`
`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 IPR2018-01710
`U.S. Patent No. 8,586,045
`___________________
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH'S
`PRELIMINARY RESPONSE UNDER 37 C.F.R. § 42.107(a)
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`Case IPR2018-01710
`Patent No. 8,586,045
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`Introduction ..................................................................................................... 1
`CGRP, CGRP receptor antagonists, and the inventors' unorthodox switch to
`CGRP antagonist antibodies to treat headaches, including migraine ............. 5
`III. The Board should deny institution under 35 U.S.C. § 325(d) because the
`Petition is based on substantially the same prior art and arguments already
`considered by the USPTO ............................................................................ 12
`A.
`The same examiner reviewed the references or equivalents
`thereof
`and
`rejected Petitioner's
`arguments during
`prosecution of the '045 patent .............................................................14
`All of the Becton Dickinson factors strongly favor denying
`institution under § 325(d) ....................................................................16
`1.
`Each of the primary references—Olesen, Tan, and
`Queen—is the same or substantially the same as the
`art that was overcome during examination .............................. 16
`The asserted art was
`fully evaluated during
`examination and was the basis for rejection ............................ 22
`The Petition's prior art references are cumulative of
`the art evaluated during prosecution ........................................ 23
`The arguments in the Petition substantially overlap
`with the arguments considered during prosecution ................. 24
`Lilly offers no explanation for how the examiner erred
`during prosecution when evaluating the same art .................... 25
`Lilly provides no justification to reconsider the same
`art and arguments from prosecution ........................................ 27
`IV. Petitioner failed to establish a reasonable likelihood of prevailing as to any
`challenged claim ........................................................................................... 28
`A.
`Claim construction ..............................................................................29
`1.
`"reducing incidence of or treating" .......................................... 30
`2.
`"effective amount" ................................................................... 31
`Person of ordinary skill in the art ........................................................32
`Lilly should be held to its Olesen, Tan, and Queen
`obviousness combination ....................................................................33
`Lilly does not demonstrate why a POSA would have been
`motivated to treat migraine with anti-CGRP antibodies .....................34
`1.
`Lilly's argument that a POSA would have understood
`Olesen's results to extend beyond the small molecule
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`B.
`
`B.
`C.
`
`D.
`
`- i -
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`

`

`2.
`
`3.
`
`2.
`
`E.
`
`F.
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`Case IPR2018-01710
`Patent No. 8,586,045
`CGRP-receptor antagonists is wrong in view of a
`plain reading of Olesen ............................................................ 36
`Lilly fails to show a motivation to target CGRP
`instead of CGRP receptors for treating migraine .................... 39
`Lilly fails to show motivation to treat migraine with
`anti-CGRP antibodies .............................................................. 44
`Lilly does not demonstrate why a POSA would have
`humanized Tan's full-length antibody to treat migraine .....................46
`1.
`Tan did not establish
`that C4.19 antagonized
`endogenous CGRP; a critical prerequisite to Lilly's
`argument that is missing for motivation .................................. 49
`Lilly fails to address why a POSA would not expect
`Tan's negative result to also apply to other full-length
`anti-CGRP antibodies .............................................................. 53
`Lilly has also failed to meet its burden with respect to its
`challenge of claim 1 ............................................................................57
`The Petition entirely fails to address motivation to humanize
`the Fab' fragment of Tan .....................................................................58
`1.
`The Petition omits a motivation, and indeed argues
`against any motivation, to humanize a Fab' fragment ............. 59
`Lilly's evidence submitted with its Petition does not
`support a motivation to humanize a Fab' fragment .................. 60
`Lilly's near-simultaneous
`invention
`theory
`is neither
`supported by the facts nor the law .......................................................61
`Conclusion .................................................................................................... 63
`
`G.
`
`2.
`
`H.
`
`V.
`
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`Case IPR2018-01710
`Patent No. 8,586,045
`Patent Owner Teva Pharmaceuticals International GmbH ("Patent Owner")
`
`provides this preliminary response to Petitioner Eli Lilly and Company's ("Lilly")
`
`petition for inter partes review of claims 1, 3, 4, 8-17, 19, 20, and 24-31 of U.S.
`
`Patent No. 8,586,045 ("the '045 patent"; EX1001) in accordance with 37 C.F.R.
`
`§ 42.107(a).
`
`I.
