`
`
`
`IN THE 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 IPR2018-01426
`Patent 9,890,211 B2
`_____________________
`
`TEVA PHARMACEUTICALS INTERNATIONAL
`GMBH’S PATENT OWNER RESPONSE
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`TABLE OF CONTENTS
`
`Case IPR2018-01426
`Patent No. 9,890,211
`
`
`I. 
`
`Introduction ..................................................................................................... 1 
`
`II.  Background................................................................................................... 9 
`
`A. 
`
`B. 
`
`Calcitonin Gene-Related Peptide (“CGRP”) ........................................ 9 
`
`The’211 patent and its commercial embodiments .............................. 10 
`
`III.  A POSA would not have had a reason to humanize anti-CGRP
`antibodies as of 2005 .................................................................................... 13 
`
`A. 
`
`B. 
`
`Lilly’s reasons to combine the art as claimed are based on
`“therapeutic use in humans” of humanized anti-CGRP
`antibodies ............................................................................................. 13 
`
`Lilly mischaracterizes what the cited art would have conveyed
`to the POSA ......................................................................................... 15 
`
`1. 
`
`2. 
`
`Tan 1995 provided no “guidance” about treating
`vasomotor symptoms with anti-CGRP antibodies in
`humans ..................................................................................... 15 
`
`Lilly’s experts internally disagree on what the cited art
`discloses ................................................................................... 16 
`
`3.  Wimalawansa provided no guidance to humanize anti-
`CGRP antagonist antibodies without conducting further
`studies ....................................................................................... 19 
`
`C. 
`
`Lilly ignored the known potentially deleterious effects of anti-
`CGRP antibodies in its “motivation” analysis .................................... 21 
`
`1. 
`
`2. 
`
`As of 2005, CGRP was known to have an important
`vasoprotective role in humans ................................................. 23 
`
`Tan 1995 and Wimalawansa also raised substantial safety
`concerns, which Lilly ignored.................................................. 24 
`
`3.  Migraine patients present even greater safety concerns
`with using antibodies, which Lilly failed to address ............... 27 
`
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`

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`Lilly’s cited art does not overcome the known safety
`concerns associated with anti-CGRP antibodies in 2005 ........ 28 
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`Case IPR2018-01426
`Patent No. 9,890,211
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`
`4. 
`
`D. 
`
`The safety concerns that Lilly overlooked provide reasons a
`POSA would not have humanized an anti-CGRP antibody ................ 36 
`
`IV.  A POSA would not have had a reasonable expectation of success .............. 38 
`
`A.  A POSA would not have had a reasonable expectation of
`success because Tan 1995 shows that the full-length antibody
`was not successful at achieving immunoblockade .............................. 38 
`
`B. 
`
`Tan’s speculation would not persuade a POSA of therapeutic
`success in view of Tan’s demonstrated potential for side effects ....... 40 
`
`V. 
`
`Lilly failed to prove that a POSA would have arrived at the claimed
`antibodies affinity (KD) to CGRP ................................................................. 41 
`VI.  Lilly’s obviousness case is the product of hindsight, driven only by
`the solution provided in the ’211 patent ....................................................... 46 
`
`VII.  Strong objective evidence compels finding non-obviousness of the
`challenged claims .......................................................................................... 51 
`
`A. 
`
`B. 
`
`C. 
`
`The challenged claims have a presumption of nexus to the
`objective indicia of nonobviousness ................................................... 51 
`
`The claimed humanized anti-CGRP antibodies have received
`industry-wide acclaim ......................................................................... 52 
`
`Humanized anti-CGRP antibodies satisfied long-felt, unmet
`need ...................................................................................................... 55 
`
`D.  Humanized anti-CGRP antibodies achieved unexpected results ........ 56 
`
`E. 
`
`F. 
`
`Humanized anti-CGRP antibodies faced industry skepticism ............ 58 
`
`Commercial success reinforces the non-obviousness of the
`claimed invention ................................................................................ 59 
`
`G.  AlderBio’s decision to take a royalty-bearing license to Teva’s
`patents supports nonobviousness ........................................................ 60 
`
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`

`

`Lilly’s simultaneous invention argument is not supported by the
`facts or the law .................................................................................... 61 
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`Case IPR2018-01426
`Patent No. 9,890,211
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`
`H. 
