`
`Filed: September 10, 2019
`
`Filed on behalf of: Eli Lilly and Company
`
`
`
`
`
`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 No. IPR2018-01427
`Patent No. 8,597,649
`______________________
`
`PETITIONER’S REPLY
`
`
`
`
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`
`I.
`II.
`
`B.
`
`TABLE OF CONTENTS
`Introduction ................................................................................................. 1
`Teva Fails to Rebut the Prior Art’s Express Motivation to Make a
`Claimed Antibody ........................................................................................ 2
`A.
`Teva’s Motivation Arguments Are Not Directed to the Claimed
`Subject Matter.................................................................................... 4
`Teva’s Unfounded Safety Concerns Do Not Undermine
`Motivation ......................................................................................... 6
`1.
`Clinical Studies Demonstrated that the CGRP Pathway
`Could Be Safely Antagonized To Treat Migraine .................... 6
`Long-Acting Ligand Antagonists Had Desirable Benefits
`and Did Not Raise Safety Concerns ........................................10
`The Prior Art Would Not Have Dissuaded a POSA from
`Pursuing a Humanized Anti-CGRP Antagonist Antibody .......13
`Absolute Risk of Stroke in Migraine Patients Was Very
`Low ........................................................................................15
`Hypothetical “Spare Receptor Theory” Concerns Did Not
`Undermine Motivation ......................................................................16
`
`2.
`
`3.
`
`4.
`
`C.
`
`Ligand Cross-Binding Did Not Undermine Motivation.....................17
`D.
`Teva’s Binding-Affinity Arguments Are Incorrect ............................18
`E.
`III. Teva’s Reasonable Expectation of Success Arguments Are Irrelevant ........19
`IV. Teva’s Alleged Secondary Considerations Do Not Support
`Nonobviousness ..........................................................................................21
`A.
`Teva’s Secondary Considerations Evidence Is Not
`Commensurate with the Scope of the Challenged Claims .................21
`Teva’s Secondary Considerations Lack Nexus to the Claims ............24
`Teva’s Reliance on Industry Acclaim Is Misplaced ..........................24
`
`B.
`C.
`
`i
`
`

`

`D.
`
`IPR2018-01427
`Patent No. 8,597,649
`Teva Failed to Establish Unexpected Results or Industry
`Skepticism ........................................................................................26
`Teva’s Purported Evidence of Commercial Success, Licensing,
`and Long-Felt Need Do Not Support Patentability ............................26
`Conclusion ..................................................................................................27
`
`E.
`
`V.
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`
`IPR2018-01427
`Patent No. 8,597,649
`
` Page(s)
`
`Federal Cases
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass. 2013) ................................................................. 5
`
`Alcon Research Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 4
`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) .......................................................................... 23
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .................................................................. 15, 24
`Cole Kepro Int’l, LLC v. VSR Indus., Inc.,
`695 F. App’x 566 (Fed. Cir. 2017) ................................................................... 27
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) ........................................................................ 22
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................. 22, 24
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .......................................................................... 3
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ........................................................................ 24
`Paint Point Med. Sys., Inc. v. Blephex, LLC,
`IPR2016-01670, Paper 44 (PTAB Feb. 28, 2018) ............................................ 27
`Par Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 6
`S. Ala. Med. Sci. Found. v. Gnosis S.P.A.,
`808 F.3d 823 (Fed. Cir. 2015) .......................................................................... 24
`
`iii
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`
`Sanofi-Aventis U.S. LLC v. Immunex Corp.,
`IPR2017-01884, Paper 96 (PTAB Feb. 14, 2019) .................................. 5, 10, 19
`Soft Gel Techs., Inc. v. Jarrow Formulas, Inc.,
`864 F.3d 1334 (Fed. Cir. 2017) .......................................................................... 3
`
`
`
`iv
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`
`CGRP
`
`FDA
`
`IPR
`
`GLOSSARY
`
`Calcitonin gene-related peptide
`
`U.S. Food and Drug Administration
`
`Inter partes review
`
`Italicized text
`
`Emphasis added unless otherwise indicated
`
`Lilly or Petitioner Eli Lilly and Company
`
`Monoclonal antibody
`
`Mean arterial pressure
`
`Medication-overuse headache
`
`Person of ordinary skill in the art
`
`Surface plasmon resonance
`
`Teva Pharmaceuticals International GmbH
`
`U.S. Patent No. 8,597,649
`
`U.S. Patent No. 6,344,438
`
`MAb
`
`MAP
`
`MOH
`
`POSA
`
`SPR
`
`Teva or Patent
`Owner
`
`’649 patent
`
`’438 patent
`
`
`
`
`
`v
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`
`I.
