062.
`5 Riechmann et al., Reshaping human antibodies for therapy, 332 Nature
`323–327 (1988). Ex. 1069.
`
`3
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`
`IPR2017-02031
`Patent 6,407,213 B1
`
`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 1:33–34.
`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. One object of the invention
`is “to provide methods for the preparation of antibodies which are less
`antigenic in humans than non-human antibodies but have desired antigen
`binding and other characteristics and activities.” Id. at 4:24–28. In
`accordance with this goal, the Specification states that embodiments within
`the scope of the claims have “low immunogenicity,” or are designed to
`“minimize the potential immunogenicity of the resulting humanized
`antibody in the clinic.” Id. at 52:54–58, 61:56–61.
`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).
`
`4
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`
`
`IPR2017-02031
`Patent 6,407,213 B1
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`
`The ’213 patent also acknowledges the following as known in the
`prior art:
`
`1. In certain cases, in order to transfer high antigen binding 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.
`2. “For a given antibody[,] a small number of FR residues are
`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. “[T]he antigen binding affinity of a humanized antibody can be
`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. In one embodiment,
`this involves:
`
`a. obtaining the amino acid sequences of at least a portion of an
`import antibody variable domain and of a consensus variable
`domain;
`
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`IPR2017-02031
`Patent 6,407,213 B1
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`
`b. identifying Complementarity Determining Region (CDR)
`amino acid sequences in the import and the human variable
`domain sequences;
`c. substituting an import CDR amino acid sequence for the
`corresponding human CDR amino acid sequence;
`d. aligning the amino acid sequences o( a Framework Region
`(FR) of the import antibody and the corresponding FR of the
`consensus antibody;
`e. identifying import antibody FR residues in the aligned FR
`sequences that are non-homologous to the corresponding
`consensus antibody residues;
`f. determining if the non-homologous import amino acid
`residue is reasonably expected to have at least one of the
`following effects: l. non-covalently binds antigen directly, 2.
`interacts with a CDR; or 3. participates in the VL-VH interface;
`and
`g. for any non-homologous import antibody amino acid residue
`which is reasonably expected to have at least one of these
`effects, substituting that residue for the corresponding amino
`acid residue in the consensus antibody FR sequence.
`Id. at 4:43–5:5. Figures 1A and 1B of the ’213 patent show alignments of
`light and heavy chain variable regions of mouse antibody muMAb4D5 with
`human antibody huMAb4D5, along with their resulting consensus sequences
`(HUVLκI and HUVHIII, respectively). See id. at 6:57–7:8 (numbering
`according to Kabat).6
`
`
`6 Elvin A. Kabat, et al., Sequences of Proteins of Immunological Interest 1–
`23 (1987) (4th Ed.) (NIH, Bethesda, Md.). Ex. 1552. See also Ex. 1001,
`10:45–56 (indicating that the Kabat numbering scheme for antibodies
`“assign[s] a residue number to each amino acid in a listed sequence”).
`6
`
`
`
`IPR2017-02031
`Patent 6,407,213 B1
`
`
`Illustrative Claims
`C.
`Among the challenged claims, claims 1, 30, 62–64, 66, 79, and 80 are
`independent. Claim 1 is illustrative and is reproduced below:
`
`A humanized antibody variable domain comprising non-
`1.
`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.
`Depending from claim 1, claim 4 limits the humanized antibody
`variable domain of claim 1 to “a consensus human variable domain.”
`
`D. Related Proceedings
`1. District Court Proceedings
`According to Petitioner, the ’213 Patent is at issue in Genentech, Inc.
`v. Amgen Inc., No. 1-17-cv-01407 (D. Del.); Amgen Inc. v. Genentech, Inc.,
`and Genentech, Inc. v. Amgen Inc., No. 1-17-cv-01471 (D. Del.). Paper 16,
`1. No. 2-17-cv-07349 (C.D. Cal.). Paper 10. Patent Owner further identifies
`Celltrion, Inc. v. Genentech, Inc., No. 18-cv-00274 (N.D. Cal.) and
`Genentech, Inc. v. Celltrion, Inc., No. 18-cv-00095 (D. Del.). Paper 18.
`
`2. Inter Partes Reviews
`On August 31, 2017, Petitioner filed both the instant Petition and
`IPR20117-02032 against claims of the ’213 Patent. Although these are the
`first petitions filed by Petitioner Boehringer, a total of eight petitions with
`related and overlapping grounds have now been filed against the ’213 patent.