`
`VIII.  Lilly has failed to carry its burden so the Board must find for Patent
`Owner ............................................................................................................ 62 
`
`IX.  Conclusion .................................................................................................... 63 
`
`CERTIFICATE OF WORD COUNT (37 C.F.R. § 42.24(d)) ................................ 64 
`
`CERTIFICATE OF SERVICE (37 C.F.R. § 42.6(e)) ............................................ 65 
`
`
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`- iii -
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`Teva Pharmaceuticals International GmbH (“Teva”) submits this Patent
`
`Case IPR2018-01426
`Patent No. 9,890,211
`
`
`
`
`Owner Response to the Petition for Inter Partes Review (“IPR”) of U.S. Patent No.
`
`9,890,211 filed by Eli Lilly and Company (“Lilly”). Teva’s Response is supported
`
`by the expert declarations of Michel Ferrari, Ian Tomlinson, Steven Foord, Alan
`
`Rapoport, and Robert Stoner. EX2214, ¶¶4-11; EX2226, ¶¶4-9; EX2232, ¶¶4-13;
`
`EX2237, ¶¶4-11; EX2243, ¶¶1-4. This filing is timely under 35 U.S.C. §§ 311-19
`
`and 37 C.F.R. § 42.120.
`
`I.
`
`Introduction
`The challenged claims recite novel humanized anti-Calcitonin Gene-Related
`
`Peptide (“CGRP”) antagonist1 antibodies useful in the treatment of various
`
`vasomotor-related ailments, including migraine. Patent Owner Teva’s discovery
`
`was a breakthrough, representing the first time that anyone, anywhere in the world
`
`developed a humanized anti-CGRP antibody that could successfully be used as a
`
`human therapeutic. As a result, Teva’s Ajovy® (fremanezumab-vfrm)—the first
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`commercial embodiment of the challenged patent claims—when approved, was the
`
`
`1 Antagonism is achieved when a molecular blocker inhibits receptor
`
`signaling. EX2232, ¶21.
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`
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`- 1 -
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`
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`first and only anti-CGRP drug to be licensed for use in humans.2 Confronted with
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`Case IPR2018-01426
`Patent No. 9,890,211
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`the pioneering nature of Teva’s invention, Lilly resorts to hindsight to build its
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`faulty obviousness case.
`
`In deciding to institute this trial, the Board accepted Lilly’s allegations that a
`
`skilled artisan (“POSA”3) would have been motivated to humanize a murine anti-
`
`CGRP antibody for therapeutic use in humans based on Tan 1995—a basic
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`laboratory research paper attempting to “prob[e] the role of CGRP as an
`
`endogenous vasodilator” in rats. EX1022, Abstract. At the time of institution, the
`
`Board had a limited record before it reflecting Lilly’s one-sided rendition of the
`
`facts. However, as shown in this Response, Lilly’s arguments suffer from multiple
`
`flaws and missing steps that defeat its obviousness case. Upon consideration of the
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`full record presented in Teva’s responding papers, the Board may, as it has done in
`
`other instances, find that substantial evidence exists to revisit and reverse its
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`preliminary determination that was based on a limited record. See Apotex Inc. et.
`
`al. v. Novartis AG, IPR2017-00854, Paper 109, 19, 23-24 (PTAB July 11, 2018).
`
`Lilly failed to show that, as of November 2005, a POSA had reason to humanize an
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`2 Ajovy® is indicated for the preventive treatment of migraine in adults.
`
`EX2168, 1.
`
`3 Teva adopts the Board’s definition of a POSA. See Decision, 7-9.
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`
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`anti-CGRP antibody for “therapeutic use” because the record evidence does not
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`Case IPR2018-01426
`Patent No. 9,890,211
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`demonstrate that a POSA would have viewed an anti-CGRP antibody as
`
`sufficiently safe or effective in humans. Whereas the Board credited Tan 1995’s rat
`
`saphenous nerve assay as “encouraging” investigation into the use of a full-length
`
`antibody such as C4.19 (Decision, 29), during cross-examination, Lilly’s expert
`
`Dr. Vasserot admitted that key results with the full-length antibody C4.19 “cannot
`
`be statistically evaluated.” and that he would take these results “with caution” and
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`“would need to repeat” the assay. EX2191, 118:12-119:1. Teva’s expert Dr. Foord
`
`agrees, explaining there is no “encouragement,” only doubt, because of these
`
`shortcomings in Tan 1995. EX2232, ¶¶49, 52-55. The only expert to disagree is the
`
`one who is least qualified to opine on this matter—Lilly’s clinician expert, Dr.
