`571.272.7822
`
`
`
`
`
` Paper: 12
`
` Entered: April 3, 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 IPR2018-01711
`Patent 9,884,907 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
`
`
`
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`
`
`
`
`
` INTRODUCTION
`Eli Lilly and Company (“Petitioner”) filed a Petition to institute an
`inter partes review of claims 1–18 of U.S. Patent 9,884,907 B2 (the “’907
`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. 11–27.
`Petitioner thereafter requested permission to file a reply to the Preliminary
`Response to address that issue, which we granted, allowing Petitioner to file
`a reply and Patent Owner to file a sur-reply. Petitioner thereafter filed its
`reply (Paper 10, “Pet. Reply”) and Patent Owner filed its sur-reply
`(Paper 11, “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 ’907 patent. Therefore, we institute an inter partes
`review for claims 1–18 of the ’907 patent.
`Related Proceedings
`A.
`Petitioner identifies a declaratory judgment action filed by Patent
`Owner on October 24, 2017, in the District Court for the District of
`
`2
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`Massachusetts (“the first DJ action”). Pet. 61–62. 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;
`9,266,951; 9,340,614; and 9,346,881. 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 No.
`9,884,908 and the ’907 patent (“the second DJ action”). Id. at 62. 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, the court dismissed Patent Owner’s amended
`complaints in the first DJ action and the second DJ action, and Patent Owner
`filed a third action for infringement of the same patents on September 27,
`2018. Id. Those patents purport to claim priority to the same provisional
`application as the ’907 patent, and 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. Petitioner also identifies
`six inter partes review proceedings that it filed naming Patent Owner, and
`that have been now been instituted. Id.; see IPR2018-01422, IPR2018-
`01423, IPR2018-01424, IPR2018-01425, IPR2018-01426, and IPR2018-
`01427. Petitioner further identifies petitions for inter partes review against
`U.S. Patent No. 8,586,045 (IPR2018-01710) and U.S. Patent No. 9,884,908
`(IPR2018-01712). Id.
`Patent Owner identifies the first DJ action and the second DJ action,
`as well as a litigation styled Teva Pharmaceuticals International GmbH v.
`Eli Lilly & Co., Civ. No. 1-18-cv-12029 (D. Mass.). Paper 6. Patent Owner
`also identifies the above-referenced inter partes reviews identified by
`Petitioner, styled Eli Lilly & Co. v. Teva Pharmaceuticals International
`
`3
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`GmbH. Id. Patent Owner also identifies U.S. Patent Nos. 9,365,648;
`9,328,168; 9,115,194; 8,734,802; and 8,007,794, in addition to the patents
`and patent applications identified by Petitioner. Id.
`The ’907 Patent (Ex. 1001)
`B.
`The ’907 patent is titled “Methods for Treating Headache Using
`Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide[1]”
`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],
`1:34–37.
`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 1:41–43. In humans, two forms of CGRP
`with similar activities (α-CGRP and β-CGRP) exist and exhibit differential
`distribution. Id. at 1:43–46. At least two CGRP receptor subtypes may also
`account for differential activities. Id. at 1:46–47. 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 1:47–51.
`CGRP-mediated vasodilatation is also 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 1:51–54. CGRP has been noted for its possible connection to
`vasomotor symptoms. Id. at 1:55–56. Vasomotor symptoms include hot
`
`
`1 Calcitonin Gene-Related Peptide is abbreviated throughout as CGRP. See
`Ex. 1001, 1:41.
`
`4
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`flushes and night sweats. Id. at 1:58–59. 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 2:20–23.
`According to the Specification, the precise pathophysiology of
`migraine is not yet well understood. Id. at 3:35–36. Dilation of blood
`vessels is associated with and exacerbates the pain symptoms of migraine.
`Id. at 3:41–42. 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 3:8–10. 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 3:11–27. 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 2:32–35, 3:27–32,
`4:22–24.