`
`Introduction
`
`In this proceeding, Lilly wants to cancel Teva's patent claims protecting its
`
`groundbreaking methods of using humanized monoclonal anti-CGRP antagonist
`
`antibodies to treat headache, including migraine1. Yet Lilly's entire effort to cancel
`
`as obvious claims to something that it once itself thought worthy of patenting is
`
`troubling. See EX1127. Until the present inventors' contribution, the early-stage
`
`therapeutic focus for CGRP receptor-mediated disorders was on CGRP receptor
`
`antagonism, and the antagonist development focused on small molecule receptor
`
`antagonists, such as BIBN4096BS. EX1025. Before the present inventors filed
`
`1 Claim 1 is directed to treating any vasomotor symptom, and is not specific
`
`to migraine. EX1001. However, Lilly's arguments against claim 1 rely on migraine
`
`treatment. Petition, 49-50. To the extent that Lilly offers an additional reason as to
`
`why a POSA would have been motivated to use an anti-CGRP antagonist antibody
`
`"to reduce incidence of or treat skin vasodilation" (Petition, 50), Lilly's argument
`
`also fails, for the reasons described below.
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`Case IPR2018-01710
`Patent No. 8,586,045
`their patent applications, to the extent that antibodies to CGRP were used, it was as
`
`research tools to answer basic science questions related to, for example, receptor-
`
`ligand interaction. That Lilly now turns to those same research tools as a basis for
`
`its obviousness challenge contradicts its own contemporaneous efforts to seek
`
`patent protection for methods of using anti-CGRP antibodies to treat migraine. See
`
`EX1127.
`
`To be instituted, an IPR petition must establish a reasonable likelihood that it
`
`could prevail against at least one challenged claim. Lilly's Petition fails to meet this
`
`requirement here for multiple separate and independent reasons, any one of which
`
`compels denial of institution. This Board routinely exercises its discretion under 35
`
`U.S.C. § 314(a) and 37 C.F.R. § 42.5 to deny institution when it determines, as it
`
`should here, that a petitioner fails to demonstrate a reasonable likelihood of
`
`prevailing on at least one challenged claim. See Apple Inc. v. ContentGuard
`
`Holdings, Inc., IPR2015-00355, Paper 9 at 15-16 (PTAB June 26, 2015).
`
`As a threshold matter, institution should be denied under 35 U.S.C. § 325(d)
`
`because Lilly's Petition does no more than attempt to resurrect the same or
`
`substantially the same prior art and arguments that were previously before the
`
`examiner during prosecution and were overcome. What's more, each of the primary
`
`references in the challenged ground were either already squarely before the
`
`examiner, or are cumulative to references raised and overcome during prosecution,
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`Case IPR2018-01710
`Patent No. 8,586,045
`and the Petition does not sufficiently demonstrate that the examiner somehow erred
`
`in evaluating those references. Thus, the Board need not, and indeed should not,
`
`waste valuable resources second-guessing the examiner without any adequate
`
`justification.
`
`Setting aside that the Board can and should deny institution here under its
`
`§ 325(d) discretion, Lilly's Petition independently deserves denial because it fails
`
`to make the necessary threshold showing of a reasonable likelihood that any
`
`challenged claim is unpatentable as obvious over the cited references. Lilly's
`
`failure, as discussed in more detail below, stems from multiple deficiencies, any
`
`one of which can independently sustain denying institution.
`
`First, the Petition does not establish that a POSA would have been
`
`motivated to 1) target CGRP, and not CGRP receptors, to treat migraine, and 2)
`
`use anti-CGRP antagonist antibodies for this purpose. Lilly's lead reference,
`
`Olesen (EX1025), tested a small molecule CGRP-receptor antagonist to treat
`
`migraine. Lilly's central premise is that Olesen's single clinical experiment with a
`
`small molecule CGRP receptor antagonist would have somehow motivated a
`
`POSA to treat migraine by targeting CGRP itself, instead of its receptors, with an
`
`antibody, instead of a small molecule. But the plain language of Olesen simply
`
`does not support Lilly's argument; the inquiry should end here.
