Trials@uspto.gov
`571.272.7822
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` Paper 14
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` Entered: February 25, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ELI LILLY AND COMPANY,
`Petitioner,
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner.
`____________
`
`Case IPR2018-01425
`Patent 9,890,210 B2
`____________
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`SMITH, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
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`
`
`571.272.7822
`
`
`
`
`
` Paper 14
`
` Entered: February 25, 2019
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`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ELI LILLY AND COMPANY,
`Petitioner,
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner.
`____________
`
`Case IPR2018-01425
`Patent 9,890,210 B2
`____________
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`SMITH, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
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`
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`IPR2018-01425
`Patent 9,890,210 B2
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` INTRODUCTION
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`Eli Lilly and Company (“Petitioner”) filed a Petition to institute an
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`inter partes review of claims 1–15 of U.S. Patent 9,890,210 B2 (the “’210
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`patent”). Paper 1 (“Pet.”). Teva Pharmaceuticals International GmbH
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`(“Patent Owner”) filed a Preliminary Response to the Petition. Paper 9
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`(“Prelim. Resp.”).
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`In its Preliminary Response, Patent Owner argued that we should
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`exercise our authority to deny the Petition based on 35 U.S.C. § 325(d)
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`because the same or substantially the same prior art or arguments previously
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`were presented to the Patent and Trademark Office. Prelim. Resp. 10–27.
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`Petitioner thereafter requested permission to file a reply to the Preliminary
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`Response to address that issue. We granted Petitioner’s request, allowing
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`Petitioner to file a reply and Patent Owner to file a sur-reply. Paper 10.
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`Petitioner thereafter filed its reply (Paper 11, “Pet. Reply”) and Patent
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`Owner filed its sur-reply (Paper 12, “PO Surreply”).
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`We have authority under 35 U.S.C. § 314 to determine whether to
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`institute an inter partes review. To institute an inter partes review, we must
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`determine that the information presented in the Petition shows “a reasonable
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`likelihood that the petitioner would prevail with respect to at least 1 of the
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`claims challenged in the petition.” 35 U.S.C. § 314(a). For the reasons set
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`forth below, we conclude that Petitioner has established a reasonable
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`likelihood that it would prevail in showing the unpatentability of at least one
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`challenged claim of the ’210 patent. Therefore, we institute an inter partes
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`review for claims 1–15 of the ’210 patent.
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`A.
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`Related Proceedings
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`Petitioner identifies a declaratory judgment action filed by Patent
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`Owner on October 24, 2017, in the District Court for the District of
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`2
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`IPR2018-01425
`Patent 9,890,210 B2
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`Massachusetts (“the first DJ action”). Pet. 56. According to Petitioner, the
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`first DJ action seeks a declaration that Petitioner’s investigational drug
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`galcanezumab will infringe U.S. Patent Nos. 8,586,045; 8,597,649;
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`9,266,951; 9,346,881; and 9,340,614, and Patent Owner filed an amended
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`complaint in the first DJ action on January 16, 2018. Id. Petitioner also
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`identifies a declaratory judgment action filed by Patent Owner on
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`February 6, 2018, seeking a declaration that Petitioner’s product will
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`infringe U.S. Patent Nos. 9,884,907 and 9,884,908 (“the second DJ action”).
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`Id. Petitioner states that Patent Owner thereafter filed an amended
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`complaint in the second DJ action to incorporate U.S. Patent No. 9,890,211
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`and the ’210 patent. Id.
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`According to Petitioner, all of the patents in the first DJ action and the
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`second DJ action purport to claim priority to the same provisional
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`application as the ’210 patent, and that two applications (15/883,218 and
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`15/956,580) based on the same provisional application are pending before
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`the United States Patent and Trademark Office. Id.
