throbber
Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 14
`Entered: February 25, 2019
`
`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 IPR2018-01427
`Patent 8,597,649 B2
`
`
`
`
`
`
`
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`RICHARD J. SMITH, Administrative Patent Judges.
`
`WORTH, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`I.
`
`INTRODUCTION
`
`On August 8, 2018, Eli Lilly and Co. (“Lilly” or “Petitioner”) filed a
`
`Petition (Paper 1, “Pet.”) requesting an inter partes review of claims 1–9
`
`(the “challenged claims”) of U.S. Patent No. 8,597,649 B2 (Ex. 1001, “the
`
`’649 patent”). On November 27, 2018, Teva Pharmaceuticals International
`
`GmbH (“Teva” or “Patent Owner”) filed a Preliminary Response (Paper 9,
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`“Prelim. Resp.”). On December 24, 2018, with authorization, Petitioner
`
`filed a Reply to Patent Owner’s Preliminary Response (Paper 11, “Reply”).
`
`On January 4, 2019, with authorization, Patent Owner filed a Surreply
`
`thereto (Paper 12, “Surreply”).
`
`Institution of an inter partes review is authorized by statute when “the
`
`information presented in the petition filed under [35 U.S.C. §] 311 and any
`
`response filed under [35 U.S.C. §] 313 shows that there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.” 35 U.S.C. § 314(a). For the reasons set
`
`forth below, we determine that Petitioner has demonstrated that there is a
`
`reasonable likelihood that claims 1–9 are unpatentable, and we institute an
`
`inter partes review of claims 1–9 based on the ground set forth in the
`
`Petition.
`
`A. Related Matters
`
`The parties note as related the following district court proceedings:
`
`Teva Pharmas. Int’l GmbH v. Eli Lilly and Co., No. 1-17-cv-12087
`
`(D. Mass., filed Feb. 6, 2018); Teva Pharmas. Int’l GmbH v. Eli Lilly and
`
`Co., No. 1-18-cv-10242 (D. Mass., filed Oct. 24, 2017). See Pet. 64,
`
`Paper 4, 1. The parties note as related the following Board proceedings:
`
`IPR2018-01422, -1423, -1424, -1425, -1426, -1710, -1711, -1712. See
`
`Pet. 64, Paper 4, 1–2, Paper 7, 1. The parties note as related the following
`
`patents: U.S. Patent Nos. 9,890,211; 9,890,210; 9,884,908; 9,884,907;
`
`9,365,648; 9,346,881; 9,340,614; 9,328,168; 9,266,951; 9,115,194;
`
`8,734,802; 8,586,045; and 8,007,794. Paper 4, 2–3. The parties note as
`
`related the following patent applications, which were pending at the time of
`
`2
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`

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`IPR2018-01427
`Patent 8,597,649 B2
`
`the parties’ notices: U.S. Patent Application Nos. 15/883,218 and
`
`15/956,580. Pet. 64, Paper 4, 3.
`
`B. The ’649 Patent (Ex. 1001)
`
`The ’649 patent is titled “Antagonist Antibodies Directed Against
`
`Calcitonin Gene-Related Peptide[1] and Methods Using Same” and “relates
`
`to the use of anti-CGRP antagonist antibodies for the prevention,
`
`amelioration, or treatment of vasomotor symptoms, such as CGRP related
`
`headaches (e.g., migraine) and hot flushes.” Ex. 1001, [54], 1:29–32.2
`
`According to the Specification, CGRP is a 37 amino acid
`
`neuropeptide, which belongs to a family of peptides that includes calcitonin,
`
`adrenomedullin, and amylin. Id. at 1:36–37. In humans, two forms of
`
`CGRP with similar activities (α-CGRP and β-CGRP) exist and exhibit
`
`differential distribution. Id. at 1:37–40. At least two CGRP receptor
`
`subtypes may also account for differential activities. Id. at 1:41–42. CGRP
`
`is a neurotransmitter in the central nervous system, and has been shown to
`
`be a potent vasodilator in the periphery, where CGRP-containing neurons
`
`are closely associated with blood vessels. Id. at 1:42–46.