`
`Andrew Charles; a treating physician with admittedly no experience in developing
`
`any therapeutic antibodies, let alone an anti-CGRP antibody. EX2192, 85:14-18.
`
`Lilly’s and Dr. Charles’s contentions are premised entirely on misreading Lilly’s
`
`cited references.
`
`For example, Dr. Charles states that Tan 1995 “provides guidance to a
`
`POSA to use anti-CGRP antagonist antibodies, including full-length antibodies, to
`
`treat vasomotor symptoms, which include migraine.” EX1012, ¶124. This is an
`
`unsupported mischaracterization: Tan has nothing to do with humans or treatment
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`of any conditions whatsoever, as Lilly’s experts admit. EX2191, 122:16-123:13;
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`Case IPR2018-01426
`Patent No. 9,890,211
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`EX2192, 154:21-156:9. It is a basic research paper, which unambiguously reported
`
`that full-length anti-CGRP antibodies failed to show any immunoblockade in a rat
`
`saphenous nerve assay with a full-length mouse antibody. EX2232, ¶52; EX2226,
`
`¶¶10-11, 66, 86-88; EX2214, ¶¶60-61. Similarly, Dr. Charles proclaims that
`
`“Wimalawansa states that humanized anti-CGRP antibodies ‘should’ be developed
`
`and used.” EX1012, ¶61. But Wimalawansa says nothing of the sort, instead
`
`explicitly informing a POSA that “[c]learly, more data from carefully designed
`
`studies are necessary before … humanized anti-CGRP monoclonal antibodies …
`
`can be evaluated as therapeutic agents.” EX1096, 567; EX2226, ¶¶80-85; EX2232,
`
`¶59. Notably, Lilly has not shown that such data existed prior to Teva’s invention.
`
`Ultimately, when confronted on cross-examination, Dr. Charles admitted
`
`that these were “his interpretations” of the references, and that he didn’t even know
`
`whether humanizing Tan’s anti-CGRP antibody would make an antibody within
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`the scope of a claim challenged in these IPR proceedings (claim 1 of related U.S.
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`Patent No. 9,890,210 which claims a full-length humanized anti-CGRP
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`monoclonal antibody). EX2192, 154:18-20. The Board, accordingly, should give
`
`little or no weight to Dr. Charles’s and Lilly’s unsupported “interpretations.”
`
`Moreover, Lilly’s motivation arguments fail because they hang entirely on
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`alleged efficacy—that a POSA reading Tan 1995 would somehow conclude that
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`Case IPR2018-01426
`Patent No. 9,890,211
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`anti-CGRP antibodies would be successful at treating human diseases, such as
`
`migraine, and, thus, would have been motivated to humanize a murine antibody,
`
`such as disclosed in Tan. This is an extreme and unsupported conclusion.
`
`In contrast, the principal conclusions of Tan 1995 were far more prosaic; a
`
`Fab’ fragment was advantageous over IgG in immunoblockade studies, and the
`
`results supported the role of CGRP in mediating skin vasodilation. EX1022,
`
`Abstract; EX2232, ¶51. But even if Lilly was right that Tan 1995 somehow
`
`suggests efficacy in using such compounds to treat, e.g., migraine, Lilly’s Petition
`
`still ignores the very important question of whether a POSA would have expected
`
`the use of anti-CGRP antibodies to treat humans to be safe. To prove motivation to
`
`humanize the anti-CGRP antibody based on the potential for human therapeutic
`
`use, as Lilly argues, requires both efficacy and safety. See, e.g., EX2226, ¶¶43-58,
`
`60. Yet on the issue of safety, Lilly says nothing.
