Trials@uspto.gov
`571.272.7822
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` Paper: 12
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` Entered: April 3, 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 IPR2018-01710
`Patent 8,586,045 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
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`
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`
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`571.272.7822
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` Paper: 12
`
` Entered: April 3, 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 IPR2018-01710
`Patent 8,586,045 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
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`IPR2018-01710
`Patent 8,586,045 B2
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`
` INTRODUCTION
`Eli Lilly and Company (“Petitioner”) filed a Petition to institute an
`inter partes review of claims 1, 3, 4, 8–17, 19, 20, and 24–31 of U.S. Patent
`8,586,045 B2 (the “’045 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. 12–28.
`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 ’045 patent. Therefore, we institute an inter partes
`review for claims 1, 3, 4, 8–17, 19, 20, and 24–31 of the ’045 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
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`Massachusetts (“the first DJ action”). Pet. 66. According to Petitioner, the
`first DJ action seeks a declaration that Petitioner’s investigational drug
`galcanezumab will infringe U.S. Patent Nos. 8,597,649; 9,266,951;
`9,340,614; 9,346,881; and the ’045 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, 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 ’045 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. at 67; see IPR2018-01422, IPR2018-
`01423, IPR2018-01424, IPR2018-01425, IPR2018-01426, and IPR2018-
`01427.
`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, and further identifies petitions for inter partes review against U.S.
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`Patent 8,586,045 B2
`Patent No. 9,884,907 (IPR2018-01711) and U.S. Patent No. 9,884,908
`(IPR2018-01712), styled Eli Lilly & Co. v. Teva Pharmaceuticals
`International 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 ’045 Patent (Ex. 1001)
`B.
`The ’045 patent is titled “Methods of Using Anti-CGRP[1] Antagonist
`Antibodies” 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],
`1:18–21.
`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 1:25–27. In humans, two forms of CGRP
`with similar activities (α-CGRP and β-CGRP) exist and exhibit differential
`distribution. Id. at 1:27–30. At least two CGRP receptor subtypes may also
`account for differential activities. Id. at 1:30–31. 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 1:31–35.
`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 1:35–38. CGRP has been noted for its possible connection to
`
`
`1 Calcitonin Gene-Related Peptide is abbreviated throughout as CGRP. See
`Ex. 1001, 1:25.
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`vasomotor symptoms. Id. at 1:39–40. Vasomotor symptoms include hot
`flushes and night sweats. Id. at 1:42–43. 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 2:3–6.
`According to the Specification, the precise pathophysiology of
`migraine is not yet well understood. Id. at 3:17–18. Dilation of blood
`vessels is associated with and exacerbates the pain symptoms of migraine.
`Id. at 3:23–24. 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 2:57–59. 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 2:60–3:8. 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 2:14–16, 3:8–13,
`4:4–6.
`The ’045 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 3:37–54. The ’045 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 3:55–4:36. 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
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`id. at 4:40–5:34, 7:64–66. Other embodiments are directed to a polypeptide,
`which may or may not be an antibody. See id. at 6:56–7:63. 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 8:9–38.
`Other embodiments are directed to methods of making the same. See id. at
`8:49–64.
`The ’045 patent includes a Table 4 showing amino acid sequences of
`different variants of human α-CGRP and related peptides. Id. at 50:55–58;
`cols. 52–53 (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 10:4–6. Table 6 provides data on
`binding affinity for G1 variants. See id. at cols. 60–65. Another table (cols.
`72–97) lists additional antibody sequences.
`Illustrative Claims
`C.
`Claims 1 and 17, the only independent claims, are illustrative:
`1. A method for reducing incidence of or treating at least one
`
`vasomotor symptom in an individual, comprising administering to the
`individual an effective amount of an anti-CGRP antagonist antibody,
`wherein said anti-CGRP antagonist antibody is a human monoclonal
`antibody or a humanized monoclonal antibody.
`Ex. 1001, 99:2–7.
`17. A method for reducing incidence of or treating headache in a
`human, comprising administering to the human an effective amount of an
`anti-CGRP antagonist antibody, wherein said anti-CGRP antagonist
`antibody is a human monoclonal antibody or a humanized monoclonal
`antibody.
`
`Id. at 100:3–7.
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`Claims 3, 4, and 8–16 depend directly on claim 1, and claims 19, 20,
`and 24–31 depend directly on claim 17. Id. at 99:17–25; 99:38–100:2;
`100:17–24, 37–59.
`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. 1014, “Charles Declaration”) and the Declaration of Dr. Alain P.
`Vasserot, Ph.D. (Ex. 1015, “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 ’045 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. 18–19 (citing Ex. 1014
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`¶¶ 76–78). Petitioner further asserts that “a POSA with respect to the
`aspects of the ’045 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. at 19 (citing Ex. 1015 ¶¶ 77–79).
`Patent Owner contends that “[b]ecause the '045 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. 32. Thus, according to Patent Owner, a POSA
`relevant to the ’045 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 32–33.