`
`CGRP-mediated vasodilatation is associated with neurogenic
`
`inflammation, as part of a cascade of events that results in extravasation of
`
`plasma and vasodilation of the microvasculature and is present in migraine.
`
`Id. at 1:46–49. CGRP has been noted for its possible connection to
`
`vasomotor symptoms. Id. at 1:50–52. Vasomotor symptoms include hot
`
`
`1 Calcitonin Gene-Related Peptide is abbreviated throughout as CGRP. See
`Ex. 1001, 1:29–36.
`
`2 Certificates of correction issued on March 31, 2015 and February 23, 2016,
`which made typographic changes to the title page. See Ex. 1001, 71–72.
`
`3
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`IPR2018-01427
`Patent 8,597,649 B2
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`flushes and night sweats. Id. at 1:53–54. CGRP is a potent vasodilator that
`
`has been implicated in the pathology of other vasomotor symptoms, such as
`
`all forms of vascular headache, including migraines (with or without aura)
`
`and cluster headache. Id. at 2:14–18.
`
`According to the Specification, the precise pathophysiology of
`
`migraine is not yet well understood. Id. at 3:25–28. Dilation of blood
`
`vessels is associated with and exacerbates the pain symptoms of migraine.
`
`Id. at 3:32–36. The variety of pharmacologic interventions that have been
`
`used to treat migraine and the variability in responses among patients
`
`indicate that migraine is a diverse disorder. Id. at 3:1–3. Different classes of
`
`drugs have been used in treatment. See id. at 3:4–19. Some patients respond
`
`well to sumatriptan, which is a 5HT1 receptor agonist, which also inhibits
`
`release of CGRP; others are relatively resistant to its effects. See id. at 2:25–
`
`27, 3:19–20, 4:14–18.
`
`The ’649 patent is directed, inter alia, to methods of treating or
`
`preventing a vasomotor symptom, migraine headache, or cluster headache in
`
`an individual using an effective amount of an anti-CGRP antagonist
`
`antibody. See id. at 3:46–64. The ’649 patent is also directed to methods of
`
`ameliorating, controlling, reducing incidence of, or delaying the
`
`development or progression of a migraine headache or cluster headache,
`
`using an effective amount of an anti-CGRP antagonist antibody with or
`
`without additional agents. See id. at 3:64–4:46. In various embodiments,
`
`the antibody is a human antibody or humanized antibody, the antibody
`
`recognizes a human CGRP, or the antibody comprises modified regions. See
`
`id. at 4:46–5:44, 8:11–12. Other embodiments are directed to a polypeptide
`
`which may or may not be an antibody. See id. at 6:65–8:9. Other
`
`4
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`IPR2018-01427
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`embodiments are directed to a polynucleotide encoding a fragment or region
`
`of the antibody or its variants, or to expression and cloning vectors and host
`
`cells comprising any of the disclosed polynucleotides. See id. at 8:22–45.
`
`Other embodiments are directed to methods of making the same. See id. at
`
`8:62–9:10.
`
`The Specification describes an experiment involving antibody G1 Fab
`
`fragment, and states that “human amylin . . . did not compete with binding of
`
`G1 Fab to human α-CGRP,” and that “[t]hese data demonstrate that G1
`
`targets a C-terminal epitope of CGRP and that both the identity of the most
`
`terminal residue (F37) and its amidation is important for binding.” Id. at
`
`67:12–18.
`
`Figure 5 (not reproduced here) shows the amino acid sequence of the
`
`heavy chain variable region (SEQ ID NO: 1) and light chain variable region
`
`(SEQ ID NO:2) of antibody G1. Id. at 10:16–18. Table 6 provides data on
`
`binding affinity for G1 variants. See id. at cols. 59–66. Another table (cols.