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`Patent Owner identifies the first DJ action and the second DJ action,
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`as well as eight inter partes reviews styled Eli Lilly and Co. v. Teva
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`Pharmaceuticals International GmbH, IPR2018-01422, IPR2018-01423,
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`IPR2018-01424, IPR2018-01426, IPR2018-01427, IPR2018-01710,
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`IPR2018-01711, and IPR2018-01712. Papers 4, 7. Patent Owner also
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`identifies U.S. Patent Nos. 9,365,648; 9,328,168; 9,115,194; 8,734,802;
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`8,007,794, in addition to the patents and patent applications identified by
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`Petitioner. Paper 4. Patent Owner also identifies a litigation styled Teva
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`Pharmaceuticals International GmbH v. Eli Lilly and Co., Civ. No. 1-18-cv-
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`12029 (D. Mass.). Paper 7.
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`3
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`IPR2018-01425
`Patent 9,890,210 B2
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`B.
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`The ’210 Patent (Ex. 1001)
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`The ’210 patent is titled “Antagonist Antibodies Directed Against
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`Calcitonin Gene-Related Peptide[1]” and “relates to the use of anti-CGRP
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`antagonist antibodies for the prevention, amelioration, or treatment of
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`vasomotor symptoms, such as CGRP related headaches (e.g., migraine) and
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`hot flushes.” Ex. 1001, [54], 1:33–36.
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`According to the Specification, CGRP is a 37 amino acid
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`neuropeptide, which belongs to a family of peptides that includes calcitonin,
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`adrenomedullin and amylin. Id. at 1:40–42. In humans, two forms of CGRP
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`with similar activities (α-CGRP and β-CGRP) exist and exhibit differential
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`distribution. Id. at 1:42–45. At least two CGRP receptor subtypes may also
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`account for differential activities. Id. at 1:45–46. CGRP is a
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`neurotransmitter in the central nervous system, and has been shown to be a
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`potent vasodilator in the periphery, where CGRP-containing neurons are
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`closely associated with blood vessels. Id. at 1:46–50.
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`CGRP-mediated vasodilatation is also associated with neurogenic
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`inflammation, as part of a cascade of events that results in extravasation of
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`plasma and vasodilation of the microvasculature and is present in migraine.
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`Id. at 1:50–53. CGRP has been noted for its possible connection to
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`vasomotor symptoms. Id. at 1:54–55. Vasomotor symptoms include hot
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`flushes and night sweats. Id. at 1:57–58. CGRP is a potent vasodilator that
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`has been implicated in the pathology of other vasomotor symptoms, such as
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`all forms of vascular headache, including migraines (with or without aura)
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`and cluster headache. Id. at 2:19–22.
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`
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`1 Calcitonin Gene-Related Peptide is abbreviated throughout as CGRP. See
`Ex. 1001, 1:40.
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`4
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`IPR2018-01425
`Patent 9,890,210 B2
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`According to the Specification, the precise pathophysiology of
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`migraine is not yet well understood. Id. at 3:35–36. Dilation of blood
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`vessels is associated with and exacerbates the pain symptoms of migraine.
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`Id. at 3:41–42. The variety of pharmacologic interventions that have been
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`used to treat migraine and the variability in responses among patients
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`indicate that migraine is a diverse disorder. Id. at 3:7–9. Different classes of
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`drugs have been used in treatment (and some patients, usually those with
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`milder symptoms, are able to control their symptoms with non-prescription
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`remedies). See id. at 3:10–27. Some patients respond well to sumatriptan,
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`which is a 5HT1 receptor agonist, which also inhibits release of CGRP;
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`others are relatively resistant to its effects. See id. at 2:31–33, 3:27–32,
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`4:22–24.
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`The ’210 patent is directed, inter alia, to methods of treating or
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`preventing a vasomotor symptom, migraine headache, or cluster headache in
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`an individual using an effective amount of an anti-CGRP antagonist
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`antibody. See id. at 3:55–4:5. The ’210 patent is also directed to methods of
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`ameliorating, controlling, reducing incidence of, or delaying the
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`development or progression of a migraine headache or cluster headache,
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`using an effective amount of an anti-CGRP antagonist antibody with or
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`without additional agents. See id. at 4:6–54. In various embodiments, the
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`antibody is a human antibody or humanized antibody, the antibody
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`recognizes a human CGRP, or the antibody comprises modified regions. See
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`id. at 4:58–5:55, 8:20–22. Other embodiments are directed to a polypeptide
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`which may or may not be an antibody. See id. at 7:10–8:19. Other
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`embodiments are directed to a polynucleotide encoding a fragment or region
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`of the antibody or its variants, or to expression and cloning vectors and host
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`cells comprising any of the disclosed polynucleotides. See id. at 8:32–61.