`
`7
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`
`
`IPR2017-02031
`Patent 6,407,213 B1
`
`
`On August 30, 2016, Mylan Pharmaceuticals Inc., filed IPR2016–
`01693 and IPR2016–01694. Patent Owner filed Preliminary Responses in
`each of these cases on December 16, 2016. On March 10, 2017, we
`terminated the Mylan cases in response to the parties’ Joint Motion to
`Terminate.
`On May 8, 2017, Celltrion, Inc. filed IPR2017-01373 and IPR2017-
`01374. Patent Owner filed Preliminary Responses on September 6, 2017,
`and we instituted inter partes reviews on December 1, 2017. The Celltrion
`IPRs are currently pending.
`On May 25, 2017, Pfizer, Inc. filed IPR2017-01488 and IPR2017-
`01489. Patent Owner filed Preliminary Responses on September 5 and 6,
`2017, respectively, and we instituted inter partes reviews on December 1,
`2017. The Pfizer IPRs are currently pending.
`On September 29, 2017, Samsung Bioepis Co. Ltd, filed IPR2017-
`02139 and IPR2017-02140, along with motions for joinder to IPR2017-
`01488 and IPR2017-01489, respectively. On February 22, 2018, we
`instituted the inter partes review and granted Bioepis’ motions for joinder.
`
`II. ANALYSIS
`Patent Owner requests that we exercise our discretion under
`35 U.S.C § 325(d) to deny institution with respect to Grounds 1–3 and 5
`because “Boehringer copied Grounds 1-3 and 5 of this Petition from
`IPR2017-01374 (Celltrion) and IPR2017-01488 (Pfizer), and copied
`Grounds 1-5 of IPR2017-02032 from IPR2017-01373 (Celltrion) and
`IPR2017-01489 (Pfizer)— without seeking joinder with those earlier-filed
`proceedings.” Prelim. Resp. 1. According to Patent Owner, “This
`redundancy would waste the Board’s and Patent Owner’s resources, and also
`
`8
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`IPR2017-02031
`Patent 6,407,213 B1
`
`would unfairly allow Boehringer to preview the parties’ arguments before
`having to address them itself.” Id. at 2. With respect to Grounds 4 and 6,
`Patent Owner further contends that we should deny institution under
`§ 325(d) “because the PTO has already found the challenged ’213 claims
`patentable over both cited references” (Jones and Riechmann). Id. We
`address Patent Owner’s arguments below.
`
`Section 325(d)
`A.
`Institution of an inter partes review is discretionary. See Harmonic
`Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) (explaining
`that under § 314(a), “the PTO is permitted, but never compelled, to institute
`an IPR proceeding”). Accordingly, our rules provide that “the Board may
`authorize the review to proceed” or “deny some or all grounds for
`unpatentability for some or all of the challenged claims.” 37 C.F.R. §
`42.108(a), (b). Our discretionary determination of whether to institute
`review is guided, in part, by 35 U.S.C. § 325(d), which states, in relevant
`part:
`
`(d) MULTIPLE PROCEEDINGS -- . . . In determining whether
`to institute or order a proceeding under this chapter, chapter 30,
`or chapter 31, the Director may take into account whether, and
`reject the petition or request because, the same or substantially
`the same prior art or arguments previously were presented to the
`Office.
`35 U.S.C. § 325(d).
`Our discretion under § 325(d) involves a balance between several
`competing interests. See Neil Ziegman, N.P.Z., Inc. v. Stephens, Case
`IPR2015-01860, slip op. at 12–13 (PTAB Feb. 24, 2016) (Paper 11) (“While
`petitioners may have sound reasons for raising art or arguments similar to
`those previously considered by the Office, the Board weighs petitioners’
`
`9
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`IPR2017-02031
`Patent 6,407,213 B1
`
`desires to be heard against the interests of patent owners, who seek to avoid
`harassment and enjoy quiet title to their rights.”) (citing H. Rep. No. 112-98,
`pt. 1, at 48 (2011)). “On the one hand, there are the interests in conserving
`the resources of the Office and granting patent owners repose on issues and
`prior art that have been considered previously.” Fox Factory, Inc. v. SRAM,
`LLC, Case IPR2016-01876, slip op. 7 (PTAB Apr. 3, 2017) (Paper 8). “On
`the other hand, there are the interests of giving petitioners the opportunity to
`be heard and correcting any errors by the Office in allowing a patent—in the
`case of an inter partes review—over prior art patents and printed
`publications.” Id.; see also, Cultec, Inc. v. Stormtech LLC, Case IPR2017-
`00777 (PTAB Aug. 22, 2017) (Paper 7) (denying institution under § 325(d)
`where reference was applied throughout prosecution).
