Trials@uspto.gov
`571.272.7822
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` Paper: 14
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` Entered: February 19, 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 IPR2018-01423
`Patent 9,266,951 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)
`
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
` Paper: 14
`
` Entered: February 19, 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 IPR2018-01423
`Patent 9,266,951 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)
`
`
`
`
`
`
`
`
`
`
`IPR2018-01423
`Patent 9,266,951 B2
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`
`
` INTRODUCTION
`Eli Lilly and Company (“Petitioner”) filed a Petition to institute an
`inter partes review of claims 1–6 and 14–19 of U.S. Patent 9,266,951 B2
`(the “’951 patent”). Paper 1 (“Pet.”). Teva Pharmaceuticals International
`GmbH (“Patent Owner”) filed a Preliminary Response to the Petition.
`Paper 8 (“Prelim. Resp.”).
`In its Preliminary Response, Patent Owner argued that we should
`exercise our authority to deny the Petition based on 35 U.S.C. § 325(d)
`because the same or substantially the same prior art or arguments previously
`were presented to the Patent and Trademark Office. Prelim. Resp. 10–29.
`Petitioner thereafter requested permission to file a reply to the Preliminary
`Response to address that issue. We granted Petitioner’s request, allowing
`Petitioner to file a reply and Patent Owner to file a sur-reply. Paper 10.
`Petitioner thereafter filed its reply (Paper 11, “Pet. Reply”) and Patent
`Owner filed its sur-reply (Paper 12, “PO Surreply”).
`We have authority under 35 U.S.C. § 314 to determine whether to
`institute an inter partes review. To institute an inter partes review, we must
`determine that the information presented in the Petition shows “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 conclude that Petitioner has established a reasonable
`likelihood that it would prevail in showing the unpatentability of at least one
`challenged claim of the ’951 patent. Therefore, we institute an inter partes
`review for claims 1–6 and 14–19 of the ’951 patent.
`A.
`Related Proceedings
`Petitioner identifies a declaratory judgment action filed by Patent
`Owner on October 24, 2017, in the District Court for the District of
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`Patent 9,266,951 B2
`Massachusetts (“the first DJ action”). Pet. 64. According to Petitioner, the
`first DJ action seeks a declaration that Petitioner’s investigational drug
`galcanezumab will infringe U.S. Patent Nos. 8,586,045; 8,597,649;
`9,340,614; 9,346,881; and the ’951 patent, and Patent Owner filed an
`amended complaint in the first DJ action on January 16, 2018. Id. Petitioner
`also identifies a declaratory judgment action filed by Patent Owner on
`February 6, 2018, seeking a declaration that Petitioner’s product will
`infringe U.S. Patent Nos. 9,884,907 and 9,884,908 (“the second DJ action”).
`Id. Petitioner states that Patent Owner thereafter filed an amended
`complaint in the second DJ action to incorporate U.S. Patent Nos. 9,890,210
`and 9,890,211. Id.
`According to Petitioner, all of the patents in the first DJ action and the
`second DJ action purport to claim priority to the same U.S. provisional
`application as the ’951 patent, and that two applications (15/883,218 and
`15/956,580) based on the same provisional application are pending before
`the United States Patent and Trademark Office. Id.
`Patent Owner identifies the first DJ action and the second DJ action,
`as well as eight inter partes reviews styled Eli Lilly and Co. v. Teva
`Pharmaceuticals International GmbH, IPR2018-01422, IPR2018-01424,
`IPR2018-01425, IPR2018-01426, IPR2018-01427, IPR2018-01710,
`IPR2018-01711, and IPR2018-01712. Papers 5, 7. Patent Owner also
`identifies U.S. Patent Nos. 9,365,648; 9,328,168; 9,115,194; 8,734,802;
`8,007,794, in addition to the patents and patent applications identified by
`Petitioner. Paper 5. Patent Owner also identifies a litigation styled Teva
`Pharmaceuticals International GmbH v. Eli Lilly and Co., Civ. No. 1-18-cv-
`12029 (D. Mass.). Paper 7.