`The ’907 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 3:55–4:5. The ’907 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 4:6–54. 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 4:58–5:55, 8:20–22. Other embodiments are directed to a polypeptide,
`
`5
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`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 8:32–61.
`Other embodiments are directed to methods of making the same. See id. at
`9:5–21.
`The ’907 patent includes a Table 4 showing amino acid sequences of
`different variants of human α-CGRP and related peptides. Id. at 51:58–62;
`col. 53 (Table 4). Table 4 identifies CGRP 1–37 (WT) as SEQ ID NO:15
`and CGRP human β (1–37) as SEQ ID NO:43. See id.
`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 10:26–28. Table 6 provides data on
`binding affinity for G1 variants. See id. at cols. 62–67. Another table (cols.
`72–103) lists additional antibody sequences.
`Illustrative Claim
`C.
`Claim 1, the only independent claim, is illustrative:
`1. A method for treating headache in an individual, comprising:
`administering to the individual an effective amount of 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.
`Id. at 103:21–35.
`
`
`
`6
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`Claims 2–18 depend directly or indirectly on claim 1. Id. at 103:36–
`104:49.
`
`
`
`
`
`The Asserted Ground of Unpatentability
`D.
`Petitioner contends that the challenged claims are unpatentable on the
`sole ground of obviousness under (pre-AIA) 35 U.S.C. § 103(a) based on the
`following combination of references:
`J. Olesen et al., Calcitonin Gene-Related Peptide Receptor Antagonist
`BIBN 4096 BS for the Acute Treatment of Migraine, N. ENG. J. MED. 350,
`1104–10 (2004) (“Olesen”). Ex. 1025.
`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
`CLINICAL SCI. 6, 565–73 (1995) (“Tan”). Ex. 1022.
`Queen et al., US 6,180,370 B1, issued Jan. 30, 2001 (“Queen”).
`Ex. 1023.
`Petitioner also relies on the Declaration of Dr. Andrew C. Charles,
`M.D. (Ex. 1016, “Charles Declaration”) and the Declaration of Dr. Alain P.
`Vasserot, Ph.D. (Ex. 1017, “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 ’907 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 of experience studying
`CGRP or treating patients with migraine.” Pet. 19 (citing Ex. 1016 ¶¶ 84–
`86). Petitioner further asserts that “a POSA with respect to the aspects of the
`
`7
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`’907 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.” Id. (citing
`Ex. 1017 ¶¶ 71–73).
`Patent Owner contends that “[b]ecause the '907 patent relates to
`methods of treatment using 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. 31. Thus, according to Patent Owner, a POSA
`relevant to the ’907 patent would have the knowledge of, or be able to draw
`upon the knowledge of, (for example): “(1) a medical doctor with a
`specialty in neurology, specifically in treating headache and migraine,
`including approximately 5 years of experience in its research, diagnosis,
`and/or treatment,” “(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 scientist having a Ph.D. in immunology,
`biochemistry, or an equivalent discipline, with approximately 3-5 years in
`antibody design and engineering.” Id. at 31–32.
`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
`
`8
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`or specialty in neurology, and several years of experience studying CGRP or
`treating patients with 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)).
`
`Claim Construction
`B.
`In this inter partes review, filed October 1, 2018,2 the claims of the
`’907 patent, which has not expired, shall be given their broadest reasonable
`construction in light of the specification. 37 C.F.R. § 42.100(b) (2018);
`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
`
`
`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 (Oct. 11, 2018) (to be codified at 37 C.F.R.
`pt. 42).
`
`9
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
`30 F.3d 1475, 1480 (Fed. Cir. 1994).
`Petitioner requests construction of the terms “treating,” “effective
`amount,” and “specific binding.” Pet. 19–23. Patent Owner argues that
`Petitioner’s proposed constructions of these terms are incorrect or
`incomplete. Prelim. Resp. 28–31. We construe those terms as follows. We
`emphasize that the foregoing constructions are preliminary at this stage of
`the proceeding.