`
`B. Grounds 1–3 and 5
`Patent Owner requests that we exercise our discretion under
`35 U.S.C § 325(d) to deny institution with respect to Grounds 1–5 because
`“Boehringer copied Grounds 1–3 and 5 of this Petition from IPR2017-01374
`(Celltrion) and IPR2017-01488 (Pfizer), and copied Grounds 1–5 of
`IPR2017-02032 from IPR2017-01373 (Celltrion) and IPR2017-01489
`(Pfizer)—without seeking joinder with those earlier-filed proceedings.”
`Prelim. Resp. 1. Consistent with that assertion, the following charts
`illustrate that each claim in Grounds 1–3, and 5 of the instant Petition was
`previously challenged in the original Mylan Petition, as well as in the
`
`10
`
`
`
`IPR2017-02031
`Patent 6,407,213 B1
`
`presently pending cases (differences from the instant Petition are
`underlined.).7
`Petition
`This Petition
`
`Ground
`1
`
`1
`
`1
`
`1
`
`Claim(s)
`1, 2, 25, 29, 63, 66, 71,
`75, 76, 78, 80, and 81
`1, 2, 25, 29, 63, 66, 71,
`75, 76, 78, 80, and 81
`1, 2, 25, 29, 63, 66, 71,
`75, 76, 78, 80, and 81
`1, 2, 25, 29, 63, 66, 67,
`71, 72, 75, 76, 78, 80, and
`81
`
`Basis Reference(s)
`§ 102 Kurrle
`
`§ 102 Kurrle
`
`§ 102 Kurrle
`
`§ 102 Kurrle
`
`IPR2016-01693
`(Mylan)
`IPR2017-01374
`(Celltrion)
`IPR2017-01488
`(Pfizer)
`Joined with
`IPR2017-02139
`(Bioepis)
`
`Petition
`This Petition
`
`IPR2016-01693
`(Mylan)
`IPR2017-01374
`(Celltrion)
`IPR2017-01488
`(Pfizer)
`Joined with
`IPR2017-02139
`(Bioepis)
`
`
`Ground
`2
`
`2
`
`2
`
`2
`
`Claim(s)
`1, 2, 4, 29, 62–64, 80, and
`81
`1, 2, 4, 29, 62–64, 80, and
`81
`1, 2, 4, 29, 62–64, 80, and
`81
`1, 2, 4, 29, 62–64, 80, and
`81
`
`Basis Reference(s)
`§ 102 Queen 1990
`
`§ 102 Queen 1990
`
`§ 102 Queen 1990
`
`§ 102 Queen 1990
`
`
`7 According to Petitioner, “[t]he present IPR petition[] offer[s] different
`arguments from the previously-filed IPR petitions.” Pet. 2. Insofar as
`Petitioner does not elaborate on this statement, and the grounds referenced in
`the above tables are the same as set forth in the prior IPRs. Accordingly, we
`presume that Petitioner refers to Grounds 4 and 6.