`
`Unable to support its central premise with Olesen, Lilly is forced to
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`Case IPR2018-01710
`Patent No. 8,586,045
`supplement Olesen with eleven additional references, and even still Lilly's efforts
`
`fail. Lilly argues that targeting CGRP itself, instead of its receptors, would have
`
`been therapeutically advantageous (Petition, 28), but the evidence fails to support
`
`this conclusion. The overwhelming focus in the art was on small molecule
`
`antagonists of the CGRP receptor. What is more, Lilly does not reconcile its
`
`alleged reasons to antagonize CGRP with the teachings in the art of the potential
`
`dangers associated with indiscriminately targeting CGRP. EX1096, 543; EX2003,
`
`904. Thus, Lilly fails to show that a POSA would have been motivated to target
`
`CGRP to treat migraine.
`
`Lilly also fails to demonstrate that a POSA would have used anti-CGRP
`
`antagonist antibodies to treat migraine. Indeed, the art proffered by Lilly either
`
`does not teach using anti-CGRP antagonist antibodies for treating migraine, or
`
`does not show that anti-CGRP antagonist antibodies could engage with CGRP at
`
`its site of action so that they can be useful to treat migraine. EX1022, EX1033,
`
`EX1055; EX1026; EX1027; EX1028. Thus, Lilly also fails to show that a POSA
`
`would have treated migraine with an anti-CGRP antagonist antibody.
`
`Second, the Petition does not, as it must under settled law, provide a
`
`sufficient reason why a POSA would have specifically modified Tan's full-length
`
`C4.19 antibody. Indeed, any reason is belied by Tan itself, which failed to show
`
`that the full-length antibody could engage with the target peptide at its site of
`
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`Case IPR2018-01710
`Patent No. 8,586,045
`action, and made no suggestion of a therapeutic use. Lilly ignored these facts in its
`
`petition, and did not articulate any credible reason that would have motivated a
`
`POSA to disregard these teachings in Tan and proceed to humanize Tan's full-
`
`length C4.19. Lilly relies instead on supposition.2 On its face, this omission
`
`exposes Lilly's textbook hindsight analysis. For any one of these reasons, the
`
`Board should deny institution.
`
`This Preliminary Response demonstrates that there is not a reasonable
`
`likelihood that the Petitioner would prevail on even one claim. Denial of institution
`
`is warranted.
`
`II. CGRP, CGRP receptor antagonists, and the inventors' unorthodox
`switch to CGRP antagonist antibodies to treat headaches, including
`migraine
`
`Calcitonin gene-related peptide ("CGRP") is a 37-amino acid
`
`neurotransmitter belonging to a family of peptides that include calcitonin,
`
`adrenomedullin, and amylin. EX2001, 1484. CGRP is expressed as two isoforms,
`
`α- and β-CGRP, which have similar activities but differential distribution. EX2002,
`
`326; EX2003, 906.
`
`In 2004, researchers believed that CGRP interacted with two receptors,
`
`CGRP1 and CGRP2, which are widely distributed throughout the body, including
`
`2 Notably, Lilly's Petition omits a reason, and supporting evidence, to
`
`humanize the other antibody in Tan: a Fab' fragment of C4.19.
`
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`Case IPR2018-01710
`Patent No. 8,586,045
`in the gastrointestinal tract, thyroid gland, pituitary, adrenals, kidneys, bones, skin,
`
`skeletal muscles, and cardiovascular, peripheral nervous and central nervous
`
`systems. EX1031, 317, 318 and 320; EX1096, 539.
`
`Based on its widespread distribution, among other things, the CGRP
`
`signaling pathway was implicated in conditions such as type II diabetes, sepsis, hot
`
`flushes and episodic sweating, and migraine. See, e.g., EX2003, 919-22; EX1096,
`
`559-68. In the 1990's and 2000's, researchers focused on developing antagonists to
`
`the CGRP receptors as potential therapeutic treatments, including for migraine and
`
`other vasomotor conditions. EX2012, 768, Abstract; EX2010, 2557, Abstract;
`
`EX2013, 1-6 and 51; EX1028, Abstract; EX2014, Abstract, 4:18-28; EX2015,
`
`1:19-2:54; and EX2016, Abstract.
`
`One of the first antagonists to the CGRP receptors, CGRP8-37, was identified
`
`in 1989. EX2004, E331; EX1024, 420; EX2003, 910. While able to block effects
`
`caused by CGRP, CGRP8-37 has a short half-life, limiting its use in vivo. EX1031,
`
`323; EX2003, 910. However, its ability to block CGRP-induced activity prompted
`
`other investigators to begin research programs into improved peptide and oral
`
`small molecule CGRP receptor antagonists that would have an affinity for the
`
`CGRP receptor similar to that of CGRP8-37, but with a longer half-life. See, e.g.,
`
`EX2012, 769; EX2017, 1:1-9:42; EX2014, Abstract; EX2015, 1:19-2:54; and
`
`EX2016, Abstract; EX2006, Abstract; EX2008, 153, Abstract.