`
`1. “treating”
`According to Petitioner, the ’907 patent “expressly defines ‘treatment’
`as ‘an approach for obtaining a beneficial or desired clinical result’—it does
`not require achieving any particular result.” Pet. 20 (citing, e.g., Ex. 1001,
`18:4–5 (emphasis by Petitioner)). Petitioner thus asserts that “‘treating’
`merely refers to an approach for a particular outcome without requiring a
`clinical response.” Id. (citing Ex. 1016 ¶ 110).
`Patent Owner argues that Petitioner’s construction of “treating” is
`incomplete, and that the ’907 patent “clearly ties ‘treating’ to achieving an
`intended clinical effect.” Prelim. Resp. 28. According to Patent Owner, the
`’907 patent “expressly defines ‘treatment’ as ‘an approach for obtaining
`beneficial or desired clinical results,’ and lists the beneficial or desired
`clinical results, e.g., ‘lessening severity, alleviation of pain intensity . . .
`reducing frequency of recurrence . . . decreasing dose of other medications
`required to treat the headache . . . .’” Id. at 28–29 (citing Ex. 1001, 18:4–
`13). Patent Owner thus asserts that “[t]hat definition is controlling . . . and
`requires administering the anti-CGRP antagonist antibody to achieve a
`clinical result.” Id. at 29.
`
`10
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`The parties appear to be in agreement, and we agree, that there is a
`definition of “treatment” in the Specification marked by the word “is,” i.e.,
`“an approach for obtaining beneficial or desired clinical results.” See
`Ex. 1001, 18:4–5. Treatment is thus defined as “an approach” and the only
`disagreement is whether there must be “beneficial or desired clinical results”
`obtained.
`We determine, on this record and at this stage of the proceeding, that
`the term “treating” refers to a statement of intended purpose, i.e. to achieve a
`clinical result, without requiring achievement of any clinical result. In our
`view, the definition uses the term “approach” to reflect an intent to benefit
`without guaranteeing a benefit. Indeed, even if the language “for obtaining
`beneficial or desired clinical results” were limiting, such results could be
`either beneficial or desired. In other words, the term “desired” reflects a
`statement of intent. Further, although Patent Owner argues that the
`Specification immediately thereafter lists beneficial or desired results, the
`list is preceded by the terms “include” and “are not limited to,” which
`indicates that what follows is exemplary and not limiting. See id. at 18:5–7.
`2. “effective amount”
`Petitioner argues that “effective amount” should be construed as
`“(1) including, at least via the doctrine of claim differentiation, doses of an
`anti-CGRP antagonist antibody that are less than 3 µg/kg, and (2) not
`requiring a clinical response.” Pet. 21–22 (citing Ex. 1016 ¶ 111–112).
`According to Petitioner, the ’907 patent states that “the term ‘effective
`amount’ encompasses amounts that produce merely biochemical or
`histochemical effects, such as stimulation of cAMP,” but should not be
`construed to require a clinical response. Id. at 22 (citing Ex. 1001, 19:3–35,
`32:34–41; Ex. 1016 ¶ 112).
`
`11
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`Patent Owner argues that Petitioner’s proposed construction of
`“effective amount” is incorrect, and refers to the Specification of the ’907
`patent. Prelim. Resp. 29–30. According to Patent Owner, the term
`“effective amount” should be tied to a clinical result and “construed as ‘an
`amount sufficient to effect beneficial or desired results.’” Id. at 30 (citing
`Ex. 1001, 19:3–5).
`An “effective amount” is defined in the ’907 patent as “an amount
`sufficient to effect beneficial or desired results.” Ex. 1001, 19:3–5.
`Therefore, although “treatment” does not necessarily involve achieving
`beneficial or desired results, an “effective amount” of a humanized
`monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist
`antibody does require achievement of beneficial or desired results.