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`5
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`Patent 9,890,210 B2
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`Other embodiments are directed to methods of making the same. See id. at
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`9:5–21.
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`The ’210 patent includes a Table 4 showing amino acid sequences of
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`different variants of human α-CGRP and related peptides. Id. at 52:14–18;
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`cols. 54–55 (Table 4). Table 4 identifies CGRP 1–37 (WT) as SEQ ID
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`NO:15 and CGRP human β (1–37) as SEQ ID NO:43. See id.
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`Figure 5 (not reproduced here) shows the amino acid sequence of the
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`heavy chain variable region (SEQ ID NO:1) and light chain variable region
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`(SEQ ID NO:2) of antibody G1. Id. at 10:26–28. Table 6 provides data on
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`binding affinity for G1 variants. See id. at cols. 62–67. Another table (cols.
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`73–103) lists additional antibody sequences.
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`C.
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`Illustrative Claim
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`Claim 1, the only independent claim challenged, is illustrative and
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`reproduced below:
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`1. A humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP)
`antagonist antibody, comprising:
`two human IgG heavy chains, each heavy chain comprising three
`complementarity determining regions (CDRs) and four framework
`regions, wherein portions of the two heavy chains together form an Fc
`region; and
`two light chains, each light chain comprising three CDRs and four
`framework regions;
`wherein the CDRs impart to the antibody specific binding to a CGRP
`consisting of amino acid residues 1 to 37 of SEQ ID NO:15 or SEQ
`ID NO: 43.
`
`Ex. 1001, 103:35–46.
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`
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`Claims 2–15 depend, directly or indirectly, on claim 1. Id. at 103:47–
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`104:60.
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`6
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`Patent 9,890,210 B2
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`D.
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`The Asserted Ground of Unpatentability
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`Petitioner contends that the challenged claims are unpatentable on the
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`sole ground of obviousness under 35 U.S.C. § 103(a) based on the following
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`combination of references:
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`K.K.C. Tan et al., Calcitonin gene-related peptide as an endogenous
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`vasodilator: immunoblockade studies in vivo with an anti-calcitonin gene-
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`related peptide monoclonal antibody and its Fab' fragment, 89 CLINICAL
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`SCI. 6, 565–73 (1995) (“Tan”). Ex. 1022.
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`S.J. Wimalawansa, Calcitonin Gene-Related Peptide and its
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`Receptors: Molecular Genetics, Physiology, Pathophysiology, and
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`Therapeutic Potentials, 17 ENDOCRINE REVIEWS 5, 533–85 (1996)
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`(“Wimalawansa”). Ex. 1096.
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`Queen et al., US 6,180,370 B1, issued Jan. 30, 2001 (“Queen”).
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`Ex. 1023.
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`Petitioner also relies on the Declaration of Dr. Andrew C. Charles,
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`M.D. (Ex. 1010, “Charles Declaration”) and the Declaration of Dr. Alain P.
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`Vasserot, Ph.D. (Ex. 1011, “Vasserot Declaration”).
`
` ANALYSIS
`
`A.
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`Person of Ordinary Skill in the Art
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`Petitioner asserts that “a POSA [person of ordinary skill in the art]
`
`with respect to the aspects of the ’210 patent pertaining to designing and
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`optimizing anti-CGRP antibodies would have generally possessed a Ph.D. in
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`immunology, molecular biology, or pharmacology with several years of
`
`post-doctoral research experience focused on antibody engineering and/or
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`antibody pharmacology.” Pet. 20 (citing Ex. 1011 ¶¶ 70–72). Petitioner
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`further asserts that “[a] POSA with respect to the aspects of the ’210 patent
`
`pertaining to using anti-CGRP antibodies would have generally possessed a
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`7
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`IPR2018-01425
`Patent 9,890,210 B2
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`Ph.D. in a relevant field (e.g., neurobiology, neurology, pharmacology) or an
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`M.D. with a residency in a relevant field (e.g., neurology), with several years
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`of experience studying CGRP or treating patients with a CGRP-related
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`disease.” Id. (citing Ex. 1010 ¶¶ 78–80).