`
`Introduction
`Teva does not challenge key elements of Lilly’s case: (1) the prior art discloses
`
`or suggests every element of the challenged claims; (2) a POSA would have been
`
`motivated to antagonize the CGRP pathway; (3) a POSA would have reasonably
`
`expected to successfully make the claimed antibodies; and (4) Teva raises no unique
`
`arguments for any dependent claim. Teva has therefore waived any argument to the
`
`contrary.
`
`Instead—notwithstanding express
`
`statements
`
`in Wimalawansa
`
`that
`
`humanized anti-CGRP antibodies “should be explored” for treating various
`
`diseases—Teva argues that a POSA would not have made humanized anti-CGRP
`
`antibodies because of purported safety concerns regarding their use in patients. Teva
`
`also argues that the “spare receptor” theory and purported cross-binding of CGRP to
`
`ancillary receptors would have undermined motivation, and alleges that a POSA
`
`would not arrive at the claimed binding affinity.
`
`It is undisputed, however, that the ’649 patent addresses none of these alleged
`
`concerns. The ’649 patent does not mention safety. It contains no pre-clinical safety
`
`data and no clinical data whatsoever, regardless of antibody affinity. It does not
`
`address the spare receptor theory or CGRP cross-binding. Teva therefore seeks to
`
`hold the prior art to a higher standard than its own patent, requiring proof of safety
`
`and efficacy. This constitutes legal error, and infects nearly every Teva argument.
`
`1
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`Teva’s error is particularly egregious because the challenged claims merely recite
`
`antibodies.
`
`Teva’s purported concerns are illusory. Teva relies on a handful of outdated
`
`studies, but by November 2005, systemically administered CGRP antagonists had
`
`repeatedly been shown to be safe and effective. Time-and-again, the art encouraged
`
`making longer-acting, high-affinity CGRP antagonists, including humanized
`
`antibodies, for therapeutic purposes. Indeed, notwithstanding Teva’s spare-receptor
`
`theory or hypothetical cross-binding concerns, researchers were actively targeting
`
`CGRP for treating migraine.
`
`As explained below, Teva also failed to establish a showing of secondary
`
`considerations for the claimed subject matter. The challenged claims are
`
`unpatentable.
`
`II. Teva Fails to Rebut the Prior Art’s Express Motivation to Make a
`Claimed Antibody
`Teva focuses its arguments on motivation, but the record is clear: the prior art
`
`provides express motivation to make a humanized anti-CGRP antagonist antibody
`
`of the challenged claims. Pet., 26-36.
`
`Wimalawansa urges one to humanize anti-CGRP antagonist antibodies: “[t]he
`
`role of … humanized monoclonal antibodies should be explored.” Ex. 1096, 570;
`
`Pet., 22, 29; see Ex. 1303, 47:22-48:5. An express recommendation for future
`
`2
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`research alone evinces motivation. Soft Gel Techs., Inc. v. Jarrow Formulas, Inc.,
`
`864 F.3d 1334, 1342 (Fed. Cir. 2017).
`
`Providing further motivation, the advantageous properties of anti-CGRP
`
`antibodies were known: Tan’s MAb C4.19 had a single-digit nanomolar binding
`
`affinity and antagonized CGRP in vitro and in vivo. Ex. 1021, 706-707; Ex. 1022,
`
`568-572; Pet., 30-32; Ex. 1303, 160:2-9, 162:12-22. As Dr. Tan contemporaneously
`
`wrote, there is “no reason” why humanized anti-CGRP antagonist antibodies should
`
`not be pursued. Ex. 1287, 247.