`
`Lilly’s silence should not be surprising because record evidence firmly
`
`undercuts Lilly’s argument that a POSA, aware of the potential for substantial
`
`safety risks, would nevertheless have pursued using anti-CGRP antibodies in
`
`humans. The record shows that a POSA would have expected anti-CGRP
`
`antibodies to eliminate CGRP’s vasoprotective role, potentially leading to
`
`
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`significant cerebrovascular and cardiovascular consequences during, e.g., ischemic
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`Case IPR2018-01426
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`attacks. EX2214, ¶¶12, 27-66. Indeed, Lilly’s principal reference, Tan 1995,
`
`illustrates this very concern by reporting an increase in blood pressure in
`
`experimental rats upon removing CGRP’s vasoprotective role. EX1022, Figures 2
`
`and 3; EX2232, ¶¶79-80; EX2214, ¶51. Moreover, Lilly’s expert Dr. Charles
`
`admitted that patients presenting with migraine exhibit a higher incidence of
`
`cerebrovascular and cardiovascular co-morbidities, e.g., risk of stroke, heart attack,
`
`and hypertension. EX2192, 116:13-21. In such patients, the sustained (i.e., weeks
`
`to months) vasoconstrictive effects of an anti-CGRP antibody, particularly given
`
`its long half-life, could be catastrophic. EX2214, ¶¶55-59; EX2232, ¶¶77, 81.
`
`Contrary to Lilly’s suggestion, the Olesen reference would not have
`
`assuaged these concerns over safety. EX2214, ¶22; EX2232, ¶¶83-95. Olesen
`
`describes using a small-molecule receptor antagonist BIBN4096BS, not a CGRP
`
`antagonist antibody as claimed. EX1025, Abstract; EX2232, ¶84. And, per
`
`Olesen’s own admission, the study did not assess cardiovascular safety of
`
`BIBN4096BS, and it is silent on cerebrovascular safety. EX1025, 1109. Thus,
`
`questions of cardiovascular safety remained unanswered. And BIBN4096BS has a
`
`half-life of hours, whereas an anti-CGRP antibody has a half-life on the order of
`
`about a month, meaning much longer exposure to cardiovascular and
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`cerebrovascular side-effects. EX2232, ¶84; EX2226, ¶¶60-71; EX2214, ¶62, 68.
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`Case IPR2018-01426
`Patent No. 9,890,211
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`And there are material differences between receptor and ligand antagonism that
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`would have further diminished the value a POSA would have drawn from Olesen
`
`vis-à-vis cardiovascular and cerebrovascular safety of anti-CGRP antibodies.
`
`EX2232, ¶¶85-95; EX2226, ¶¶73-75; EX2214, ¶¶67-70.
`
`When accounting for safety, Lilly’s alleged therapeutic motivation begins to
`
`unravel. As Lilly’s expert Dr. Vasserot admitted, a POSA would have needed to
`
`see much more in the way of safety and efficacy beyond what Tan disclosed before
`
`having any meaningful reason to embark on the costly and burdensome endeavor
`
`to humanize a murine anti-CGRP antibody. EX2191, 65:2-71:19, 75:4-13; 97:15-
`
`106:19. This is exactly what Wimalawansa, Lilly’s second primary reference, says:
`
`“Clearly, more data from carefully designed studies are necessary before any
`
`definitive conclusions can be reached and before CGRP antagonist, humanized
`
`anti-CGRP monoclonal antibodies, or both, can be evaluated as therapeutic agents
`
`in humans.” 4 EX1096, 567.
`
`Likewise, nothing on the record Lilly advanced gave a POSA a reasonable
`
`expectation of humanizing an anti-CGRP antibody to provide therapeutic benefit
`
`that outweighed the substantial expected cerebrovascular and cardiovascular risks.
`
`
`4 Emphasis added throughout unless otherwise noted.
`
`
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`Lilly instead repeatedly relies upon data related to a small-molecule CGRP
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`Case IPR2018-01426
`Patent No. 9,890,211
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`receptor antagonist. But Lilly’s reliance on data relating to small-molecule
`
`receptor antagonism as a proxy for ligand antagonism with an antibody is fraught
`
`with holes, as explained by Drs. Foord and Dr. Tomlinson, and is insufficient to
`
`prove obviousness. EX2232, ¶¶83-95; EX2226, ¶¶72-76.