`
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`Patent No. 8,586,045
`Indeed, at least five pharmaceutical companies had programs to develop
`
`small molecule CGRP receptor antagonists in the decade before the inventors'
`
`priority filing in November 2005 (EX2012, Abstract; EX2017; EX2014; EX2015;
`
`and EX2016):
`
`1) In 1997, Boehringer Ingelheim filed a patent application to the same
`
`small molecule CGRP receptor antagonist, BIBN4096BS (olcegepant),
`
`later reported in Olesen's clinical trial for migraine treatment. EX1024,
`
`420; EX2017. BIBN4096BS performed well in pre-clinical studies and
`
`ultimately eight clinical trials were performed, one for migraine.
`
`EX2021.
`
`2) In 1999, Merck Sharpe & Dohme filed a patent application to
`
`benzimidazolinylpiperidine derivatives, which are CGRP receptor
`
`antagonists. EX2014, Abstract. Merck later filed a patent application to
`
`MK-0974 (telcagepant), a small molecule CGRP receptor antagonist, and
`
`a method of using MK-0974 to treat headache, including migraine.
`
`EX2018, 2:65-3:2; 142:36-44; 131:30-135:12. Despite success during
`
`pre-clinical experiments and investigation in 16 clinical trials for
`
`migraine, Merck ultimately discontinued MK-0974. EX2022.
`
`3) In 2001, SmithKline Beecham published the results of a high-throughput
`
`screening of small molecule libraries to identify potential CGRP receptor
`
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`Case IPR2018-01710
`Patent No. 8,586,045
`antagonists because of their potential for use in, e.g., migraine. EX2012,
`
`770. With the optimization of a hit for CGRP receptor binding,
`
`SmithKline Beecham developed SB-273779, which is a selective CGRP
`
`receptor antagonist with an IC50 of approximately 200-300 nM. Id., 773.
`
`4) In 2004, Grunenthal GmbH filed a patent application on substituted
`
`cyclopentene compounds found to have "an elevated affinity for the
`
`CGRP receptor and are suitable as antagonists," and claimed methods of
`
`treating, inter alia, migraine, using such compounds. EX2015, 2:6-7;
`
`20:2-42; 23:60-63.
`
`5) In 2005, Bristol-Myers Squibb filed a patent application directed to
`
`bicyclic and tricyclic CGRP receptor antagonists and methods of using
`
`these compounds for migraine and other vasodilatory conditions.
`
`EX2016, Abstract. And a later-filed patent application by Bristol-Myers
`
`Squibb disclosed another CGRP receptor antagonist, BMS-927711
`
`(rimegepant). EX2020, 1:13-2:60. BMS-927711 showed promising
`
`results in the preclinical phase, and there have been 10 clinical trials with
`
`this drug for migraine. EX2023; EX2046.
`
`These exemplary references illustrate that between the 1990s and the mid-
`
`2000s, the overwhelming majority of pharmacological agents under clinical
`
`development targeted the CGRP receptors, similar to CGRP8-37, using non-peptide
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`Case IPR2018-01710
`Patent No. 8,586,045
`small molecules for treatment of migraine or other vasomotor symptoms.
`
`Well into the 2000's, the field was uniformly focused on developing small
`
`molecule antagonists to CGRP receptors as potential therapeutic treatments for
`
`numerous reasons. First, a POSA simply did not consider targeting CGRP, let
`
`alone using antibodies to CGRP, because the field's overwhelming focus was on
`
`developing orally administered, small molecule approaches to inhibit signaling
`
`pathways by binding to the CGRP receptor. See, e.g., EX1031, 326 ("The
`
`encouraging results obtained in a proof of concept study with BIBN4096BS,
`
`administered i.v., in the acute treatment of migraine holds significant promise to
`
`suggest that orally effective CGRP receptor antagonists will become available in
`
`the not too distant future."). Indeed, antibodies, as large molecules, could only be
`
`administered as non-oral formulations (injections) to patients.