`
`Salmon, Sveinsson, and the ’438 patent provide additional motivation,
`
`disclosing and claiming anti-CGRP antagonist antibodies for treating chronic human
`
`diseases. Pet., 27-30; Ex. 1002 ¶¶64-66. As Drs. Tomlinson and Ferrari conceded,
`
`a POSA would have understood that administering antibodies to humans for chronic
`
`use, as taught by these references, would require humanization. Ex. 1301, 211:2-15;
`
`Ex. 1303, 49:1-20.
`
`Teva misinterprets Kinetic Concepts, Inc. v. Smith & Nephew, Inc., 688 F.3d
`
`1342, 1360 (Fed. Cir. 2012), arguing the art disclosed neither a known problem nor
`
`a solution to that problem. POR, 50. Regardless, the prior art repeatedly and
`
`unambiguously identified a need for new therapies, including migraine, and
`
`expressly proposed humanized anti-CGRP antagonist antibodies as the solution.
`
`Pet., 60-61; Ex. 1303, 205:8-12.
`
`3
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`A. Teva’s Motivation Arguments Are Not Directed to the Claimed
`Subject Matter
`The challenged claims lack any meaningful structural requirements, and are
`
`broadly directed to any humanized anti-CGRP antagonist antibody having known
`
`functional properties. Pet. 55-56. Attempting to downplay the art’s express
`
`motivation to make such an antibody, Teva seeks to limit the claims to antibodies
`
`that will be safe and effective in human patients. POR, 2-3; Ex. 1303, 38:22-39:10,
`
`44:3-45:5; Ex. 2141 ¶28; Ex. 1304, 143:6-23; Ex. 1301, 129:16-130:20.
`
`It is undisputed, however, that Teva’s patent does not mention safety. It
`
`contains no pre-clinical safety data and no clinical data whatsoever. Ex. 1303, 55:7-
`
`57:19. As Teva’s expert Dr. Foord testified, the limited animal studies in Teva’s
`
`patent “will never satisfy concerns about safety and efficacy.” Ex. 1300, 173:20-
`
`175:6; see also Ex. 1303, 31:8-14, 54:12-23.
`
`Reading safety and efficacy requirements into the claims, Teva seeks to
`
`require more from the prior art than it disclosed in its patent by importing a
`
`reasonable expectation inquiry into motivation. This is improper. Alcon Research
`
`Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (“While it is true that [the
`
`prior art] does not expressly disclose that olopatadine would be safe for use in human
`
`eyes, neither does the ’805 patent. The patent is not based on testing in humans;
`
`4
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`instead it reports only in vitro tests.”); see also Sanofi-Aventis U.S. LLC v. Immunex
`
`Corp., IPR2017-01884, Paper 96 at 17 (PTAB Feb. 14, 2019).
`
`The law is clear that the prospect of creating a “potential therapeutic” is
`
`sufficient motivation to humanize. Immunex, IPR2017-01884, Paper 96 at 17, 19-24
`
`(holding claims to humanized antibodies obvious based on motivation of creating a
`
`“potential therapeutic”); Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`
`971 F. Supp. 2d 171, 185 (D. Mass. 2013) (holding claims to human antibodies
`
`obvious where the antibodies merely “could be therapeutic”).
`
`That standard is consistent with the evidence here. Dr. Vasserot testified that
`
`a POSA would have been motivated to humanize a murine antibody when it “had
`
`been shown to exhibit functional properties that could be useful in treating a
`
`disease.” Ex. 1003 ¶¶83-85; Pet., 34-36. He testified that “[w]e have started projects
`
`with less data than [Tan.]” Ex. 2191, 100:8-15, 97:15-100:1. Teva’s own expert
`
`admitted that he and his colleagues “humanized antibodies all the time.” Ex. 1301,
`
`55:5-6. Further, Teva’s experts conceded that a POSA would have found it
`
`appropriate to use humanized antibodies throughout drug development, including
`
`5
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`binding assays, in vitro testing, and animal studies.1 Id., 208:3-12; Ex. 1303, 54:25-
`
`55:6; Ex. 1304, 145:23-146:3.
`
`To establish motivation, all the law requires is a “suitable option from which
`
`the prior art did not teach away.” Par Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d
`
`1186, 1197-98 (Fed. Cir. 2014) (emphasis in original). As explained below, Teva’s
`
`overblown safety concerns would not have undermined the express motivation to
`
`pursue humanized anti-CGRP antagonist antibodies for therapeutic use.
`
`B.