`Nevertheless, the Specification proceeds to define what the achieved
`“beneficial or desired results” are:
`For prophylactic use, beneficial or desired results include results
`such as eliminating or reducing the risk, lessening the severity,
`or delaying the outset of the disease, including biochemical,
`histological and/or behavioral symptoms of the disease, its
`complications and
`intermediate pathological phenotypes
`presenting during development of the disease. For therapeutic
`use, beneficial or desired results include clinical results such as
`reducing pain intensity, duration, or frequency of headache
`attack, and decreasing one or more symptoms resulting from
`headache
`(biochemical, histological and/or behavioral),
`including its complications and intermediate pathological
`phenotypes presenting during development of the disease,
`increasing the quality of life of those suffering from the disease,
`decreasing the dose of other medications required to treat the
`disease, enhancing effect of another medication, and/or delaying
`the progression of the disease of patients.
`Id. at 19:6–22.
`
`12
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`Although the Specification describes blocking or decreasing CGRP
`receptor activation as including cAMP activation, and measures cAMP to
`determine the extent of receptor activation blocked or decreased by anti-
`CGRP antibodies (see id. at 26:20–25, 32:11–13, 32:39–40, 35:1–3, 55:1–
`57, & Tables 2, 3), it is unclear on this record whether the referenced
`“biochemical” and “histological” symptoms include cAMP stimulation, as
`argued by Petitioner.
`On this record and at this stage of the proceeding, we determine that
`an “effective amount” means “an amount sufficient to effect beneficial or
`desired results,” including results of prophylactic or therapeutic use, as those
`terms are used in the ’907 patent. See, e.g., Ex. 1001, 19:3–22. We do not
`take a position on this record, as requested by Petitioner, as to the specific
`dosages that produce such results. See Curtiss-Wright Flow Control Corp.
`v. Velan, Inc., 438 F.3d 1374, 1381 (Fed. Cir. 2006) (“‘[c]laim
`differentiation is a guide, not a rigid rule.’”) (quoting Laitram Corp. v.
`Rexnord, Inc., 939 F.2d 1533, 1538 (Fed. Cir. 1991)).
`3. “specific binding”
`According to Petitioner, the term “specific binding” includes
`antibodies that may bind to more than one isoform of CGRP, and does not
`preclude binding to another peptide. Pet. 22–23 (citing Ex. 1016 ¶ 114;
`Ex. 1017 ¶ 76). Petitioner further asserts that pursuant to the ’907 patent, a
`binding preference for a first target or a second target is not required, and
`that “specific binding” is not limited to “exclusive binding.” Id. at 23 (citing
`Ex. 1016 ¶ 114; Ex. 1017 ¶¶ 76–77; Ex. 1001, 16:36–39).
`Patent Owner does not agree with Petitioner’s proposed construction
`of the claim term “specific binding.” Prelim. Resp. 30–31. According to
`Patent Owner, Petitioner’s construction is “impermissibly broad” because it
`
`13
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`does not require specific binding to any target and does not account for the
`language of claim 1. Id.
`We agree with Patent Owner that claim 1 uses the term “specific
`binding” in the phrase stating “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, 103:33–35. However, we do not
`view Petitioner’s statement that “under the ’907 patent’s definition, a
`binding preference for a first target or a second target is not required” to be
`inconsistent with the recitation in claim 1 that “the CDRs impart to the
`antibody specific binding to a CGRP consisting of . . . .” Rather, we view
`Petitioner’s statement to be an attempt to capture the Specification’s
`statement that “an antibody . . . that specifically or preferentially binds to a
`first target may or may not specifically or preferentially bind to a second
`target. . . . . ‘[S]pecific binding’ or ‘preferential binding’ does not
`necessarily require (although it can include) exclusive binding.” Ex. 1001,
`16:34–39. Thus, in view of the arguments at this time and the apparent lack
`of inconsistency in the positions of the parties, we determine that it is not
`necessary to construe the term “specific binding” on this record and at this
`stage of the proceeding.