`
`Lilly’s petition also fails to prove that a POSA would have been motivated
`
`to arrive at an antibody having the claimed binding affinity (KD). As Dr.
`
`Tomlinson explains, Tan 1994’s radioimmunoassay (RIA) was not designed in a
`
`manner draw conclusions regarding affinity. EX2226, ¶¶104-109. RIA allows for
`
`estimating the KD of the antibody to the ligand only when the radiolabelled and
`
`unlabeled ligands are the same. Id. But Tan 1994 did not use the same ligands: he
`
`attempted to displace radiolabelled human CGRP with unlabeled rat CGRP,
`
`and did so at 4 ºC, not 37 ºC as claims. EX1021, 704-705. Dr. Charles admits,
`
`human and rat CGRPs are not the same. EX1012, ¶18. And Dr. Vasserot
`
`confirms that differences in amino acids and in temperature matter. EX2191,
`
`154:21-156:12, 165:19-157:10. When different ligands are used in an RIA, like in
`
`Tan 1994, there is no way to independently measure the interaction between each
`
`ligand and the antibody. EX2226, ¶¶106-107. Therefore, the 1.9 and 2.5 nM values
`
`for anti-CGRP antibodies that Lilly relies on are, in fact, not instructive to a POSA.
`
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`Id., ¶107.
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`Case IPR2018-01426
`Patent No. 9,890,211
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`Finally, multiple objective indicia provide real-world, corroborating
`
`evidence that Teva’s invention was not obvious. Lilly’s arguments ignore the long-
`
`standing admonition that inventions should be viewed as real problems solved by
`
`real people, and that patent validity is not a game played with “pieces of paper.”
`
`Rosemount, Inc. v. Beckman Instruments, Inc., 727 F.2d 1540, 1544 (Fed. Cir.
`
`1984). Lilly’s assertion that its four-reference combination would have rendered
`
`Teva’s groundbreaking compounds obvious to a POSA is directly contradicted by
`
`real world facts, which couldn’t be summed up any better than Lilly’s own expert’s
`
`statement, made outside the context of this case: “The notion that we would be
`
`using antibodies to treat migraine is really quite a radical concept.” EX2053, 23.
`
`Dr. Charles was quoted as saying this in 2018 when speaking about anti-CGRP
`
`antibodies in the real world, well over a decade after Teva’s invention. If Teva’s
`
`invention were obvious in 2005, as Lilly contends, Dr. Charles would not be
`
`calling it “radical” in 2018. Teva’s patent claims should be upheld.
`
`II. Background
`A. Calcitonin Gene-Related Peptide (“CGRP”)
`Calcitonin gene-related peptide (“CGRP”) is a 37-amino acid
`
`neurotransmitter belonging to a family of peptides that include calcitonin,
`
`adrenomedullin, and amylin. EX2232, ¶¶22-24; EX1022, 569-570; EX2003, 904-
`- 9 -
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`905. CGRP is expressed as two isoforms, α- and β-CGRP, which have similar
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`Case IPR2018-01426
`Patent No. 9,890,211
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`activities but differential distribution. EX2232, ¶22; EX2003, 905; EX2008, 153.
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`CGRP is “the most potent vasodilating substance known” and is “distributed
`
`throughout the central and peripheral nervous systems.” EX2003, 905-906;
`
`EX2232, ¶23.
`
`In 2004, researchers believed that CGRP interacted with receptors that are
`
`widely distributed throughout the body, including in the gastrointestinal tract,
`
`thyroid gland, pituitary, adrenals, kidneys, bones, skin, skeletal muscles, and
`
`cardiovascular, peripheral nervous and central nervous systems. EX1031, 317, 318,
`
`320; EX1096, 539; EX2232, ¶22; EX2003, 904.
`
`Because of its potent vasodilation properties, CGRP plays a “pivotal role” in
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`the “physiology and pathophysiology of cardiovascular regulation.” EX2003, 923;
`
`EX2232, ¶23; EX2003, 923. By 2005, CGRP was known to be involved in the
`
`long-term regulation of resting blood pressure, protecting against development of
`
`hypertension, and preventing escalation of mild ischemic event into full-blown
`
`infarctions, like stroke and heart attacks. EX2226, ¶¶64-65, 69-70; EX2214, ¶¶36-
`
`41; EX2232, ¶74; EX2058, Abstract; EX2150, 503; EX2164, 174; EX2151;
`
`EX2079, Abstract; EX2003, 919; EX2009, 614-615; EX1035, 293; EX2019, 139.