`
`Second, researchers focused overwhelmingly on targeting CGRP receptors
`
`because they understood that blocking CGRP, one of the most potent vasodilators
`
`known (EX1031, 317-18; EX2003, 905 and 907), could cause systemic
`
`vasoconstriction and potential deleterious side effects on the cardiovascular
`
`system. EX1096, 568. In addition, researchers were concerned that blocking CGRP
`
`could cause cerebral vasoconstriction. EX2019, 140. There was also a concern that
`
`a CGRP antagonist could worsen other illnesses, such as Raynaud's disease,
`
`pulmonary hypertension, ischemia, or congestive heart failure, because it would
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`Case IPR2018-01710
`Patent No. 8,586,045
`decrease CGRP activity systemically. EX2003, 922. Indeed, studies of α-CGRP
`
`gene knockout mice showed that lack of α-CGRP could make the heart and
`
`kidneys more vulnerable to hypertension-induced organ damage. EX2011, 113.
`
`Thus, the art recognized that indiscriminately removing CGRP from the general
`
`circulation, as might be expected to result from administering anti-CGRP
`
`antagonist antibodies, could cause deleterious side-effects on other systems that
`
`were not the target of treatment.
`
`These were real-world concerns about the potential dangers associated with
`
`removing CGRP from the general circulation. And the real-world solutions offered
`
`before the '045 patent were those offered by, for example, Wimalawansa—a
`
`reference Lilly relies upon heavily in its arguments—which suggested targeting the
`
`CGRP receptors in a tissue specific manner. According to Wimalawansa, "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." EX1096, 568. Also, "[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., 5673. And as
`
`discussed above, Wimalawansa's view in 1996 was shared by the field. Targeting
`
`the ligand, CGRP, was not pursued as a pharmacological approach in part because
`
`3 Emphasis added throughout unless otherwise noted.
`
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`Case IPR2018-01710
`Patent No. 8,586,045
`of these safety concerns caused by the inability to antagonize with specificity.
`
`In contrast, the inventors here completely diverted from the path other
`
`researchers had followed, and instead 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. In doing so, the inventors demonstrated, for the first time, the
`
`therapeutic efficacy of a humanized monoclonal anti-CGRP antagonist antibody by
`
`showing activity in a therapeutically-relevant headache model. EX1001, 68:58-
`
`69:39. The inventors also demonstrated the efficacy of a humanized monoclonal
`
`anti-CGRP antagonist antibody compared to Olesen's BIBN4096BS small
`
`molecule CGRP receptor antagonist. Id., 69:39. Surprisingly, the inventors found
`
`that their anti-CGRP antagonist antibodies can not only access the relevant site of
`
`action, but also that they can do so in a sufficient concentration to inhibit CGRP
`
`activity with equivalent efficacy and far greater longevity compared to the small
`
`molecule antagonist for CGRP receptors, BIBN4096BS. Id.
`
`Recognizing the innovative contribution to the art, the USPTO has rightly
`
`awarded the inventors the '045 patent, along with several others, that are now
`
`before the Board in co-pending IPR proceedings.
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`Case IPR2018-01710
`Patent No. 8,586,045
`III. The Board should deny institution under 35 U.S.C. § 325(d) because the
`Petition is based on substantially the same prior art and arguments
`already considered by the USPTO
`
`As an initial matter, the Board should deny institution here even before
`
`turning to the merits of Lilly's obviousness challenge. Lilly's Petition improperly
`
`seeks to rehash the same or similar arguments and art that were already considered
`
`and overcome during prosecution. What's more, each of the primary references in
`
`Lilly's proposed ground—Olesen, Tan, and Queen—were either already squarely
`
`before the examiner, or are cumulative to references raised and overcome during
`
`prosecution. And the Petition does not sufficiently demonstrate that the examiner
`
`somehow erred in evaluating those references. Thus, the Board need not, and
`
`indeed should not, waste valuable resources second guessing the examiner without
`
`any adequate justification.
`
`Institution of inter partes review is discretionary. See Harmonic Inc. v. Avid
`
`Tech, Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) ("the PTO is permitted, but never
`
`compelled, to institute an IPR proceeding"). Under 35 U.S.C. § 325(d), the Board
`
`has broad discretion to deny a petition that raises substantially the same prior art or
`
`arguments previously presented to the Office. See, e.g., Microsoft Corporation v.
`
`Koninklijke Philips N.V., IPR2018-00279, Paper 11 at 8 (PTAB June 8, 2018); Neil
`
`Ziegman, N.P.Z., Inc., v. Carlis G. Stephens, IPR2015-01860, Paper 11 at 13
`
`(PTAB Feb. 24, 2016).