`
`72–102) lists additional antibody sequences.
`
`C. Illustrative Claim
`
`Claim 1, reproduced below, is the sole independent claim and is
`
`illustrative of the subject matter:
`
`An isolated human or humanized anti-CGRP
`1.
`antagonist antibody with a binding affinity (KD) to human
`α-CGRP of 50 nM or less as measured by surface plasmon
`resonance at 37° C.
`
`Ex. 1001, 101:38–40.
`
`5
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`
`D. The Prior Art
`
`Petitioner relies on the following prior art:
`
`K.K.C. Tan et al., Calcitonin gene-related peptide as an
`endogenous vasodilator: immunoblockade studies in vivo with
`an anti-calcitonin gene-related peptide monoclonal antibody
`and its Fab' fragment, 89 CLIN. SCI. 565–573 (Dec. 1995)
`(Ex. 1022, “Tan”)3;
`
`S.J. Wimalawansa, Calcitonin Gene-Related Peptide and
`Its Receptors: Molecular Genetics, Physiology,
`Pathophysiology, and Therapeutic Potentials, 17(5) ENDOCRINE
`REVIEWS 533–585 (Oct. 1996) (Ex. 1096, “Wimalawansa”);
`
`U.S. Patent No. 6,180,370 B1, iss. Jan. 30, 2001
`(Ex. 1023, “Queen”).
`
`E. The Alleged Ground of Unpatentability
`
`Petitioner challenges claims 1–9 of the ’649 patent as unpatentable
`
`under 35 U.S.C. § 103(a) over the combination of Tan, Wimalawansa, and
`
`Queen.
`
`II. ANALYSIS
`
`A.
`
`Person of Ordinary Skill in the Art
`
`Petitioner asserts that “a POSA [person of ordinary skill in the art]
`
`with respect to the aspects of the ’649 patent pertaining to designing and
`
`optimizing anti-CGRP antibodies would have generally possessed a Ph.D. in
`
`immunology, molecular biology, or pharmacology with several years of
`
`post-doctoral research experience focused on antibody engineering and/or
`
`antibody pharmacology.” Pet. 24 (citing Ex. 1003 ¶¶ 77–79). Petitioner
`
`further asserts that “[a] POSA with respect to the aspects of the ’649 patent
`
`pertaining to using anti-CGRP antibodies would have generally possessed a
`
`
`3 Petitioner refers to Tan as “Tan 1995.”
`
`6
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`IPR2018-01427
`Patent 8,597,649 B2
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`Ph.D. in a relevant field (e.g., neurobiology, neurology, pharmacology) or an
`
`M.D. with a residency in a relevant field (e.g., neurology), with several years
`
`of experience studying CGRP or treating patients with a CGRP-related
`
`disease.” Id. (citing Ex. 1002 ¶¶ 78–80.)
`
`Patent Owner contends that “[b]ecause the ’649 patent relates to anti-
`
`CGRP antagonist antibody therapeutics, a POSA would draw upon the
`
`knowledge and experience of related disciplines of a multi-disciplinary team
`
`that might lie outside the POSA’s primary training.” Prelim. Resp. 28–29.
`
`Thus, according to Patent Owner, a person of ordinary skill relevant to the
`
`’649 patent would have the knowledge of, or be able to draw upon the
`
`knowledge of (for example): “(1) a scientist having a Ph.D. in immunology,
`
`biochemistry, or an equivalent discipline, with approximately 3-5 years in
`
`antibody design and engineering;” or “(2) a scientist having a Ph.D. in
`
`pharmacology, pharmacy, or an equivalent discipline, with approximately 3-
`
`5 years of experience in preclinical and clinical pharmacokinetics and
`
`pharmacodynamics;” or “(3) a doctor having an M.D. with a specialty in
`
`neurology, specifically in treating headache and migraine, including
`
`approximately 5 years of experience in its research, diagnosis, and/or
`
`treatment.” Id. at 29.