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`Patent 9,266,951 B2
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`The ’951 Patent (Ex. 1001)
`B.
`The ’951 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], 1:36–39.
`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 1:43–45. In humans, two forms of CGRP
`with similar activities (α-CGRP and β-CGRP) exist and exhibit differential
`distribution. Id. at 1:45–48. At least two CGRP receptor subtypes may also
`account for differential activities. Id. at 1:48–49. 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 1:49–53.
`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 1:53–56. CGRP has been noted for its possible connection to
`vasomotor symptoms. Id. at 1:57–58. Vasomotor symptoms include hot
`flushes and night sweats. Id. at 1:60–61. 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 2:21–24.
`
`
`1 Calcitonin Gene-Related Peptide is abbreviated throughout as CGRP. See
`Ex. 1001, 1:43.
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`Patent 9,266,951 B2
`According to the Specification, the precise pathophysiology of
`migraine is not yet well understood. Id. at 3:31–34. Dilation of blood
`vessels is associated with and exacerbates the pain symptoms of migraine.
`Id. at 3:39–40. 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 3:7–9. Different classes of
`drugs have been used in treatment (and some patients, usually those with
`milder symptoms, are able to control their symptoms with non-prescription
`remedies). See id. at 3:10–25. 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 2:32–34, 3:25–30,
`4:19–21.
`The ’951 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 3:53–4:3. The ’951 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 4:4–4:54. 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 4:55–5:49, 8:24–25. Other embodiments are directed to a polypeptide
`which may or may not be an antibody. See id. at 7:10–8:19. Other
`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 8:26–55.
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`Patent 9,266,951 B2
`Other embodiments are directed to methods of making the same. See id. at
`8:66–9:14.
`The Specification states that CGRP promotes a number of measurable
`changes in responsive cells, including stimulation of cAMP in the cell. Id. at
`32:9–12. An Example 2 is described wherein antagonist activity is
`measured by cAMP assay and antibodies that inhibit activation of cAMP by
`α-CGRP were identified. Id. at 53:16–54:8.
`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 10:19–21. Table 6 provides data on
`binding affinity for G1 variants. See id. at cols. 60–65. Another table (cols.
`71–99) lists additional antibody sequences.
`C.
`Illustrative Claim
`Claim 1, the only independent claim challenged, is illustrative and
`reproduced below:
`1. A human or humanized monoclonal anti-CGRP antagonist antibody that
`(1) binds human α-CGRP and (2) inhibits cyclic adenosine monophosphate
`(cAMP) activation in cells.
`Ex. 1001, 99:21–23.
`
`Claims 2–6 and 14–19 depend, directly or indirectly, on claim 1. Id.
`at 99:24–41, 100:38–55.
`The Asserted Ground of Unpatentability
`D.
`Petitioner contends that the challenged claims are unpatentable on the
`sole ground of obviousness under 35 U.S.C. § 103(a) based on the following
`combination of references:
`K.K.C. Tan et al., Calcitonin gene-related peptide as an endogenous
`vasodilator: immunoblockade studies in vivo with an anti-calcitonin gene-
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`related peptide monoclonal antibody and its Fab' fragment, 89 CLINICAL
`SCI. 6, 565–73 (1995) (“Tan”). Ex. 1022.
`S.J. Wimalawansa, Calcitonin Gene-Related Peptide and its
`Receptors: Molecular Genetics, Physiology, Pathophysiology, and
`Therapeutic Potentials, 17 ENDOCRINE REVIEWS 5, 533–85 (1996)
`(“Wimalawansa”). Ex. 1096.
`Queen et al., US 6,180,370 B1, issued Jan. 30, 2001 (“Queen”).
`Ex. 1023.