`
`The’211 patent and its commercial embodiments
`
`B.
`The art at the time of Teva’s invention was focused on investigating
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`
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`blocking the CGRP receptors, not antagonizing the CGRP ligand itself. EX2232,
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`Case IPR2018-01426
`Patent No. 9,890,211
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`¶¶57-59. For example, Wimalawansa—one of Lilly's primary references—
`
`provided a summary of literature exclusively dealing with tissue-specific CGRP
`
`receptors. EX1096, 545-568. In describing the ideal “CGRP antagonist” for
`
`treating migraine, Wimalawansa stated: the compound “should be a peptide
`
`mimetic of simple structure specific to cardiovascular CGRP receptors, so that the
`
`drug can be given orally, buccally, or sublingually,” and “the antagonist must be
`
`extremely specific to the CGRP receptors located in cerebral arteries to avoid
`
`potential deleterious side effects caused by blocking other vascular and
`
`nonvascular CGRP receptors.” Id., 568. And Wimalawansa specifically cited
`
`adverse events as the reason for focusing on tissue specific receptors (as opposed
`
`to ligand antagonists): “[s]ome of the potential side effects of CGRP antagonists
`
`could possibly be minimized by being designed specifically to act on only one
`
`subtype of receptor.” Id., 567.
`
`Against this backdrop, and in contrast to the conventional thinking at the
`
`time, the inventors of the ’211 patent developed humanized monoclonal anti-
`
`CGRP antagonist antibodies, pivoting away from 1) CGRP receptor antagonism; 2)
`
`small molecule or even peptide-based CGRP receptor antagonists; and 3) oral
`
`administration. These inventors demonstrated, for the first time, the therapeutic
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`value of a humanized monoclonal anti-CGRP antagonist antibody by showing
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`Case IPR2018-01426
`Patent No. 9,890,211
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`activity in a therapeutically-relevant headache model. EX1001, 70:12-58. Teva’s
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`Ajovy® and Lilly’s Emgality® fall within the challenged claims, and each has
`
`satisfied a long-felt need, enjoyed industry-wide acclaim, and captured a
`
`significant portion of the migraine market within just a few months of approval.
`
`See §VI.
`
`The USPTO rightly awarded the inventors the ’211 patent for their
`
`innovative contribution. Lilly’s petition has not justified why this Board should
`
`reverse that decision, and strip the inventors of what they rightfully earned.
`
`ARGUMENT
`
`It is well-settled, “[a] patent composed of several elements is not proved
`
`obvious merely by demonstrating that each of its elements was, independently,
`
`known in the prior art.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007).
`
`Rather, obviousness requires proof that a POSA would have had (1) reason to
`
`combine the references to solve a real-world problem by making the claimed
`
`invention; and (2) a reasonable expectation of success in doing so. Institut Pasteur
`
`v. Focarino, 738 F.3d 1337, 1346 (Fed. Cir. 2013).
`
`Lilly has failed to establish either prong of obviousness.
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`III.
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`Case IPR2018-01426
`Patent No. 9,890,211
`
` A POSA would not have had a reason to humanize anti-CGRP
`antibodies as of 2005
`A. Lilly’s reasons to combine the art as claimed are based on
`“therapeutic use in humans” of humanized anti-CGRP antibodies
`
`Lilly predicates its obviousness ground on a POSA being motivated to
`
`develop a humanized anti-CGRP antibody for human therapeutic use. Lilly
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`repeatedly emphasizes CGRP’s role in human diseases. For example, Lilly states
`
`“CGRP has powerful vasodilatory effects that, by 2005, had been directly linked to
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`various human diseases;” and that “[a]nti-CGRP antibodies were well known in
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`the art and had been disclosed for therapeutic use in humans.” Petition, 12-13.
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`Lilly’s alleged reason to combine references stems from the “clinical value” of
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`anti-CGRP antibodies, e.g., “to treat human diseases and conditions.” Id., 25-28.