`
`On this record and at this stage of the proceeding, we do not discern
`
`an appreciable difference in the parties’ respective definitions of a person of
`
`ordinary skill in the art. Accordingly, for purposes of the present Decision,
`
`we find that a person of ordinary skill in the art would have (1) a Ph.D. in a
`
`relevant field, such as immunology, biochemistry, or pharmacology, with
`
`several years of post-doctoral experience in antibody engineering,
`
`pharmacokinetics, and pharmacodynamics, or (2) an M.D. with a residency
`
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`Patent 8,597,649 B2
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`or specialty in neurology, and several years of experience studying CGRP or
`
`treating patients with a CGRP-related disease, such as migraine headaches.
`
`We further note that 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)).
`
`B. Claim Construction
`
`In this inter partes review, filed August 8, 2018, a claim in an
`
`unexpired patent shall be given 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, 2142 (2016) (affirming
`
`applicability of broadest reasonable construction standard to inter partes
`
`review proceedings). Under that standard, and absent any special
`
`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
`
`time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`
`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`
`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
`
`30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`Petitioner requests construction of the following terms: “anti-CGRP
`
`antagonist antibody” and “humanized antibody,” citing the Specification of
`
`the ’649 patent. Pet. 24–25. Patent Owner does not request special
`
`construction of any terms, stating that “for purposes of this proceeding, the
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`Patent 8,597,649 B2
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`Board should construe the ’649 patent claims according to their plain and
`
`customary meaning.” Prelim. Resp. 28.
`
`Petitioner argues that the ’649 patent expressly defines “antibody” to
`
`encompass “not only intact polyclonal or monoclonal antibodies, but also
`
`fragments thereof (such as Fab, Fab', F(ab')2, Fv).” Pet. 25 (citing Ex. 1001,
`
`12:28–34, 26:16–26; Ex. 1002 ¶ 103; Ex. 1003 ¶¶ 80–81). The Specification
`
`of the ’649 patent states:
`
`An “antibody” is an immunoglobulin molecule capable of
`specific binding
`to a
`target, such as a carbohydrate,
`polynucleotide, lipid, polypeptide, etc., through at least one
`antigen recognition site, located in the variable region of the
`immunoglobulin molecule. As used herein,
`the
`term
`encompasses not only
`intact polyclonal or monoclonal
`antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2,
`Fv), single chain (ScFv), mutants thereof, fusion proteins
`comprising an antibody portion (such as domain antibodies), and
`any other modified configuration of the immunoglobulin
`molecule that comprises an antigen recognition site. An antibody
`includes an antibody of any class, such as IgG, IgA, or IgM (or
`sub-class thereof), and the antibody need not be of any particular
`class.
`
`Ex. 1001, 12:24–34; see also id. at 26:16–36. We agree with Petitioner that
`
`this constitutes an express definition of the term “antibody” and we so
`
`construe the term. We agree with Petitioner that “antibody” includes
`
`antibody fragments.
`
`Petitioner argues that the ’649 patent expressly defines “humanized”
`
`antibodies in the same manner, i.e., encompassing “forms of non-human
`
`(e.g., murine) antibodies that are specific chimeric immunoglobulins,
`
`immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab')2
`
`or other antigen-binding subsequences of antibodies) . . . .” Pet. 25 (citing
`
`9
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`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`Ex. 1001, 13:4–9; Ex. 1002 ¶ 103; Ex. 1003 ¶ 81). The Specification of the
`
`’649 patent states:
`
`As used herein, “humanized” antibodies refer to forms of non-
`human (e.g. murine) antibodies that are specific chimeric
`immunoglobulins, immunoglobulin chains, or fragments thereof
`(such as Fv, Fab, Fab', F(ab')2 or other antigen-binding
`subsequences of antibodies) that contain minimal sequence
`derived from non-human immunoglobulin.