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`Patent No. 8,586,045
`In evaluating whether to exercise this discretion, the Board has weighed
`
`some common non-exclusive factors, such as: (1) the similarities and material
`
`differences between the asserted art and the prior art involved during examination;
`
`(2) the cumulative nature of the asserted art and the prior art evaluated during
`
`examination; (3) the extent to which the asserted art was evaluated during
`
`examination, including whether the prior art was the basis for rejection; (4) the
`
`extent of the overlap between the arguments made during examination and the
`
`manner in which Petitioner relies on the prior art or Patent Owner distinguishes the
`
`prior art; (5) whether Petitioner has pointed out sufficiently how the examiner
`
`erred in his evaluation of the asserted prior art; and (6) the extent to which
`
`additional evidence and facts presented in the Petition warrant reconsideration of
`
`the prior art or arguments. Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`
`IPR2017-01586, Paper 8 at 17-18 (PTAB Dec. 15, 2017).
`
`These Becton Dickinson factors weigh heavily against Lilly, and confirm
`
`that the Office has properly performed its job, already having thoroughly
`
`considered and nevertheless found the claimed subject matter patentable over
`
`substantially the same art and arguments as those raised in the Petition. Lilly
`
`provides no arguments as to any material differences between the asserted art and
`
`the prior art involved during examination; the cumulative nature of the asserted art
`
`and the prior art evaluated during examination; or the extent of the overlap
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`Case IPR2018-01710
`Patent No. 8,586,045
`between the arguments made during examination and the manner in which
`
`Petitioner relies on the prior art.
`
`The Board should exercise its discretion under 35 U.S.C. § 325(d) to deny
`
`institution for the following reasons:
`
`A. The same examiner reviewed the references or equivalents thereof and
`rejected Petitioner's arguments during prosecution of the '045 patent
`
`The '045 patent issued from U.S. Patent Application No. 13/179,846 ("the
`
`'846 application"), which claims priority to November 14, 2005, through a chain of
`
`applications and a provisional application as shown in the following family tree4.
`
`EX1001, EX2024-EX2032.
`
`
`4 This tree shows IPR proceedings involving patents in the '045 patent
`
`family.
`
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`Patent No. 8,586,045
`
`
`
`Examiners Saoud and Lockard examined all the applications in this family
`
`tree from the '045 patent onward. See, e.g., EX1001, EX2025-EX2032, face page.
`
`In addition, prosecution of parent applications is relevant to prosecution of a child
`
`application and is considered part of the file history of the child application.
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`Omega Eng'g, Inc., v. Raytek Corp., 334 F.3d 1314, 1333 (Fed. Cir. 2003), see
`
`also, Microsoft Corp. v. Multi-Tech Sys., Inc., 357 F.3d 1340, 1349 (Fed. Cir.
`
`2004). Thus, any arguments or art considered in related applications is applicable
`
`to the '045 patent; and Examiners Saoud and Lockard would have been familiar
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`with such arguments and art.
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`B. All of the Becton Dickinson factors strongly favor denying institution
`under § 325(d)
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`Lilly asserted, in a single, short paragraph, that the "evidence identified in
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`this Petition was either not before the examiner or not fully considered during
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`prosecution." Petition, 65. But Lilly's Petition addressed only Information
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`Disclosure Statements submitted during prosecution of the '045 patent. Moreover,
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`Lilly did not address how the teachings relied upon in the Petition are not
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`cumulative to those relied upon in rejections, discussed on the record, and
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`overcome during prosecution. Indeed, Lilly did not address any of the Becton
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`Dickinson factors, which, as shown below, weigh in favor of the Board exercising
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`its discretion to deny institution.
`
`1.
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`Each of the primary references—Olesen, Tan, and Queen—
`is the same or substantially the same as the art that was
`overcome during examination
`Olesen. While the examiner did not specifically cite Olesen, the examiner
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`nevertheless was aware of and considered the same disclosure from Olesen during
`
`prosecution. Lilly relies upon Olesen for its teaching that a small molecule CGRP-
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`Case IPR2018-01710
`Patent No. 8,586,045
`receptor antagonist BIBN4096BS could be used to treat migraine. Petition, 1, 14-
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`15, 24-26, 28, 31, 32-33, 37-38, 48, 57. But those disclosures were before the
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`examiner.