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`Patent Owner contends that “[b]ecause the '210 patent relates to anti-
`
`CGRP antagonist antibody therapeutics, a POSA would draw upon the
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`knowledge and experience of related disciplines of a multi-disciplinary team
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`that might lie outside the POSA's primary training.” Prelim. Resp. 28–29.
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`Thus, according to Patent Owner, a POSA relevant to the ’210 patent would
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`have the knowledge of, or be able to draw upon the knowledge of, (for
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`example): “(1) a scientist having a Ph.D. in immunology, biochemistry, or
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`an equivalent discipline, with approximately 3-5 years in antibody design
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`and engineering;” or “(2) a scientist having a Ph.D. in pharmacology,
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`pharmacy, or an equivalent discipline, with approximately 3-5 years of
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`experience in preclinical and clinical pharmacokinetics and
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`pharmacodynamics;” or “(3) a doctor having an M.D. with a specialty in
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`neurology, specifically in treating headache and migraine, including
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`approximately 5 years of experience in its research, diagnosis, and/or
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`treatment.” Id. at 29.
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`On this record and at this stage of the proceeding, we do not discern
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`an appreciable difference in the parties’ respective definitions of a person of
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`ordinary skill in the art. Accordingly, for purposes of the present Decision,
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`we find that a person of ordinary skill in the art would have (1) a Ph.D. in a
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`relevant field, such as immunology, biochemistry, or pharmacology, with
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`several years of post-doctoral experience in antibody engineering,
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`pharmacokinetics, and pharmacodynamics, or (2) an M.D. with a residency
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`8
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`IPR2018-01425
`Patent 9,890,210 B2
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`or specialty in neurology, and several years of experience studying CGRP or
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`treating patients with a CGRP-related disease, such as migraine headaches.
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`We further note that the prior art itself demonstrates the level of skill
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`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
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`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
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`ordinary skill level are not required “where the prior art itself reflects an
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`appropriate level and a need for testimony is not shown”) (quoting Litton
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`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
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`1985)).
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`B.
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`Claim Construction
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`In this inter partes review, filed August 8, 2018,2 a claim in an
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`unexpired patent shall be given its broadest reasonable construction in light
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`of the specification of the patent in which it appears. 37 C.F.R. § 42.100(b);
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`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142 (2016) (affirming
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`applicability of broadest reasonable construction standard to inter partes
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`review proceedings). Under that standard, and absent any special
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`definitions, we generally give claim terms their ordinary and customary
`
`meaning, as would be understood by one of ordinary skill in the art at the
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`time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
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`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`
`
`
`2 The claim construction standard to be employed in inter partes reviews has
`changed for proceedings in which the petition was filed on or after
`November 13, 2018. See Changes to the Claim Construction Standard for
`Interpreting Claims in Trial Proceedings Before the Patent Trial and Appeal
`Board, 83 Fed. Reg. 51,340 (Nov. 13, 2018) (to be codified at 37 C.F.R.
`pt. 42).
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`9
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`Patent 9,890,210 B2
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`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
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`30 F.3d 1475, 1480 (Fed. Cir. 1994).
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`Petitioner requests construction of the term “specific binding,” citing
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`to the Specification of the ’210 patent. Pet. 20–22. According to Petitioner,
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`the term “specific binding” includes antibodies that may bind to more than
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`one isoform of CGRP, and does not preclude binding to another peptide. Id.
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`at 21 (citing Ex. 1010 ¶ 105; Ex. 1011 ¶¶ 75–76). Petitioner further asserts
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`that pursuant to the ’210 patent, a binding preference for a first target or a
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`second target is not required, and that “specific binding” is not limited to
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`“exclusive binding.” Id. at 22 (citing Ex. 1010 ¶ 105; Ex. 1011 ¶¶ 75–76;
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`Ex. 1001, 16:36–39).