`
`Ex. 1001, 13:4–9; see also id. at 26:16–36. We agree with Petitioner that
`
`this constitutes an express definition of the term “humanized antibody” and
`
`we so construe the term. We agree with Petitioner that “humanized
`
`antibody” includes antibody fragments.
`
`We determine that no other term requires express construction at this
`
`time. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`
`(Fed. Cir. 1999) (only those terms need be construed that are in controversy,
`
`and only to the extent necessary to resolve the controversy).
`
`C. Obviousness of Claims 1–9 over Tan 1995 (Ex. 1022),
`Wimalawansa (Ex. 1096), and Queen (Ex. 1023)
`
`Petitioner contends that claims 1–9 are unpatentable as obvious over
`
`Tan 1995, Wimalawansa, and Queen. Pet. 26–60. Petitioner relies on the
`
`declarations of Andrew C. Charles, M.D. (Ex. 1002, “Charles Decl.”) and
`
`Alain P. Vasserot, Ph.D. (Ex. 1003, “Vasserot Decl.”) in support. Patent
`
`Owner opposes. Prelim. Resp. 27–63.
`
`1.
`
`Tan (Ex. 1022)
`
`Tan states that “[i]mmunoblockade may be described as the blockade
`
`of the effects of a biological mediator by inhibition of its binding to specific
`
`receptors with antibodies directed against the mediator.” Ex. 1022, 566.
`
`Tan describes a comparative study, wherein the results of using an anti-
`
`10
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`

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`CGRP monoclonal antibody (MAb) IgG and its Fab' fragment for
`
`immunoblockade in vivo were compared to those obtained by receptor
`
`blockade with hαCGRP8–37 . Id.
`
`Tan also reports on an in vivo study with intravenous administration
`
`of rat CGRP and various anti-CGRP antibody preparations in male Sprague-
`
`Dawley rats. See Ex. 1022, 565–566. The effects of an anti-CGRP
`
`monoclonal antibody (MAb C4.19) and its Fab' fragment on CGRP changes
`
`in blood pressure were studied in anaesthetized rats. Id. at 565. Tan reports
`
`that MAb C4.19 IgG increased MAP [mean arterial pressure] slightly, but
`
`MAP was decreased by rαCGRP in a dose-dependent manner. Id. at 568. In
`
`experiments involving MAb C4.19 Fab' fragment, a control dose of 0.1
`
`nmol/kg rαCGRP decreased MAP by 29.5 mm Hg. Id. at 569. The
`
`hypotensive response to rαCGRP was accompanied by a dose-dependent
`
`tachycardia in some experiments. Id. at 568. Tan states that “[t]his study
`
`has clearly demonstrated the ability of MAb C4.19 IgG and its Fab' fragment
`
`to block the hypotensive effects of exogenous rαCGRP.” Id. at 570.
`
`Tan reports that the skin blood flow response to antidromic
`
`stimulation of the saphenous nerve was effectively blocked 30 min after
`
`administration of MAb C4.19 Fab' fragment (2 mg/rat) but not 60 minutes
`
`after administration of MAb C4.19IgG (1 mg/rat). See id. at 565, 569–570.
`
`Nerve stimulation performed at 2 hours after 3 mg/rat MAb C4.19 IgG
`
`produced an AUC (area under the flux-time curve attributable to nerve
`
`stimulation) that was slightly smaller compared with baseline stimulation.
`
`Id. at 569. Tan states that the slow distribution of IgG to the site of
`
`immunoblockade could be overcome by chronic or repeated administration
`
`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.
`
`2. Wimalawansa (Ex. 1096)
`
`Wimalawansa is a review article that describes the molecular biology,
`
`distribution, activity, and “therapeutic potentials” of CGRP. See Ex. 1096,
`
`533–570. According to Wimalawansa, CGRP is a 37-amino acid
`
`neuropeptide resulting from alternative splicing of the primary RNA
`
`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.