`
`Teva’s Unfounded Safety Concerns Do Not Undermine
`Motivation
`Contrary to Teva’s unfounded safety allegations (POR, 22), the prior art
`
`repeatedly demonstrated that blocking the CGRP pathway was both safe and
`
`effective for treating migraine.
`
`1.
`
`Clinical Studies Demonstrated that the CGRP Pathway Could
`Be Safely Antagonized To Treat Migraine
`By November 2005, the prior art had established that antagonizing the CGRP
`
`pathway was understood to be safe and effective. Ex. 1330 §IV, ¶¶76-77; Ex. 1303,
`
`70:13-75:11, 84:13-22; Ex. 1304, 91:6-10; Exs. 1291, 1292.
`
`
`1 Claims 8 and 9 encompass formulations of anti-CGRP antagonist antibodies and
`
`intravenous administration that would be useful for pre-clinical testing, as taught in
`
`Queen and Tan. Pet., 54-55.
`
`6
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`Sumatriptan, FDA-approved since the early 1990s, was a safe and effective
`
`migraine-specific treatment that inhibited CGRP. Ex. 1330 ¶¶11, 44; Ex. 1303,
`
`18:7-19:3, 211:2-9; Ex. 1282, 1519-1520. Indeed, by 2005, inhibiting CGRP release
`
`was understood as one of “the most important contribution[s]” to sumatriptan’s anti-
`
`migraine effects. Ex. 1303, 23:22-24:22; Ex. 1304, 90:10-15. Despite “transient”
`
`blood pressure increases observed in some patients, sumatriptan was considered
`
`“very safe” when prescribed to appropriate patients. Ex. 1330 ¶44; Ex. 1282, 1521;
`
`Ex. 1308, 1673. Consistent with the well-recognized safety of sumatriptan, Teva’s
`
`clinician experts advocated daily triptan administration for up to a year for
`
`preventative migraine treatment. Ex. 1294, Abstract, 487; Ex. 1295, Abstract, 1405;
`
`Ex. 1330 ¶12.
`
`In 2004, Olesen again confirmed that antagonizing the CGRP pathway
`
`produced no serious side effects and no cardiovascular events. Ex. 1025, 1109;
`
`Ex. 1330 ¶¶33-34; Pet., 29-30; Ex. 1303, 84:13-22. Contradicting Teva’s argument
`
`that “Olesen says nothing about cerebrovascular safety” (POR, 29), Olesen states
`
`that BIBN4096BS “had no constrictor effect on the middle cerebral, radial, or
`
`superficial temporal artery or on regional cerebral blood flow, blood pressure, or
`
`7
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`heart rate.” Ex. 1025, 1108.2 Moreover, Olesen reported that BIBN4096BS further
`
`improved over triptans as the “first migraine-specific medication that is not a
`
`vasoconstrictor.” Id.; Ex. 2010, 2561 (BIBN4096BS is “devoid of vasoconstrictive
`
`actions in humans”).
`
`Similarly, Iovino and Petersen reported “a very favourable safety profile” for
`
`BIBN4096BS in human volunteers. Ex. 1042, Abstract (reporting no “clinically
`
`relevant, drug-induced changes” in blood pressure, pulse rate, blood flow, or vital
`
`signs); Ex. 2019, Abstract (reporting “no effect of CGRP-receptor blockade on the
`
`cerebral or systemic circulation in humans”); Ex. 1330 ¶¶35-38; Ex. 1303, 84:23-
`
`85:7, 87:1-11, 90:22-92:20.
`
`In 2005, in view of these studies, both of Teva’s clinician experts
`
`independently praised “CGRP antagonists” as promising antimigraine drugs.
`
`Ex. 1290, 657 (advocating “CGRP antagonists” as “promising, new antimigraine
`
`drugs without vascular side effects”); Ex. 1297, S119 (recommending “antagonising
`
`the effect of CGRP” for acute and preventive migraine therapies).
`
`
`2 Teva incorrectly asserts that Dr. Charles failed to consider safety concerns. POR,
`
`33. Dr. Charles considered Olesen, Tan, Iovino, Andrew, and Wong, all of which
`
`reveal an absence of safety concerns. Ex. 1002, Appendix B.