`
`
`11
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`
`IPR2017-02031
`Patent 6,407,213 B1
`
`
`Petition
`This Petition
`
`Ground
`3
`
`3
`
`3
`
`3
`
`IPR2016-01693
`(Mylan)
`
`IPR2017-01374
`(Celltrion)
`
`IPR2017-01488
`(Pfizer)
`Joined with
`IPR2017-02139
`(Bioepis)
`
`
`
`Claim(s)
`1, 2, 4, 25, 29, 62–64, 66,
`67, 69, 71, 72, 75, 76, 78,
`80, and 81
`1, 2, 4, 25, 29, 62–64, 65,
`66, 67, 69, 71, 72, 75, 76,
`78, 80, and 81
`1, 2, 4, 25, 29, 62–64, 66,
`67, 69, 71, 72, 75, 76, 78,
`80, and 81
`1, 2, 4, 25, 29, 62–64, 66,
`67, 69, 71, 72, 75, 76, 78,
`80, and 81
`
`Basis Reference(s)
`§ 103 Kurrle and
`Queen 1990
`
`§ 103 Kurrle and
`Queen 1990
`
`§ 103 Kurrle and
`Queen 1990
`
`§ 103 Kurrle and
`Queen 1990
`
`Petition
`This Petition
`
`Ground
`5
`
`Claim(s)
`73 and 77
`
`IPR2016-01693
`(Mylan)
`
`IPR2017-01374
`(Celltrion)
`
`5
`
`5
`
`73, 74, 77, and 79
`
`65, 73, 74, 77, and 79
`
`Basis Reference(s)
`§ 103 Kurrle,
`Queen 1990,
`and Chothia
`& Lesk
`§ 103 Kurrle,
`Queen 1990,
`and Chothia
`& Lesk
`§ 103 Kurrle,
`Queen 1990,
`and Chothia
`& Lesk
`§ 103 Kurrle,
`Queen 1990,
`and Chothia
`& Lesk
`
`5
`
`73 and 77
`
`IPR2017-01488
`(Pfizer)
`Joined with
`IPR2017-02139
`(Bioepis)
`According to Patent Owner, “[t]his redundancy would waste the Board’s and
`Patent Owner’s resources, and also would unfairly allow Boehringer to
`
`12
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`IPR2017-02031
`Patent 6,407,213 B1
`
`preview the parties’ arguments before having to address them itself.” Id. at
`2. We find Patent Owner’s argument persuasive.
`In determining whether to institute an inter partes review, we “may
`take into account whether, and reject the petition or request because, the
`same or substantially the same prior art or arguments previously were
`presented to the Office.” 35 U.S.C. § 325(d). As Patent Owner correctly
`points out, Grounds 1–3 and 5 asserted in the Petition “are essentially
`identical to those already instituted in” IPR2017-01374 and IPR2017-01488.
`Prelim. Resp. 12–13. Petitioner filed this Petition before we issued the
`decisions instituting inter partes reviews in IPR2017-01374 and IPR2017-
`01488. Thus, Petitioner could have sought to join the pending IPRs. It did
`not do so and the time for requesting joinder has expired. See 37 C.F.R. §
`42.122. As such, we exercise our discretion under § 325(d) and deny the
`Petition with respect to Grounds 1–3 and 5.
`
`C. Grounds 4 and 6
`Petitioner challenges claims 1, 2, 4, 25, 29, 62, 64, 66, 69, 71, 73, 75–
`78, 80, and 81 as anticipated by Jones (Ground 4), and further challenges
`claim 63 as obvious over Jones in view of Riechmann (Ground 6). Pet. 54–
`64. Patent Owner does not respond on the merits, but argues that we should
`deny institution of Grounds 4 and 6 under § 325(d) “because the PTO has
`already found the challenged ’213 claims patentable over both cited
`references.” Prelim. Resp. 2, 15–16. We address, in turn, Patent Owner’s
`§ 325(d) argument and the merits of Petitioner’s challenge.
`
`1. Analysis under §325(d)
`The inventors first raised Jones and Riechmann in the Background
`section of the Specification as illustrating prior efforts to “substitut[e] . . .
`
`13
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`IPR2017-02031
`Patent 6,407,213 B1
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`rodent CDRs or CDR sequences for the corresponding segments of a human
`antibody.” Ex. 1001, 2:20–26. According to the inventors, Jones shows
`that, in some cases, “substituting CDRs from rodent antibodies for the
`human CDRs in human frameworks is sufficient to transfer high antigen
`binding affinity,” whereas Riechmann found it “necessary to additionally
`replace one . . . framework region (FR) residue[].” Id. at 2:53–61.
`Jones and Riechmann were also raised in the prosecution leading to
`the issuance of the ’213 patent. In addressing a rejection under 35 USC §
`112, first paragraph, Applicants pointed to Jones and Riechmann as among
`fifteen references exemplifying “potential candidates for humanization . . . .
`provided in the background section of the application.” Ex. 1002, 370; see
`id. at 252, 384–390 (Examiner’s rejection). Although the prosecution
`history contains only this passing reference to Jones, Riechmann was
`repeatedly cited by the Examiner as part of multiple obviousness rejections
`involving two or more other references. Id. at 253–254, 386–388, 415–418.