`
`Wimalawansa teaches that CGRP and CGRP receptors are widely
`
`distributed in the mammalian nervous system (e.g., discrete brain areas and
`
`the peripheral nervous system), in the cardiovascular system (e.g., arteries,
`
`veins, and the heart), the gastrointestinal tract, and several endocrine organs
`
`(e.g., the thyroid gland and pancreatic islet cells), often co-located with other
`
`neurotransmitters and neuropeptides. See id. at 539–540. Wimalawansa
`
`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
`
`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).
`
`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
`
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`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.
`
`In a section titled “Therapeutic potentials of CGRP antagonists,”
`
`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,
`
`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
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`inflammation, type II diabetes, and in conditions with intractable
`hypotension, such as septic shock syndrome.
`
`Id. at 569–570.
`
`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], 1:19–24.
`
`
`
`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.
`
`14
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`
`
`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
`
`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 1–9 are disclosed in, or obvious over, the combination
`
`of Tan, Wimalawansa, and Queen. Pet. 26–60. Patent Owner opposes.
`
`Prelim. Resp. 27–63. 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.
`
`15
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`
`a. Claim 1
`
`i. “An isolated human or humanized anti-CGRP antagonist antibody”
`
`Petitioner asserts, inter alia, that Tan describes murine anti-CGRP
`
`antagonist antibodies, including a full-length antibody, that blocked the
`
`effects of CGRP both in vitro and in vivo and that that an anti-CGRP
`
`antagonist antibody with the claimed properties could be readily prepared by
`
`known, established, and conventional techniques. Pet. 26 (citing Ex. 1022;
`
`Ex. 1002 ¶¶ 69–70). Petitioner asserts that Wimalawansa proposes using
`
`humanized anti-CGRP monoclonal antagonistic antibodies as therapeutic
`
`agents for several diseases, e.g., migraine, inflammation, and cardiogenic
`
`shock. Id. (citing Ex. 1002 ¶ 73); see also id. 29 (citing Ex. 1096, 567, 570;
`
`Ex. 1002 ¶¶ 73, 111). Petitioner asserts that Queen describes routine and
`
`conventional humanization technologies, using human IgG scaffolds. Id.
`
`(citing Ex. 1023; Ex. 1003 ¶ 48). Petitioner argues that Wimalawansa “and
`
`others” taught a myriad of reasons to make humanized anti-CGRP
`
`antagonist antibody and that the prior art provided a reasonable expectation
`
`of success in so doing. Pet. 27 (citing, e.g., Ex. 1002 ¶¶ 104–149; Ex. 1003
`
`¶¶ 82–117; Ex. 1001, 28:61–29:3); see also id. at 27–51.
`
`Patent Owner argues (1) that a person of ordinary skill would not have
`
`selected Tan’s full-length C4.19 antibody in the first instance based on Tan’s
`
`results, and (2) that Wimalawansa and Queen provide insufficient reason to
`
`humanize Tan’s full-length C4.19 antibody. Prelim. Resp. 38; see also id. at
`
`37–54. We explore these arguments as follows.
`
`Patent Owner argues that Petitioner does not demonstrate why a
`
`person of ordinary skill would have had a reason to select and humanize
`
`Tan’s full-length antibody. Prelim. Resp. 28, 37–47. Patent Owner asserts
`
`16
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`that Petitioner has not shown that the data in Tan demonstrates that C4.19
`
`would be useful in vivo as a therapeutic antibody. Id. at 38–39. Patent
`
`Owner also argues that Tan did not establish that C4.19 antagonized
`
`endogenous CGRP at its site of action and that a person of ordinary skill
`
`would have expected this “negative result” to other full-length anti-CGRP
`
`antibodies. Id. at 40–48.