`
`8
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`Contrary to Teva’s incorrect arguments (POR, 20-21), safety lessons from
`
`antagonizing the CGRP pathway with sumatriptan and BIBN4096BS were pertinent
`
`for therapeutics that directly target CGRP. By 2005, the prior art described targeting
`
`CGRP and its receptor as “alternative” techniques for antagonizing the CGRP
`
`pathway. Ex. 1022, 566, 571; Ex. 1033, 95; Ex. 1002 ¶113; Ex. 1329 ¶¶35-39.
`
`Indeed, the art recognized that “inhibition of CGRP or antagonism of CGRP
`
`receptors could be a viable therapeutic target” for treating migraine—and
`
`researchers were already targeting both CGRP and its receptor. Ex. 1040, 182;
`
`Ex. 1330 ¶¶37, 15-17.
`
`For example, citing Wimalawansa, researchers had developed αCGRP ligand
`
`antagonists—e.g., aptamers that bound CGRP—for treating migraine. Ex. 1082,
`
`Abstract, 2 (ref. 19). Upon anti-CGRP aptamer administration, researchers reported
`
`that “[b]asal blood flow and systemic arterial pressure were unchanged.” Ex. 1240,
`
`923; Ex. 1329 ¶¶38, 54. The prior art explained that “aptamers can be thought of as
`
`… analogs to antibodies,” and recognized their relatively longer half-life. Ex. 1309,
`
`Abstract; Ex. 1240, 923; Ex. 1082, Abstract, 7. Thus, the prior art demonstrated that
`
`longer acting anti-CGRP drugs were desirable and indicated as safe. Ex. 1330 ¶¶5-
`
`17, 41-51; Ex. 1329 ¶¶48-55.
`
`Accordingly, by 2005 purported theoretical safety concerns of targeting the
`
`CGRP pathway would not have undermined the clear motivation to develop a
`
`9
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`humanized anti-CGRP antagonist antibody. Immunex, IPR2017-01884, Paper 96 at
`
`17, 19-24 (rejecting patentee’s “theoretical” side effect arguments against a
`
`motivation to humanize).
`
`2.
`
`Long-Acting Ligand Antagonists Had Desirable Benefits and
`Did Not Raise Safety Concerns
`Teva contends that the relatively long half-lives of antibodies would have been
`
`expected to exacerbate any potential CGRP-blocking side effects. POR, 29-30. To
`
`the contrary, a POSA would have viewed anti-CGRP drugs with longer half-lives as
`
`desirable for preventative migraine treatments, without posing safety concerns.
`
`Ex. 1330 ¶¶5-17, 46-50; Ex. 1329 ¶¶48-55; Pet., 34-36. As explained above, the art
`
`was developing aptamer “analogs” to antibodies targeting CGRP for treating
`
`migraine. These compounds did not affect basal blood flow or systemic arterial
`
`pressure. Ex. 1240, 923.
`
`Teva nevertheless argues that the transient and mild increase in blood pressure
`
`observed in Tan would raise safety concerns. POR, 25-26. But as Lilly’s expert Dr.
`
`Balthasar explains,3 a POSA would have understood that the minor blood-pressure
`
`
`3 In contrast to Dr. Balthasar’s antibody-pharmacology expertise, Dr. Foord
`
`admitted his grasp of immunology was “tenuous.” Ex. 1300, 33:8-11. Dr. Ferrari
`
`likewise has a deficient understanding of antibodies. Ex. 1303, 69:10-16.
`
`10
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`increase in Tan’s anesthetized rats normalized within 10 to 15 minutes of
`
`administering MAb C4.19, and “had no relationship to the half-life” of the antibody.
`
`Ex. 1329 ¶¶56-60; Ex. 1022, 568. Teva also greatly exaggerates Tan’s blood-
`
`pressure effects, alleging a “13-fold” increase whereas Dr. Foord admitted it was
`
`only “1.1-fold.” Compare POR, 25 with Ex. 1300, 129:21-130:4.
`
`A POSA would not have viewed Tan’s minor, transient blood-pressure
`
`increase in anesthetized rats as a safety concern. Ex. 1330 ¶¶41-45; see Ex. 1303,
`
`25:11-17 (transient blood-pressure increase for sumatriptan was not “a major
`
`concern”). Indeed, Teva omits that a similar blood pressure increase was observed
`
`with the CGRP-receptor antagonist CGRP8-37, but that did not deter development of
`
`BIBN4096BS or other receptor antagonists. Ex. 1022, 569; Ex. 1025, 1109.