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`Patent Owner does not request special construction of any terms,
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`stating that “for purposes of this proceeding, the Board should construe the
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`'210 patent claims according to their plain and customary meaning.” Prelim.
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`Resp. 28. However, Patent Owner does not agree with Petitioner’s proposed
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`construction of the claim term “specific binding.” Id. According to Patent
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`Owner, Petitioner’s construction is “impermissibly broad” because it does
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`not require specific binding to any target and does not account for the
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`language of claim 1. Id.
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`We provide the following comments, but emphasize that they are
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`preliminary in nature at this stage of the proceeding.
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`We agree with Patent Owner that claim 1 uses the term “specific
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`binding” in the phrase stating “wherein the CDRs impart to the antibody
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`specific binding to a CGRP consisting of amino acid residues 1 to 37 of SEQ
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`ID NO:15 or SEQ ID NO: 43.” Ex. 1001, 103:44–46. However, we do not
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`view Petitioner’s statement that “under the ’210 patent’s definition, a
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`binding preference for a first target or a second target is not required” to be
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`10
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`IPR2018-01425
`Patent 9,890,210 B2
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`inconsistent with the recitation in claim 1 that “the CDRs impart to the
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`antibody specific binding to a CGRP consisting of . . . .” Rather we view
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`Petitioner’s statement to be an attempt to capture the Specification’s
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`statement that “an antibody . . . that specifically or preferentially binds to a
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`first target may or may not specifically or preferentially bind to a second
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`target. . . . ‘specific binding’ or ‘preferential binding’ does not necessarily
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`require (although it can include) exclusive binding.” Ex. 1001, 16:34–39.
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`Thus, in view of the arguments at this time and the apparent lack of
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`inconsistency in the positions of the parties, we determine that it is not
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`necessary to construe the term “specific binding” on this record and at this
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`stage of the proceeding.
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`We also determine, for purposes of determining whether to institute
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`an inter partes review in this case, that we need not expressly construe any
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`undisputed terms. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
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`795, 803 (Fed. Cir. 1999) (only those terms which are in controversy need to
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`be construed and only to the extent necessary to resolve the controversy).
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`C.
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`Principles of Law
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`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
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`differences between the claimed subject matter and the prior art are such that
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`the subject matter, as a whole, would have been obvious at the time the
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`invention was made to a person having ordinary skill in the art to which said
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`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
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`(2007). The question of obviousness is resolved on the basis of underlying
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`factual determinations, including: (1) the scope and content of the prior art;
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`(2) any differences between the claimed subject matter and the prior art;
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`(3) the level of ordinary skill in the art; and (4) objective evidence of
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`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
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`11
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`An obviousness analysis “need not seek out precise teachings directed
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`to the specific subject matter of the challenged claim, for a court can take
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`account of the inferences and creative steps that a person of ordinary skill in
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`the art would employ.” KSR, 550 U.S. at 418; see Translogic, 504 F.3d at
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`1262. “Often, it will be necessary for a court to look to interrelated
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`teachings of multiple patents; the effects of demands known to the design
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`community or present in the marketplace; and the background knowledge
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`possessed by a person having ordinary skill in the art, all in order to
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`determine whether there was an apparent reason to combine the known
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`elements in the fashion claimed by the patent at issue.” KSR, 550 U.S. at
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`418.
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`We analyze the asserted ground of unpatentability in accordance with
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`the above-stated principles.
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`D. Obviousness over Tan, Wimalawansa, and Queen
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`Petitioner asserts that claims 1–15 of the ’210 patent are unpatentable
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`as obvious over Tan, Wimalawansa, and Queen. Pet. 22–55. Patent Owner
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`opposes. Prelim. Resp. 27–54.
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`1.
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`Tan (Ex. 1022)
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`Tan states that “[i]mmunoblockade may be described as the blockade
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`of the effects of a biological mediator by inhibition of its binding to specific
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`receptors with antibodies directed against the mediator.” Ex. 1022, 566.
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`Tan describes a comparative study, wherein the results of using an
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`anti-CGRP monoclonal antibody (MAb) IgG and its Fab' fragment for
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`immunoblockade in vivo were compared to those obtained by receptor
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`blockade with hαCGRP8–37. Id.