`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,
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`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 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 4, 2018,2 the claims of the
`’045 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).
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`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
`30 F.3d 1475, 1480 (Fed. Cir. 1994).
`Petitioner requests construction of the terms “reducing incidence of or
`treating,” “effective amount,” “anti-CGRP antagonist antibody,” and
`“humanized monoclonal antibody.” Pet. 19–24. Patent Owner disputes
`Petitioner’s proposed constructions of “reducing incidence of or treating”
`and “effective amount,” but does not (at this stage of the proceeding) dispute
`Petitioner’s proposed constructions of “anti-CGRP antagonist antibody” or
`“humanized monoclonal antibody.” Prelim. Resp. 29–32.
`“reducing incidence of or treating”
`Petitioner argues that “[t]he ’045 patent expressly defines ‘treatment’
`
`as ‘an approach for obtaining a beneficial or desired result’—it does not
`require achieving any particular result.” Pet. 20 (citing Ex. 1001, 17:37–38
`(emphases by Petitioner)). Thus, according to Petitioner, “‘treating’ merely
`refers to an approach for a particular outcome without requiring a clinical
`response.” Id. (citing Ex. 1014 ¶ 102 (emphasis by Petitioner)). Similarly,
`Petitioner contends that “the ’045 patent expressly defines ‘reducing
`incidence of’ to encompass merely ‘administering the anti-CGRP antagonist
`antibody based on a reasonable expectation that such administration may
`likely cause such a reduction in incidence’—it does not require achieving
`any particular ‘reduction.’” Id. at 21 (citing Ex. 1001, 17:61–65 (emphases
`by Petitioner)). Thus, according to Petitioner, “[t]he express definitions [of
`‘reducing incidence of’ or ‘treating’] do not require a clinical response.”
`Pet. 20.
`
`Patent Owner argues that Petitioner’s proposed construction is
`“incomplete” and that the ’045 patent clearly ties both “reducing incidence
`of” and “treating” to achieving an intended clinical effect. Prelim. Resp. 30–
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`31. Patent Owner further argues that “the explicit definition of treatment
`provided in the specification . . . requires administering the anti-CGRP
`antagonist antibody to achieve a clinical result.” Id.
`
`On this record and at this stage of the proceeding, we determine that
`“reducing incidence of or treating” is a statement of intended purpose that
`does not require achieving a result. For example, a method of “reducing
`incidence of” headache in an individual, “reflects administering the anti-
`CGRP antagonist antibody based on a reasonable expectation that such
`administration may likely cause such a reduction in incidence in that
`particular individual.” Ex. 1001, 17:60–65.
`“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 (citing Ex. 1014 ¶ 104). According to
`Petitioner, the ’045 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 22–23.
`
`Patent Owner argues that Petitioner’s proposed construction of
`“effective amount” is incorrect, and refers to the Specification of the ’045
`patent. Prelim. Resp. 31–32. 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 31 (citing
`Ex. 1001, 18:38–40).
`An “effective amount” is defined in the ’045 patent as “an amount
`sufficient to effect beneficial or desired results.” Ex. 1001, 18:38–40.
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`Therefore, an “effective amount” of an anti-CGRP antagonist antibody
`requires 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 18:41–57.
`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 25:51–55, 31:31–36, 61–64, 34:21–25, 53:36–
`54:64, & 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 ’045 patent. See, e.g., Ex. 1001, 18:41–57. We do not
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`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)).
`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).
`
`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
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`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 Olesen, Tan, and Queen
`Petitioner asserts that claims 1, 3, 4, 8–17, 19, 20, and 24–31 of the
`’045 patent are unpatentable as obvious over Olesen, Tan, and Queen.
`Pet. 24–55. Patent Owner opposes. Prelim. Resp. 28–54.
`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%
`
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`3 The article refers to BIBN4096BS throughout as “BIBN 4096 BS.” See
`generally Ex. 1025.
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`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.
`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
`
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`Patent 8,586,045 B2
`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.
`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
`
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`IPR2018-01710
`Patent 8,586,045 B2
`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.
`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.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
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`IPR2018-01710
`Patent 8,586,045 B2
`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
`have 65% to 70% homology or more to the donor framework sequence. Id.
`at 13:5–36. As further step(s), amino acids in the human acceptor sequence
`will be replaced by corresponding amino acids from the donor sequence if
`(1) the amino acid is in a CDR; (2) the amino acid in the human framework
`region is rare for that position and the 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; and/or (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
`2:61–3:26.
`
`Analysis
`4.
`Petitioner sets forth its contentions as to why claims 1, 3, 4, 8–17, 19,
`20, and 24–31 are obvious over the combination of Olesen, Tan, and Queen.
`Pet. 24–63. Patent Owner opposes. Prelim. Resp. 28–63. We address the
`parties’ respective contentions below. We emphasize that the following
`
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