`According to the Examiner, Riechmann taught “a method of reshaping
`human antibodies for therapy by CDR grafting” that involved “altering the
`sequence of the antibody to restore packing or to increase binding affinity.”
`Id. at 253. Applicants expressly addressed the teachings of Riechmann in
`traversing the rejections. See id. at 372–374, 430–435. The Examiner
`withdrew the rejections involving Riechmann without further comment. See
`id. at 508–511.
`In contrast to the Examiner’s focus on Riechmann in setting forth the
`above rejections, Petitioner’s arguments supporting Grounds 4 and 6 focus
`on Jones as the sole or primary reference. See Pet. 54–64. And, as
`discussed in more detail below, Petitioner broadly interprets the instant
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`claims as encompassing the CDR-grafted antibodies disclosed in Jones
`without further amino acid substitution—a construction, Petitioner contends,
`was apparently not contemplated by the Examiner. See id. Petitioner’s
`arguments with respect to Jones, therefore, differ substantially from
`positions taken by the Examiner during prosecution. Petitioner also relies on
`the testimony and analysis of Dr. Hale as evidence of unpatentability not
`available during prosecution. See, e.g., Ex. 1003 ¶¶ 228–232; Ex. 1003C,
`779.
`
`Given the limited discussion of Jones in the intrinsic record, and in
`light of Petitioner’s new arguments and evidence, we decline to exercise our
`discretion to deny institution with respect to these grounds under 35 U.S.C §
`325(d).
`
`2. Analysis on the Merits
`To anticipate a claim under 35 U.S.C. § 102, “a single prior art
`reference must expressly or inherently disclose each claim limitation.”
`Finisar Corp. v. DirecTV Group, Inc., 523 F.3d 1323, 1334 (Fed. Cir. 2008).
`That “single reference must describe the claimed invention with sufficient
`precision and detail to establish that the subject matter existed in the
`prior art.” Verve, LLC v. Crane Cams, Inc., 311 F.3d 1116, 1120 (Fed. Cir.
`2002).
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented 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 that
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). In analyzing the obviousness of a combination of prior art elements,
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`it can be important to identify a reason that would have prompted one of
`skill in the art “to combine . . . known elements in the fashion claimed by the
`patent at issue.” Id. at 418.
`A precise teaching directed to the specific subject matter of a
`challenged claim is not necessary to establish obviousness. Id. Rather, “any
`need or problem known in the field of endeavor at the time of invention and
`addressed by the patent can provide a reason for combining the elements in
`the manner claimed.” Id. at 420. Accordingly, a party that petitions the
`Board for a determination of unpatentability based on obviousness 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) (internal quotations and citations omitted).
`
`3. Person of Ordinary Skill in the Art
`According to Petitioner, a person of ordinary skill in the art
`would have held a Ph.D. or equivalent in chemistry, biological
`chemistry, structural biology or a closely related field, or an M.D.
`with practical academic or
`industrial experience
`in
`the
`production of recombinant proteins. Such experience could
`include, e.g., 3-D computer modeling of immunoglobulin
`structures, antibody domain and sequence manipulation and
`swapping, CDR grafting and framework substitution
`in
`humanizing antibodies, construction and expression of
`recombinant antibodies, antibody binding (specificity and
`affinity) testing, and immunogenicity testing. Such person may
`have consulted with one or more other experienced professionals
`to develop a humanized monoclonal antibody for therapeutic use,
`to select non-human monoclonal antibodies (such as a mouse
`monoclonal antibody) for humanization, and subsequent testing
`of the humanized antibody and its intermediates.
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`Patent 6,407,213 B1
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`Pet. 13–14 (internal citations to Ex. 1003 ¶¶ 24–26 omitted). Patent Owner
`does not address the level of skill in the art in its Preliminary Response, but
`has done so in the Pfizer and Celltrion IPRs, which address the same claims
`of the ’213 patent. See IPR2017-01488, Paper 6 at 18; IPR2017-01374,
`Paper 7 at 17–18. Although Petitioner’s proposed definition is somewhat
`more detailed than that previously argued by Patent Owner, at this stage of
`the proceeding, any differences would not affect the outcome. Accordingly,
`for purposes of this Decision, and in the interest of consistency, 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 experience
`with antibody structural characterization, engineering, and/or biological
`testing, or an M.D. with practical academic or industrial experience in
`antibody development,” as we have previously done in the Pfizer and
`Celltrion IPRs. See IPR2017-01488, Paper 27 at 8; IPR2017-01374, Paper
`15 at 10–11.