`
`Similarly, Teva omits that Tjen-A-Looi observed a stronger blood pressure increase
`
`with CGRP8-37 than an anti-CGRP antisera, which similarly did not deter
`
`development of CGRP-receptor antagonists. Ex. 2084, H687 (disclosing testing
`
`under non-physiologic, hypoxic conditions); Ex. 1329 ¶¶66-70.
`
`Teva incorrectly attempts to undermine Tan’s disclosures by characterizing it
`
`as a “basic research paper” and citing purported personal knowledge of its authors.
`
`Ex. 2141 ¶70; POR, 51. But in describing his own work, Dr. Tan wrote in 1994 that
`
`there was “no reason” why humanized anti-CGRP monoclonal antibodies should not
`
`be investigated and used as “therapeutic agents” for migraine and other diseases.
`
`11
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`Ex. 1287, 247 (similarly discussing human anti-CGRP MAbs as an “exciting
`
`possibility” for administration “in man”). Dr. Tan’s contemporaneous statements
`
`were written with first-hand knowledge of the blood pressure results focused on by
`
`Teva and directly contradict Teva’s position.
`
`Other prior art further confirms that anti-CGRP antagonist antibodies did not
`
`have any chronic blood-pressure or vascular effects. Ex. 1329 ¶¶61-65; Ex. 1330
`
`¶¶43-53. For instance, Wong conducted in vivo blood pressure testing on the same
`
`antibody (4901) that Teva evaluated in its specification and concluded that it “had
`
`no significant effect on MAP [mean arterial pressure] and heart rate.” Ex. 1033, 101;
`
`Ex. 1001, 51:30. Similarly, Andrew evaluated immunized animals with “high levels
`
`of circulating antibodies to rat CGRP” after 10-15 weeks and confirmed that “they
`
`did not show any signs of physical or behavioural abnormality.” Ex. 1055, 88, 93.
`
`Salmon and other researchers disabled αCGRP production entirely in knockout
`
`mice, and rather than experiencing any safety concerns, they claimed therapeutic
`
`uses of anti-CGRP antagonist antibodies. Ex. 1027, ¶[0069], claims 8, 9; Ex. 1026,
`
`claim 2; Ex. 1288, Abstract. Teva and its experts disregard this compelling evidence
`
`of safety entirely.
`
`12
`
`

`

`IPR2018-01427
`Patent No. 8,597,649
`The Prior Art Would Not Have Dissuaded a POSA from
`Pursuing a Humanized Anti-CGRP Antagonist Antibody
`Ignoring more recent prior art (supra §§II.B.1-2 and below), Teva cites several
`
`3.
`
`early studies, largely published before Wimalawansa proposed exploring humanized
`
`anti-CGRP antibodies, to support its hypothetical safety arguments. POR, 23-24;
`
`Ex. 2141 ¶¶27-47. But Teva’s cited studies do not indicate that antagonizing
`
`endogenous CGRP—as an anti-CGRP antagonist antibody would have been
`
`expected to do—would have affected cardiovascular or cerebrovascular safety.
`
`Ex. 1330 ¶¶18-25; Ex. 1303, 108:25-133:7.
`
`For example, Teva relies on early studies reporting the effects of administering
`
`exogenous CGRP (Exs. 2058, 2079, 2139), which increases CGRP levels instead of
`
`antagonizing endogenous CGRP. Ex. 1330 ¶21. Teva also relies on early studies
`
`attempting to discern CGRP’s biological effects without the benefit of a specific
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`antagonist, making it impossible to separate the effects of CGRP from other
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`vasopeptides. Id. ¶¶22-23; Exs. 2150, 2151, 2154, 2070, 2089, 2209. In the one
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`study that used CGRP8-37 (a receptor antagonist) under physiological conditions, no
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`vascular changes were observed. Ex. 2152, 165; Ex. 1330 ¶24; Ex. 1303, 111:23-
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`119:13.