`Doods et al., Pharmacological Profile of BIBN4096BS, the first
`selective small molecule CGRP antagonist, 129 BR. J. PHARMACOL. 420–23
`(2000) (“Doods”). Ex. 1024.
`Petitioner also relies on the Declaration of Dr. Andrew C. Charles,
`M.D. (Ex. 1004, “Charles Declaration”) and the Declaration of Dr. Alain P.
`Vasserot, Ph.D. (Ex. 1005, “Vasserot Declaration”).
` ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`Petitioner asserts that “a POSA [person of ordinary skill in the art]
`with respect to the aspects of the ’951 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. 1005 ¶¶ 65–67). Petitioner
`further asserts that “[a] POSA with respect to the aspects of the ’951 patent
`pertaining to using anti-CGRP antibodies would have generally possessed a
`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
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`Patent 9,266,951 B2
`of experience studying CGRP or treating patients with a CGRP-related
`disease.” Id. (citing Ex. 1004 ¶¶ 89–91).
`Patent Owner contends that “[b]ecause the '951 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. 30.
`Thus, according to Patent Owner, a POSA relevant to the ’951 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 30–31.
`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
`or specialty in neurology, and several years of experience studying CGRP or
`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
`in the art at the time of the invention. See Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001) (explaining that specific findings regarding
`ordinary skill level are not required “where the prior art itself reflects an
`appropriate level and a need for testimony is not shown”) (quoting Litton
`Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir.
`1985)).
`
`Claim Construction
`B.
`In this inter partes review, filed August 8, 2018,2 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).
`
`
`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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`Patent 9,266,951 B2
`Petitioner requests construction of the following terms: “anti-CGRP
`antagonist antibody” and “humanized antibody,” citing to the Specification
`of the ’951 patent. Pet. 24–25. Patent Owner does not request special
`construction of any terms, stating that “for purposes of this proceeding, the
`Board should construe the '951 patent claims according to their plain and
`customary meaning.” Prelim. Resp. 30.
`Petitioner argues that the ’951 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,
`12:29–39, 26:24–34; Ex. 1004 ¶ 114; Ex. 1005 ¶ 68). The Specification of
`the ’951 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, 12:29–42; see also id. at 26:24–45. 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 ’951 patent expressly defines “humanized”
`antibodies in the same manner, i.e., encompassing “forms of non-human
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`(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
`Ex. 1001, 13:9–14; Ex. 1004 ¶ 114; Ex. 1005 ¶ 69). The Specification of the
`’951 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, 13:9–14; see also id. at 26:24–45. 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.
`Principles of Law
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations, including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
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`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966).
`An obviousness analysis “need not seek out precise teachings directed
`to the specific subject matter of the challenged claim, for a court can take
`account of the inferences and creative steps that a person of ordinary skill in
`the art would employ.” KSR, 550 U.S. at 418; see Translogic, 504 F.3d at
`1262. “Often, it will be necessary for a court to look to interrelated
`teachings of multiple patents; the effects of demands known to the design
`community or present in the marketplace; and the background knowledge
`possessed by a person having ordinary skill in the art, all in order to
`determine whether there was an apparent reason to combine the known
`elements in the fashion claimed by the patent at issue.” KSR, 550 U.S. at
`418.
`
`We analyze the asserted ground of unpatentability in accordance with
`the above-stated principles.
`D. Obviousness over Tan, Wimalawansa, Queen, and Doods
`Petitioner asserts that claims 1–6 and 14–19 of the ’951 patent are
`unpatentable as obvious over Tan, Wimalawansa, Queen, and Doods.
`Pet. 26–60. Patent Owner opposes. Prelim. Resp. 29–62.
`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-
`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.
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`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 C4.19 IgG (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 561. Tan further states that “MAb C4.19 does not cross-react
`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)
`Wimalawansa is a review article that describes the molecular biology,
`distribution, activity, and “therapeutic potentials” of CGRP. See Ex. 1096,
`533–70. 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
`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.