`
`With respect to Tan’s saphenous nerve assay, Tan reports “that
`
`effective immunoblockade was achieved with MAb C4.19 Fab' fragment 30
`
`min after administration, while the IgG was ineffective up to 2h after the
`
`dose.” Ex. 1022, 571. Nevertheless, based on Tan’s own studies and the
`
`studies of others, Tan also concluded that “[g]iven an adequate incubation
`
`period in a tissue bath, Mab C4.19 IgG clearly diffuses into the synaptic cleft
`
`since it was effective at blocking CGRP released from primary afferent
`
`nerves by capsaicin in vitro,” “[t]he slow distribution of whole IgG to the
`
`site of immunoblockade could be overcome by . . . chronic administration of
`
`IgG,” and “[w]ith repeated administration, IgG should eventually distribute
`
`into interstitial space and achieve the sufficiently high concentrations
`
`required for immunoblockade.” Id. at 571; see Pet. 20–21.
`
`We understand Patent Owner to essentially argue that the particular
`
`experimental results reported by Tan would have discouraged or taught
`
`away from the use of a full length antibody generally, and specifically the
`
`C4.19 antibody. Prelim. Resp. 40–48. But a reference “does not teach away
`
`. . . if it merely expresses a general preference for an alternative invention
`
`but does not ‘criticize, discredit, or otherwise discourage’ investigation into
`
`the invention claimed.” See DePuy Spine, Inc. v. Medtronic Sofamor Danek,
`
`Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009) (citation omitted)); see also
`
`17
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`Bayer Pharma AG v. Watson Labs., Inc., 874 F.3d 1316, 1327 (Fed. Cir.
`
`2017). Rather than discouraging further investigation into the use of a full-
`
`length antibody such as C4.19, Tan actually encourages such investigation
`
`and use by explaining the protocols that would lead to successful results.
`
`Ex. 1022, 570–72. To the extent that Tan may suggest that use of a Fab'
`
`fragment may generally be preferred over a full length antibody, that does
`
`not constitute a teaching away on the record at this stage of the proceeding.
`
`See Bayer, 874 F.3d 1327. Indeed, Tan’s teachings must be considered
`
`together with other evidence of record, such as Wimalawansa, which
`
`suggests therapeutic uses for anti-CGRP antibodies. See Ex. 1096, 567–
`
`570.4
`
`Patent Owner argues that Wimalawansa provides no reason to
`
`humanize Tan’s “failed” full-length C4.19 antibody because Wimalawansa
`
`focuses on antagonizing CGRP’s receptors instead of antagonizing CGRP
`
`itself. Prelim. Resp. 48 (citing Ex. 1096, 568).
`
`Even if we accept Patent Owner’s premise that the focus of
`
`Wimalawansa is on CGRP receptor antagonists, that does not diminish
`
`
`4 We further note that the claim 1 may very well encompass both full-length
`antibodies and antibody fragments. In other words, at least as a matter of
`claim construction, we determine that the term “antibody” encompasses both
`full-length antibodies and antibody fragments, based on a definition in the
`’649 patent. See § II.B., supra. Therefore, assuming (as Patent Owner
`argues) that Tan indicates a preference for the use of antibody fragments, it
`is not clear why such a preference would defeat a ground of obviousness
`based on Tan. Patent Owner includes a section near the end of its
`Preliminary Response that contends that the Petition fails to address
`antibody fragments or a motivation to humanize them. See Prelim. Resp.
`50–52. However, the Petition also addresses antibody fragments as part of
`its discussion of obviousness. See, e.g., Pet. 31, 44.
`
`18
`
`

`

`IPR2018-01427
`Patent 8,597,649 B2
`
`Wimalawansa’s teachings regarding antagonists to CGRP itself. The fact
`
`that Wimalawansa actually encourages further studies of CGRP antagonist,
`
`humanized anti-CGRP monoclonal antibodies thus provides a reason to
`
`make and test such antibodies. See Ex. 1096, 567, 570.
`
`Patent Owner also argues that Wimalawansa states that “[c]learly,
`
`more data from carefully designed studies are necessary before any
`
`definitive conclusions can be reached and before CGRP antagonist,
`
`humanized anti-CGRP monoclonal antibodies, or both, can be evaluated as
`
`therapeutic agents in humans.”

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