`We also determine, for purposes of determining whether to institute
`an inter partes review in this case, that we need not expressly construe any
`undisputed terms. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d
`795, 803 (Fed. Cir. 1999) (only those terms which are in controversy need to
`be construed and only to the extent necessary to resolve the controversy);
`see also Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d
`1013, 1017 (Fed. Cir. 2017) (applying Vivid Techs. in the context of an inter
`partes review).
`
`14
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`
`
`
`
`
`Principles of Law
`C.
`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;
`(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.
`
`15
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`D. Obviousness over Olesen, Tan, and Queen
`Petitioner asserts that claims 1–18 of the ’907 patent are unpatentable
`as obvious over Olesen, Tan, and Queen. Pet. 23–58. Patent Owner
`opposes. Prelim. Resp. 27–28, 33–55.
`Olesen (Ex. 1025)
`1.
`Olesen is an article published in the New England Journal of
`Medicine that describes a multicenter clinical trial of BIBN4096BS3, a
`highly specific and potent nonpeptide CGRP-receptor antagonist, to test its
`efficacy in the treatment of migraine attacks. Ex. 1025, 1104. Using a
`group-sequential adaptive treatment-assignment procedure, 126 patients
`presenting with acute migraine received one of the following: placebo or
`0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN4096BS intravenously over a period of
`10 minutes. Id. at 1104, 1107. Patients receiving 2.5 mg had a 66%
`response rate, with a pain-free rate of 44% after two hours, and a recurrence
`rate of 19%. Id. at 1107, 1109.
`Olesen states that proof of concept was established and that the main
`end point, the rate of response to pain two hours after treatment, was
`significantly higher than placebo. Id. at 1108–1109. The adverse event rate
`was 25% for the 2.5 mg group and 20% overall for the treatment group,
`which Olesen considers to be a low overall rate of adverse events. Id. at
`1108–09. Olesen characterized the adverse events as mild or moderate, with
`the most frequent adverse events (within 15 hours after infusion) being
`paresthesia, nausea, headache, dry mouth, and abnormal vision. Id. at 1109
`& Table 3.
`
`
`3 The article refers to BIBN4096BS throughout as “BIBN 4096 BS.” See
`generally Ex. 1025.
`
`16
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`With respect to adverse events and potential clinical applications,
`Olesen concludes:
`Paresthesia was the only adverse event of note. BIBN 4096 BS
`does not seem to have vasoconstrictor properties, but our data
`base was too small for us to assess cardiovascular safety. If
`subsequent studies prove the drug to be without vasoconstrictor
`properties, this will represent an advantage over the triptans.
`Our results pose some important clinical and fundamental
`pathophysiological questions. Would patients who have no
`response to triptans benefit from treatment with a CGRP
`antagonist, or would the benefit be confined to those who have a
`response to triptans? How would a CGRP antagonist and a triptan
`compare if studied contemporaneously? Given that CGRP
`antagonists have no direct vasoconstrictor effects, would this
`class of compounds offer similar efficacy and be safer than
`triptans? Can CGRP antagonists establish the primacy of the
`nerve over the vessel during a migraine attack? Only future
`studies that use a more easily administered formulation of a
`CGRP antagonist can answer these questions, but our findings
`offer the prospect of both better treatment and a greater
`understanding of one of the most common clinical problems in
`medicine.
`Id. at 1109 (internal footnote omitted).
`
`Tan (Ex. 1022)
`2.
`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.
`
`17
`
`
`
`
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`Tan 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 minutes 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 571. 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.
`
`18
`
`
`
`IPR2018-01711
`Patent 9,884,907 B2
`
`
`
`
`
`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], 1:19–23.
`
`Queen describes problems with prior art monoclonal antibodies, i.