`
`Lilly states the prior art “provided express motivation to prepare a humanized anti-
`
`CGRP antagonist antibody against human CGRP suitable for administration to
`
`humans,” and that “[t]hese factors would have motivated a POSA to make an anti-
`
`CGRP antagonist antibody that binds human CGRP for therapeutic uses.” Id., 25-
`
`28. Further, Lilly also highlights that Wimalawansa “proposes using humanized
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`anti-CGRP monoclonal antagonistic antibodies as therapeutic agents for CGRP-
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`related diseases.” Id., 24. The Petition’s very reason for humanizing a murine
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`antibody is to retain “the antibody’s therapeutic utility” “in humans” by
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`minimizing “the risk of immunogenicity.” Id., 33.
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`Moreover, Lilly especially focuses on migraine, asserting “the prior art had
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`Case IPR2018-01426
`Patent No. 9,890,211
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`expressly proposed generating humanized anti-CGRP antagonist antibodies for
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`treating human diseases such as migraine and other conditions [and] validated
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`blocking the CGRP pathway as a therapeutic target for treating diseases and
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`conditions such as migraine ….” Id., 29. Also, “[b]y November 14, 2005, the art
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`recognized th[ese] general principle[s] and described anti-CGRP antagonist
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`antibodies for treating migraine.” Id., 28. Lilly’s expert, Dr. Charles, an expert in
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`“treating patients with migraine and other neurological diseases,” admitted that
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`migraine was part of Lilly’s motivation argument during cross examination: “Q. Is
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`understanding of migraine relevant to designing anti-CGRP antibodies? A. Yes.”
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`EX2192, 73:6-74:11; see also EX1012 ¶¶3, 12, 104-105, 107-108, 111, 114. Dr.
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`Vasserot too relies on migraine as motivation. EX1013, ¶¶85-86, 96, 138; EX2232,
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`¶¶61-68. Lilly cannot now retreat from its “therapeutic use in humans” motivation
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`rationale and argue that a POSA simply would have had just any reason to
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`humanize a murine anti-CGRP antibody.
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`Finally, the Federal Circuit typically considers the specific therapeutic utility
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`of a chemical/pharmaceutical compound, even when such utility is not recited in
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`the claims. Otsuka Pharm. Co. Ltd. v. Sandoz Inc., 678 F.3d 1280, 1291 (Fed. Cir.
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`2012). The claims in Otsuka were directed to carbostyril compounds the
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`specification described as useful antipsychotics to treat schizophrenia. In assessing
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`Patent No. 9,890,211
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`obviousness, the Federal Circuit highlighted that “[t]here were no carbostyril
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`compounds that were … known to have potent antipsychotic activity with minimal
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`side effects. Carbostyrils were thus not plausible lead compounds, except in
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`retrospect.” Id., 1293. Similarly, the utility of the claimed antibody must be
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`considered here, namely “preventing or treating CGRP associated disorders such as
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`vasomotor symptoms, including headaches (e.g., migraine, cluster headache, and
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`tension headache) and hot flushes.” EX1001, Abstract. Lilly agrees. Petition, 4.
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`And when utility is considered, it is readily apparent that Lilly failed to
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`demonstrate obviousness.
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`B.
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`Lilly mischaracterizes what the cited art would have conveyed to
`the POSA
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`Lilly vastly overstates what a POSA would have allegedly understood about
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`anti-CGRP antibodies from Tan 1995 and Wimalawansa. As explained below,
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`neither of those references, nor the art as a whole, provided any reason to a POSA
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`to pursue an anti-CGRP antagonist antibody for human therapeutic use. EX2232,
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`¶59-60, 82-83; EX2226, ¶¶79-100; EX2214, ¶¶60-64, 71-77.
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`1.