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`Teva also ignored more recent prior-art studies demonstrating that blocking
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`the effects of endogenous CGRP with specific antagonists does not worsen ischemic
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`events. Ex. 1330 ¶¶26-32. For instance, a 1998 publication reported that blocking
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`endogenous CGRP did not worsen ischemia in pigs. Ex. 1283, 498 (“locally
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`released CGRP does not function as a cardioprotective agent”); Ex. 1303, 134:23-
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`136:17. A 2001 study investigating BIBN4096BS in ischemic rats reported that
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`CGRP antagonism produced no effect on infarct size. Ex. 1284, Abstract; Ex. 1303,
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`140:5-7, 142:2-7. Similarly, a 2003 study antagonizing CGRP in dogs with chronic
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`heart failure reported that “endogenous α-CGRP does not appear to play a major role
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`in the regulation of cardiac and peripheral vascular dynamics in the late stage of
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`heart failure.” Ex. 1285, Abstract; Ex. 1303, 142:24-143:22. Another 2003
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`publication involving repeated administration of BIBN4096BS concluded that
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`CGRP played no major role in cardiovascular regulation. Ex. 1318, 76.
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`Teva even overlooked a 2004 publication from Dr. Ferrari’s Ph.D. advisor, Dr.
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`Saxena, studying global and regional cardio- and cerebro-vascular effects of
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`antagonizing the CGRP pathway with BIBN4096BS. Ex. 1263, Abstract; Ex. 1303,
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`97:10-98:2. No undesired effects were observed, even at high doses, leading the
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`investigators to conclude that “endogenous CGRP does not play an important role in
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`regulating systemic and regional haemodynamics.” Ex. 1263, 296; Ex. 1303, 102:9-
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`106:19. Summarizing the pre-clinical and clinical data, Dr. Saxena wrote later in
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`2004 that “[a]n important advantage of CGRP antagonists over the triptans [for
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`migraine treatment] can be their use in patients with coronary artery disease.”
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`Ex. 1031, 326; Ex. 1330 ¶¶39-40.
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`Absolute Risk of Stroke in Migraine Patients Was Very Low
`4.
`Teva alleges that migraine is a risk factor for stroke. POR, 26-27. But these
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`arguments directed to specific subpopulations of migraine patients are legally
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`irrelevant. Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369,
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`1376 (Fed. Cir. 2013) (rejecting patient sub-population arguments where “the [drug]
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`product claims at issue do not distinguish between target patient populations”).
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`Teva’s arguments are also irrelevant for most migraine patients. Ex. 1330
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`¶¶57-62. For example, over two-thirds of migraine patients experience migraine
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`without aura, for which no correlation between migraine and stroke was known to
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`exist. Ex. 1040, 177; Ex. 1303, 193:3-10. Moreover, while an increased relative
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`risk was observed among young women compared to the general populace, “the
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`absolute risk of stroke in young women with migraine is low: 18 per 100,000 per
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`year.” Ex. 2157, 535; Ex. 1303, 190:3-193:12. A similarly low absolute risk of
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`myocardial ischemia among young women was also known as of 2005. Ex. 1315,
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`Abstract; Ex. 2157, 536 (from a vascular standpoint, migraine is “mostly benign”).
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`Thus, there is no significant overlap between migraine patients and individuals at
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`high risk of stroke or myocardial infarction.
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`Even if there had been potential safety concerns, they would not—and in fact
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`did not—discourage researchers from pursuing anti-CGRP therapies. Anti-migraine
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`treatments could be contraindicated in patients with particular risk factors, as had
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`been done with sumatriptan and ergots. Ex. 1330 ¶¶63-64; Ex. 1282, 1520;
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`Ex. 1290, 564-565. Teva offers no reason why anti-CGRP antagonist antibodies
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`would have been viewed differently, especially when the safety profile of CGRP-
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`antagonists was deemed favorable.
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`In sum, even if the Board determines that safety should be considered in
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`evaluating motivation, the hypothetical concerns alleged by Teva neither teach away
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`nor undermine the express prior-art motivation to explore humanized anti-CGRP
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`antagonist antibodies for therapeutic use.
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`C. Hypothetical “Spare Receptor Theory” Concerns Did Not
`Undermine Motivation
`Teva incorrectly asserts that a POSA would lack motivation to block the
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`CGRP ligand based on Teva’s theory that “in the CGRP receptor system, less than
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`1% of [CGRP] receptors needed to be bound by ligand to elicit a full response.”