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`Tan reports on an in vivo study with intravenous administration of rat
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`CGRP and various anti-CGRP antibody preparations in male Sprague-
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`12
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`Dawley rats. See Ex. 1022, 565–566. The effects of an anti-CGRP
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`monoclonal antibody (MAb C4.19) and its Fab’ fragment on CGRP changes
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`in blood pressure were studied in anaesthetized rats. Id. at 565. Tan reports
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`that MAb C4.19 IgG increased MAP [mean arterial pressure] slightly, but
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`MAP was decreased by rαCGRP in a dose-dependent manner. Id. at 568. In
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`experiments involving MAb C4.19 Fab' fragment, a control dose of
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`0.1 nmol/kg rαCGRP decreased MAP by 29.5 mm Hg. Id. at 569. The
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`hypotensive response to rαCGRP was accompanied by a dose-dependent
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`tachycardia in some experiments. Id. at 568. Tan states that “[t]his study
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`has clearly demonstrated the ability of MAb C4.19 IgG and its Fab’
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`fragment to block the hypotensive effects of exogenous rαCGRP.” Id. at
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`570.
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`Tan reports that the skin blood flow response to antidromic
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`stimulation of the saphenous nerve was effectively blocked 30 min after
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`administration of MAb C4.19 Fab' fragment (2 mg/rat) but not 60 minutes
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`after administration of MAb C4.19 IgG (1 mg/rat). See id. at 565, 569–570.
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`Nerve stimulation performed at 2 hours after 3 mg/rat MAb C4.19 IgG
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`produced an AUC (area under the flux-time curve attributable to nerve
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`stimulation) that was slightly smaller compared with baseline stimulation.
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`Id. at 569. Tan states that the slow distribution of IgG to the site of
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`immunoblockade could be overcome by chronic or repeated administration
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`of IgG. Id. at 571. Tan further states that “MAb C4.19 does not cross-react
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`with rat amylin in vitro” and that “the routine use of Fab' fragment should be
`
`advocated for acute immunoblockade experiments in vivo.” Id. at 572.
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`2. Wimalawansa (Ex. 1096)
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`Wimalawansa is a review article that describes the molecular biology,
`
`distribution, activity, and “therapeutic potentials” of CGRP. See Ex. 1096,
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`13
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`533–570. According to Wimalawansa, CGRP is a 37-amino acid
`
`neuropeptide resulting from alternative splicing of the primary RNA
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`transcript of the CT [calcitonin]/CGRP gene. Id. at 534. There are two
`
`genes, responsible for α and β subforms of the peptide. See id.
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`Wimalawansa teaches that CGRP and CGRP receptors are widely
`
`distributed in the mammalian nervous system (e.g., discrete brain areas and
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`the peripheral nervous system), in the cardiovascular system (e.g., arteries,
`
`veins, and the heart), the gastrointestinal tract, and several endocrine organs
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`(e.g., the thyroid gland and pancreatic islet cells), often co-located with other
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`neurotransmitters and neuropeptides. See id. at 539–40. Wimalawansa
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`suggests that CGRP has potent vasodilatory activity, may play a major role
`
`in regulating peripheral vascular tone, and has an ability to change coronary
`
`blood flow. Id. at 540. Wimalawansa also suggests an association between
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`a decrease in CGRP and strokes and heart attacks in older populations, e.g.,
`
`during parts of the circadian cycle. See id. at 543. CGRP has various direct
`
`and indirect mechanisms for its vasodilatory effects, including causing
`
`vasorelaxation through specific receptors in vascular smooth muscle (e.g., in
`
`coronary vasculature). Id. at 553, 556 & Fig. 18 (not reproduced here).
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`Wimalawansa discloses that α- and β- CGRP are agonists for all
`
`receptor subtypes, but a synthetically-derived fragment of CGRP (e.g.,
`
`CGRP8-37) instead acts as a competitive antagonist at certain receptor
`
`subtypes, e.g., CGRP-type 1 receptors. Id. at 543, 547. Receptors that do
`
`not respond to the antagonist CGRP8-37 are generally grouped as CGRP-type
`
`2 receptors, but other receptor types have been postulated. Id. at 548.