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`Tan 1995 provided no “guidance” about treating vasomotor
`symptoms with anti-CGRP antibodies in humans
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`Tan 1995 is a basic science pharmacology paper that draws no therapeutic or
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`clinical conclusions. EX2232, ¶50; EX2214, ¶¶60-64; EX2226, ¶¶86-88. The
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`authors intended simply “to investigate immunoblockade as an alternative strategy
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`for probing the role of CGRP as a vasodilator in vivo.” EX1022, Abstract. Thus,
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`Tan 1995 was trying to elucidate CGRP’s role in vasodilation in an experimental
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`animal; not whether an anti-CGRP antibody could be safely developed for human
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`therapeutic use. EX2232, ¶50; EX2214, ¶61. Lilly and its expert Dr. Charles
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`grossly mischaracterize Tan 1995 by arguing that it provides “guidance to a POSA
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`to use anti-CGRP antagonist antibodies, including full-length antibodies, to treat
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`vasomotor symptoms, which include migraine.” EX1012, ¶124;; EX2232, ¶53. But
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`nothing in Tan 1995 has anything to do with humans, treatments, or dosing.
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`Indeed, Lilly’s expert Dr. Vasserot admitted that Tan 1995 is silent as to “specific
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`human diseases” or “efficacy of administering an anti-CGRP antagonist antibody
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`to humans to treat a disease.” EX2191, 122:16-123:13. And Dr. Charles could not
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`show otherwise. EX2192, 182:21-183:12. The evidence simply does not support
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`Lilly’s assertion that Tan 1995 teaches use of anti-CGRP antibodies in humans, let
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`alone provides “guidance” on how to use them to treat human diseases, and
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`migraine in particular.
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`2.
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`Lilly’s experts internally disagree on what the cited art
`discloses
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`Given the liberties Dr. Charles takes in interpreting the prior art, it is
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`unsurprising that Lilly’s other expert, Dr. Vasserot, disagrees with his opinions.
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`For example, Dr. Charles asserts that “the full-length antibody showed a 16%
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`reduction in skin blood flow using a two hour incubation period and slightly higher
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`dose” in a saphenous nerve assay. EX1012, ¶134. But he bases his opinion on Tan
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`1995’s ambiguous statement that further nerve stimulation with longer incubation
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`time of a full-length anti-CGRP antagonist antibody “produced an AUC which was
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`slightly smaller compared with baseline stimulation, but not by more than 16%
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`(n=2).” EX1022, 569. As Teva’s pharmacology expert, Dr. Foord explains, a
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`POSA would have understood that this result is not statistically significant given
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`the small sample size (n=2), and would have considered the result to be negative
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`(i.e., not effective). EX2232, ¶52. Tan acknowledged as much. EX1022, 517 (“the
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`results could not be evaluated statistically due to the inadequate sample sizes (n =
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`2).”). Dr. Tomlinson agrees. EX2226, ¶88. More notably, Lilly’s other expert, Dr.
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`Vasserot, also agreed with Teva’s experts on the significance of Tan 1995’s small
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`sample size. EX2191, 118:12-119:1. According to Dr. Vasserot, a POSA would
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`not have drawn any meaningful conclusion from Tan 1995’s “not more than 16%
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`(n=2)” statement; instead, Dr. Vasserot testified that these results are “something
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`that [he] would take with caution and would need to repeat.” EX2191, 118:21-
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`119:1.
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`Dr. Vasserot’s conclusions regarding Tan 1995 in his deposition do not align
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`with the motivations to humanize he gives in his declaration. But during his
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`deposition, it came to light that Dr. Vasserot’s declaration conclusions on the state
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`of the art for CGRP antibodies were based on erroneous facts Lilly’s attorneys
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`asked him to assume. For example, Lilly’s attorneys asked Dr. Vasserot to
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`presuppose key facts like “several research groups explored an antibody against
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`alpha CGRP as a treatment option for diseases such as migraine, psoriasis,
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`neurogenic inflammatory pain, and opiate withdrawal;” and that “several research
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`groups expressly suggested using an anti-CGRP antagonist antibody in treating
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`diseases such as migraine.” EX2191, 21:13-22:1; 22:22-23:5. Dr. Vasserot cited no
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`evidence to support these facts, and, when not being told what to say by his
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`attorneys5, Dr. Vasserot correctly acknowledged that Tan 1995 offered little insight
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`on the utility of an anti-CGRP antibody for treatment in humans. EX2191, 122:16-
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`123:15. That is a fundamental gap in Lilly’s argument, since its obviousness
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`ground is premised on the notion that a POSA would want to humanize a murine
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`anti