`We further note that the prior art itself demonstrates this 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)).
`
`4. Overview of Jones (Ex. 1033)
`Jones “grafted the CDRs from the VH domain of the mouse
`monoclonal antibody B1-8 into the VH domain of the human myeloma
`
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`protein NEWM.” Ex. 1033, 523. The resulting antibody variable domain,
`HUVNP, was subsequently grafted to a human ε constant region and co-
`expressed with human λ light chains to form the humanized IgE antibody,
`HUVNP-IgE. Id. at 523; see Ex. 1003 ¶¶ 128–130. HUVNP-IgE retained the
`binding specificity of the mouse B1-8 CDRs. Ex. 1033, 524 & Table 1; Ex.
`1003 ¶ 131. Figure 2a of the reference compares the human and mouse
`framework and variable regions of NEWM and B1-8. Ex. 1033, 524. The
`amino acid sequence of the hybrid HUVNP antibody variable domain of
`HUVNP-IgE is set forth in Figure 2b. Id. According to Jones, HUVNP-IgE
`lost antigenic determinants associated with the parent mouse antibody. Id. at
`525 & Fig. 3.
`
`5. Overview of Riechmann (Ex. 1069)
`In order to reduce the antigenicity of therapeutically administered
`non-human antibodies, Riechmann “attempted to build rodent antigen
`binding sites directly into human antibodies by transplanting only the
`antigen binding site, rather than the entire variable domain, from a rodent
`antibody.” Ex. 1069, 323. In particular, Riechmann substituted the CDRs of
`a human antibody variable domain with the CDRs of rat antibody directed
`against the human lymphocyte/monocyte antigen CAMPATH-1. Id. at 325.
`Anti-CAMPATH-1 antibodies “have important applications in
`problems of immunosuppression: for example control of graft-versus-host
`disease in bone marrow transplantation; management of organ rejection; the
`prevention of marrow rejection; and the treatment of various lymphoid
`malignancies.” Id. Riechmann proposes that the CDR-grafted “human
`antibody with specificity for the CAMPATH-1 antigen should permit a full
`analysis of the in vivo potency and immunogenicity of an anti-lymphocyte
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`antibody with wide therapeutic potential. Even if anti-idiotypic responses
`are eventually observed, considerable therapeutic benefit could be derived
`from an extended course of treatment.” Id. at 327.
`
`6. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, we presume that a claim term carries its “ordinary and
`customary meaning,” which “is the meaning that the term would have to a
`person of ordinary skill in the art in question” at the time of the invention.
`In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); see also
`Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under
`a broadest reasonable interpretation, words of the claim must be given their
`plain meaning, unless such meaning is inconsistent with the specification
`and prosecution history.”). Any special definition for a claim term must be
`set forth in the specification with reasonable clarity, deliberateness, and
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Limitations,
`however, may not be read from the specification into the claims (In re Van
`Geuns, 988 F.2d 1181, 1184 (Fed. Cir. 1993)), nor may the Board “construe
`claims during [an inter partes review] so broadly that its constructions are
`unreasonable under general claim construction principles” (Microsoft Corp.
`v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015) (overruled on other
`grounds by Aqua Products, Inc. v. Matal, 872 F.3d 1290 (Fed. Cir. 2017))).
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`Claim 1 of the ’231 patent recites “[a] humanized antibody variable
`domain . . . 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.” Depending from claim 1, claim 4 limits the
`humanized antibody variable domain of claim 1 to “a consensus human
`variable domain.”8
`Petitioner reasons that “[b]ecause claim 1 requires substitutions in the
`variable domain, claim 4 must also require substitutions in the variable
`domain” such that the claims “encompass[] humanized antibody variable
`domains where only some of the residues in the sequence are ‘consensus’
`residues, and where other, non-consensus residues are ‘substitutions’ in the
`consensus sequence.” Pet. 7–8.
`Petitioner further argues “substitution,” and the related term
`“substituted,” do not require the intentional replacement of amino acids i
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