`
`Wimalawansa states: “The fact that different vascular beds respond
`
`differently to CGRP and CGRP8-37 may indicate receptor heterogeneity.” Id.
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`In a section titled “Therapeutic potentials of CGRP antagonists,”
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`Wimalawansa states “[c]learly, more data from carefully designed studies
`
`are necessary before any definitive conclusions can be reached and before
`
`CGRP antagonist, humanized anti-GCRP monoclonal antibodies, or both,
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`can be evaluated as therapeutic agents in humans.” Id. at 567. In a
`
`subsection on “Migraine headache and premenstrual syndrome,”
`
`Wimalawansa states:
`
`CRGP agonists designed specifically for cerebral vascular bed,
`when available, can be used during the early phase (i.e.
`vasoconstructive phase) of migraine headaches, and CGRP
`antagonist can be used in the late phase (prolonged vasodilatory
`phase). However, the antagonist must be extremely specific to
`the CGRP receptors located in cerebral arteries to avoid potential
`deleterious side effects caused by blocking other vascular and
`nonvascular CGRP receptors. Ideally, this compound should be
`a peptide mimetic of simple structure specific to cardiovascular
`CGRP receptors, so that the drug can be given orally, buccally,
`or sublingually.
`
`Id. at 568.
`
`
`
`Wimalawansa concludes:
`
`CGRP is a potent neuropeptide involved in human
`physiopathology but, in spite of 14 yr of intense research, its role
`is still not fully understood.
`
`. . .
`
`The role of CGRP antagonists and humanized monoclonal
`antibodies should be explored with respect to control of pain and
`inflammation, type II diabetes, and in conditions with intractable
`hypotension, such as septic shock syndrome.
`
`Id. at 569–70.
`
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`3.
`
`Queen (Ex. 1023)
`
`Queen is titled “Humanized Immunoglobulins and Methods of
`
`Making the Same,” and “relates generally to the combination of recombinant
`
`DNA and monoclonal antibody technologies for developing novel
`
`therapeutic agents and, more particularly, to the[] production of
`
`non-immunogenic antibodies having strong affinity for a predetermined
`
`antigen.” See Ex. 1023, [54], 1:19–23.
`
`
`
`Queen describes problems with prior art monoclonal antibodies, i.e.,
`
`most monoclonal antibodies were mouse derived and did not fix human
`
`complement well, lacked other functional characteristics when used in
`
`humans, and contained substantial stretches of amino acid sequences that
`
`would be immunogenic when injected into a human patient. Id. at 1:26–47.
`
`According to Queen, the production of so-called “chimeric antibodies” (e.g.,
`
`mouse variable regions joined to human constant regions) proved somewhat
`
`successful but a significant immunogenicity problem remained. Id. at 1:58–
`
`61. Queen discloses that then-recent recombinant DNA technology had
`
`been used to produce immunoglobulins with reduced immunogenicity,
`
`called “reshaped” or “humanized” antibodies, which have human framework
`
`regions with complementarity determining regions (CDRs) from a donor
`
`mouse. Id. at 1:65–2:11. However, Queen discloses that a major problem
`
`existed with humanized antibodies, i.e., a loss of affinity for the target
`
`antigen (by 10-fold or more) with poorer function and higher adverse effects
`
`(e.g., if a higher dose is consequently administered). Id. at 2:13–27.
`
`
`
`Queen discloses a method of humanizing donor (e.g., mouse)
`
`antibodies by selecting a human framework sequence (i.e., containing a light
`
`chain or heavy chain) from a collection of sequences based on homology to
`
`the donor sequence such that the selected human framework sequence will
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`16
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`have 65% to 70% homology or more to the donor framework sequence. Id.
`
`at 13:5–36. As further step(s), the human sequence will be replaced by
`
`corresponding amino acids from the donor sequence if they are (1) in a
`
`CDR, and/or (2) if the amino acid is rare for that position and that
`
`corresponding amino acid in the donor sequence is common for that position
`
`in human sequences, (3) the amino acid is immediately adjacent to one of
`
`the CDRs, (4) the amino acid is predicted to be within about 3A of the CDRs
`
`in a three-dimensional model and capable of interacting with the antigen or
`
`CDRs of the donor or humanized immunoglobulin, (5) the amino acid is rare
`
`for that position in a human sequence and the corresponding amino acid
`
`from the donor sequence is also rare, relative to other human sequences. See
`
`id. at 2:41–3:26.