`
`Olesen's teachings that BIBN4096BS could be used to treat migraine was in
`
`front of the examiner in the form of the specification's extensive discussion of the
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`same teachings. For example, the '045 patent specification explicitly mentions
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`BIBN4096BS's effects on migraine: "[p]ossible CGRP involvement in migraine
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`has been the basis for the development and testing of a number of compounds that
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`... antagonize at the CGRP receptor (e.g., dipeptide derivative BIBN4096BS
`
`(Boehringer Ingelheim)." EX1001, 2:14-23. The '045 patent also provides data
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`relating to Olesen's disclosures, by way of Example 6, which compares the effects
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`of BIBN4096BS to an anti-CGRP antagonist antibody. Id., Example 6, Figure 9.
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`And the examiner was aware of these data, as seen by Applicant's discussion of
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`Example 6's use of anti-CRGP antagonists in a migraine model when responding to
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`an enablement rejection during the prosecution of the '045 patent. EX2034, 497.
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`Thus, the examiner already considered the knowledge in the art relating to using
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`small molecule inhibitors of CGRP-receptors to treat migraine. The teachings Lilly
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`relies upon from Olesen are not materially different.
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`Tan. During prosecution, Applicant submitted a complete copy of Tan to the
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`Office, and the examiner fully considered it at least in four different respects: First,
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`Case IPR2018-01710
`Patent No. 8,586,045
`Tan was cited in an IDS in every application throughout the priority chain of the
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`'045 patent (both parent and child applications). And, in every application, the
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`examiner considered Tan as evidenced by the examiner's filing of a copy of the
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`IDS with the examiner's signature and noting the date on which the cited references
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`were considered. EX2005, 295; EX2033, 442; EX2034, 480; EX2035, 212;
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`EX2036, 269; EX2037, 364; EX2038, 369; EX2039, 370; EX2040, 362; EX2041,
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`344; EX2042, 200; EX2043, 199; EX2044, 201; and EX2045, 212.
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`Second, as acknowledged in the Petition, Tan is cited multiple times in the
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`'045 specification. Petition, 7. For example, the '045 patent expressly cites Tan
`
`when acknowledging that "[a]nti-CGRP antagonist antibodies are known in the art.
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`See, e.g., Tan et al., Clin. Sci. (Lond). 89:565-73, 1995." EX1001, 25:59-61 (citing
`
`EX1022). Tan is again cited in Example 3, when describing the rat saphenous
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`nerve assay. See id., 55:55-58. There is no question that the examiner would have
`
`been aware of Tan's anti-CGRP antagonist antibodies and rat saphenous nerve
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`assay—the disclosures from Tan that are central to Lilly's challenge—when
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`reading the '045 specification.
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`Third, Tan was squarely before the same examiner in the prosecution of the
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`co-pending related application that issued as the '649 patent. EX2005, 182. In a
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`response to an Office Action during prosecution of the '649 patent, Applicant
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`directed the examiner to Tan and explained how it gave a POSA no motivation to
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`Case IPR2018-01710
`Patent No. 8,586,045
`humanize an anti-CGRP antibody. Id. Applicant's remarks regarding Tan were
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`made on September 5, 2013, that is, while the '045 patent application was still
`
`pending. The Corrected Notice of Allowance for the '045 patent and the Notice of
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`Allowance for the '649 patent were both issued on September 23, 2013, and
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`therefore the Examiner had reviewed Applicant's comments on Tan (and Tan itself)
`
`before allowing the '045 patent. EX2005, 278-280; EX2034, 542-544. And, as
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`discussed above, the same examiner was responsible for both the '045 and '649
`
`patents. EX1001; EX2025. Thus, Tan itself was squarely in front of, and has been
`
`considered before by, the Office.
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`Fourth, the very disclosure in Tan upon which Lilly relies in the Petition
`
`was already before the examiner, and was raised in a rejection during prosecution
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`of related, co-pending applications in the form of Frobert. Lilly relies upon Tan for
`
`teaching mouse monoclonal antibodies that block CGRP from binding to its
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`receptor. Petition, 1, 7, 16-17, 24-25. Frobert provides the same teachings, which
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`the examiner considered during prosecution of the related '794 and '649 patents.
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`EX2033, 393, 429-430. According to the examiner, "Frobert teaches
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`agonists/antagonists that compete with ligands to the CGRP receptors such as
`
`monoclonal