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`POR, 32. As with safety, Teva’s patent does not address the spare receptor theory.
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`Teva’s hypothetical is contradicted by the prior art, which indicated the spare
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`receptor theory does not apply. Ex. 1329 ¶¶40-47. Indeed, Dr. Foord conceded that
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`Shekyzade (Ex. 2065), far from disclosing that 1% CGRP receptor occupancy elicits
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`a full biological response, instead discloses that 27% CGRP receptor occupancy is
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`required to generate a half-maximal response. Ex. 1300, 68:19-69:8. Thus, a POSA
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`would have understood that a large percentage of CGRP receptors would need to be
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`bound to elicit a full biological response, contrary to Teva’s hypothetical. Ex. 1329
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`¶42.
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`The prior-art clinical evidence also contradicts Teva’s spare receptor theory.
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`Ex. 1330 ¶¶65-69. Successfully treating migraine does not require antagonizing
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`99.999% of CGRP ligands to effectively abolish all CGRP activity, as Teva contends.
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`POR, 32. Rather, only elevated or inappropriate levels of CGRP were recognized
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`as a cause of migraine, while normalizing CGRP levels was accompanied by
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`subsidence of migraine headache. E.g., Ex. 1044, Abstract; Ex. 1096, 567; Pet., 29.
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`Regardless, Teva’s hypothetical “spare receptor” theory did not, in fact, deter
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`targeting CGRP. Ex. 1330 ¶¶17, 69; Pet., 27-30.
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`D. Ligand Cross-Binding Did Not Undermine Motivation
`Teva also contends that targeting the CGRP ligand and inhibiting its ability to
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`bind to calcitonin, adrenomedullin, and amylin receptors would have been
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`undesirable. POR, 31-32. Safety concerns resulting from ligand cross-binding are
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`not addressed in Teva’s patent. Regardless, Teva is incorrect.
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`As Dr. Foord admitted, “by 2005 it was unclear what physiological activities
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`were mediated by CGRP binding at these [other] receptors.” Ex. 2054 ¶34. His own
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`table of binding potency for various ligands at these ancillary receptors illustrates
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`that CGRP is a secondary or worse binding ligand to non-CGRP receptors. Id.;
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`Ex. 2059, 63. Mere speculation about theoretical physiological effects from CGRP’s
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`poor binding to other receptors would not have deterred development of a humanized
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`anti-CGRP antagonist antibody. Ex. 1330 ¶¶70-75. Moreover, to the extent it is
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`deemed relevant at all, ligand cross-binding favored targeting CGRP rather than its
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`receptor because it would minimize any perceived risk. Ex. 1330 ¶¶73-74; Ex. 2003,
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`912-914, 919-921.
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`Teva’s Binding-Affinity Arguments Are Incorrect
`E.
`Contrary to Teva’s arguments (POR, 44-48), a POSA would have been
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`motivated to make, and readily expected to obtain, antibodies against human αCGRP
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`with affinities lower than 50 nM. Ex. 1021, 707 (1.9 nM to rat CGRP); Ex. 1055,
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`92 (4 nM to human CGRP); Ex. 1033, 102 (reporting “high affinity” antibody 4901);
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`Ex. 1329 ¶¶71-78; Pet., 38-41. All of these values are consistent with the ’649
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`patent’s admission that prior-art antibody 4901 had an affinity of 3.4 nM to CGRP
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`as measured by SPR at 37ºC, illustrating that Teva’s arguments about different
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`affinity-measurement techniques and temperatures are overblown. Ex 1001, 52:15.
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`The parties’ experts agree that single-digit nM affinities are typically obtained as a
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`“general rule,” and that further affinity maturation was routine. Ex. 1301, 211:22-
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`214:25; Ex. 1068, 351; Ex. 1329 ¶72; Ex. 1003 ¶¶114-117.
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`Indeed, Dr. Tomlinson admitted that “strong binding affinity” is a desirable
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`characteristic for therapeutic antibodies. Ex. 1301, 211:16-21; see also Ex. 1266,
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`521 (explaining that “[a]n ideal drug would have … very high affinity and exquisite
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`specific