`
`4.
`
`Analysis
`
`In its Petition, Petitioner sets forth its contentions as to how the
`
`limitations of claims 1–15 are obvious over the combination of Tan,
`
`Wimalawansa, and Queen. Pet. 22–53. Patent Owner opposes. Prelim.
`
`Resp. 27–54. We address these contentions below. We emphasize that the
`
`following determinations regarding the sufficiency of the Petition are
`
`preliminary in nature at this stage of the proceeding.
`
`Claim 1
`
`Petitioner argues that “[e]ach and every element of [Patent Owner’s]
`
`claims is disclosed or suggested by the prior art.” Pet. 22. Petitioner points
`
`to Tan’s description of murine anti-CGRP antagonist antibodies, including a
`
`full-length antibody, that blocked the effects of CGRP both in vitro and in
`
`vivo. Id. (citing Ex. 1010 ¶¶ 69–70). Petitioner also points to Wimalawansa
`
`as proposing the use of humanized anti-CGRP monoclonal antagonistic
`
`antibodies as therapeutic agents for CGRP-related diseases (id. (citing
`
`17
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`IPR2018-01425
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`Ex. 1096, 567, 570; Ex. 1010 ¶ 73)), and Queen’s description of routine and
`
`conventional humanization technologies using human IgG scaffolds (id.
`
`(citing Ex. 1011 ¶ 48; see generally Ex. 1023)).
`
`Petitioner also argues that a person of ordinary skill in the art would
`
`have been motivated to generate a humanized anti-CGRP antagonist
`
`antibody of claim 1. Pet. 23–30. Petitioner points to Wimalawansa as
`
`teaching that CGRP was implicated in human diseases and conditions
`
`associated with vasodilation such as migraine and inflammation, and that
`
`Wimalawansa specifically identified humanized anti-CGRP antagonist
`
`antibodies for treating diseases such as migraine, inflammation, and
`
`cardiogenic shock. Id. at 23, 25 (citing Ex. 1010 ¶¶ 109–116; Ex. 1096, 567,
`
`570 (“The role of CGRP antagonists and humanized monoclonal antibodies
`
`should be explored. . . .” (emphasis added by Petitioner))). Thus, according
`
`to Petitioner, “the prior art—replete with exemplary disclosures of anti-
`
`CGRP antagonist antibodies, including humanized antibodies, to treat human
`
`diseases and conditions—provided express motivation to prepare a
`
`humanized anti-CGRP antagonist antibody against human CGRP suitable
`
`for administration to humans.” Id. at 26 (citing Ex. 1010 ¶¶ 109–116;
`
`Ex. 1011 ¶¶ 82, 88–92). Petitioner thus asserts that a POSA “would have
`
`been motivated to combine and follow the disclosures of Tan 1995,
`
`Wimalawansa, and Queen to obtain a humanized anti-CGRP antagonist
`
`antibody that would have the recited property of specifically binding to
`
`human αCGRP or βCGRP.” Id. at 29–30 (citing Ex. 1010 ¶¶ 126–133;
`
`Ex. 1011 ¶¶ 88–95).
`
`Petitioner further argues that a POSA would have had a reasonable
`
`expectation of successfully making a humanized anti-CGRP antagonist
`
`antibody of claim 1. Pet. 30–36. Petitioner asserts that a POSA would have
`
`18
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`reasonably expected to succeed in making an anti-CGRP antagonist antibody
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`that specifically bound human CGRP like those reported in Tan and
`
`elsewhere. Id. at 31 (citing Ex. 1010 ¶¶ 135–140; Ex. 1011 ¶¶ 98–102;
`
`Ex. 10213, 706; Ex. 1055, 88, 90, 93). According to Petitioner, generating
`
`anti-CGRP antagonist antibodies against human CGRP instead of
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