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`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
`inflammation, type II diabetes, and in conditions with intractable
`hypotension, such as septic shock syndrome.
`Id. at 569–570.
`
`15
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`IPR2018-01423
`Patent 9,266,951 B2
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`Queen (Ex. 1023)
`3.
`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.
`
`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
`
`16
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`IPR2018-01423
`Patent 9,266,951 B2
`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.
`
`Doods (Ex. 1024)
`4.
`Doods states that CGRP is one of the most potent endogenous
`vasodialators known, and “is increased during migraine attacks and has been
`implicated in the pathogenesis of migraine headache.” Ex. 1024, Abstract.
`Doods describes in vitro and in vivo testing of BIBN4096BS, a small-
`molecule CGRP receptor antagonist. Id.
`The in vitro testing involved a radioligand binding assay using two
`different cell types. In the first assay, rat spleen homogenates were prepared
`and incubated with 125I-hCGRP (the radioligand) and BIBN4096BS, and a
`gamma counter was used to measure the inhibition of 125I-hCGRP to CGRP
`receptors. Id. at 420. Doods reports that in this assay BIBN4096BS
`inhibited the binding of 125I-hCGRP to rat CGRP receptors. Id. at 422;
`Ex. 1004 ¶ 84.
`
`17
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`IPR2018-01423
`Patent 9,266,951 B2
`SK-N-MC3 cells were used in the second assay, and the results
`showed that BIBN4096BS inhibited the binding of 125I-hCGRP to human
`CGRP receptors in SK-N-MC cells. Ex. 1024, 420–22; Ex. 1004 ¶ 85.
`Doods also used SK-N-MC cells to measure BIBN4096BS’s antagonistic
`effects on inhibiting cAMP activation. Ex. 1024, 420–21. Doods confirmed
`that BIBN4096BS antagonizes CGRP because it inhibited CGRP-induced
`cAMP activation. Ex. 1024, 422; Ex. 1004 ¶¶ 85–86.
`The in vivo testing reported by Doods measured the inhibition of
`CGRP’s effects on facial blood flow in marmosets, and Doods reports that
`BIBN4096BS inhibits blood flow. Ex. 1024, 421–22; Ex. 1004 ¶ 87. Doods
`concludes by stating that “[s]ince several lines of evidence indicate that
`CGRP might be a key factor in the initiation of migraine headache, we
`expect that CGRP antagonists will be effective anti-migraine drugs.”
`Ex. 1024, 422.
`
`Analysis
`5.
`In its Petition, Petitioner sets forth its contentions as to how the
`limitations of claims 1–6 and 14–19 are obvious over the combination of
`Tan, Wimalawansa, Queen, and Doods. Pet. 26–60. Patent Owner opposes.
`Prelim. Resp. 29–62. 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. 26. Petitioner points
`
`
`3 SK-N-MC, as used by Doods, stands for “neuroblastoma cell line of human
`origin.” Ex. 1024, Abstract (Abbreviations).
`18
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`IPR2018-01423
`Patent 9,266,951 B2
`to Tan’s description of murine monoclonal anti-CGRP antagonist antibodies,
`and contends that one of those antibodies (MAb C4.19) was a full-length
`antibody that blocked the effects of CGRP both in vitro and in vivo. Id.
`(citing Ex. 1004 ¶ 74; Ex. 1022). 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
`Ex. 1096, 567, 570; Ex. 1004 ¶ 78)), and Queen’s description of routine and
`conventional humanization technologies (id. (citing Ex. 1005 ¶ 48; see
`generally Ex. 1023)). Petitioner also refers to Doods as confirming “that
`inhibiting cAMP activation was merely a known and expected property of
`anti-CGRP antagonists that block the CGRP pathway.” Id. (citing Ex. 1024,
`420–422).
`Petitioner also argues that a person of ordinary skill in the art would
`have been motivated to generate the humanized anti-CGRP antagonist
`antibody of claim 1. Pet
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