`
`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 IPR2018-01425
`Patent 9,890,210
`_____________________
`
`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 IPR2018-01425
`Patent No. 9,890,210
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`
`B. 
`
`2. 
`
`Introduction ..................................................................................................... 1 
`CGRP, CGRP receptor antagonists, and the inventors' unorthodox switch to
`CGRP antagonist antibodies ........................................................................... 4 
`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 ............................................................................ 10 
`A. 
`The same examiner reviewed the references or equivalents
`thereof
`and
`rejected Petitioner's
`arguments during
`prosecution of the '210 patent and its parent '649 patent .................... 12 
`All of the Becton Dickinson factors strongly favor denying
`institution under § 325(d) .................................................................... 14 
`1. 
`Each of the primary references—Tan, Wimalawansa,
`and Queen—is the same or substantially the same as
`the art that was overcome during examination ........................ 15 
`The asserted art was
`fully evaluated during
`examination and was the basis for rejection ............................ 21 
`The Petition's prior art references are cumulative of
`the art evaluated during prosecution ........................................ 21 
`The arguments in the Petition substantially overlap
`with the examiner's arguments during prosecution ................. 22 
`Lilly offers no explanation for how the examiner erred
`during prosecution when evaluating the same art .................... 24 
`Lilly provides no justification to reconsider the same
`art and arguments from prosecution ........................................ 26 
`IV.  Petitioner failed to establish a reasonable likelihood of prevailing as to any
`challenged claim ........................................................................................... 27 
`A. 
`Claim construction .............................................................................. 28 
`B. 
`Person of ordinary skill in the art ........................................................ 28 
`C. 
`Lilly should be held to its Tan 1995, Wimalawansa, and
`Queen obviousness combination ......................................................... 29 
`Lilly does not demonstrate why a POSA would have
`humanized Tan's full-length antibody ................................................. 31 
`1. 
`Lilly fails to provide any reason a POSA would have
`had to modify Tan 1995's full-length C4.19 antibody
`by humanization ....................................................................... 32 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`D. 
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`a) 
`
`b) 
`
`b) 
`
`that C4.19
`Tan 1995 did not establish
`antagonized endogenous CGRP; a critical
`prerequisite to Lilly's argument that is missing
`for motivation ................................................................ 34 
`Lilly fails to address why a POSA would not
`expect Tan 1995's negative result to also apply
`to other full-length anti-CGRP antibodies ..................... 38 
`2.  Wimalawansa provides no reason to humanize Tan
`1995's failed full-length C4.19 antibody ................................. 42 
`a) 
`Lilly argues that Wimalawansa would have
`motivated a POSA to generate humanized anti-
`CGRP antagonist antibodies for therapeutic use,
`but Wimalawansa
`cautions
`against
`this
`approach, focusing on receptor antagonists
`instead ............................................................................ 43 
`Lilly does not provide any evidence of the "data
`from
`carefully
`designed
`studies"
`that
`Wimalawansa deemed necessary before a
`POSA would begin to evaluate anti-CGRP
`monoclonal antibodies for human use ........................... 48 
`Lilly's near-simultaneous
`invention
`theory
`is neither
`supported by the facts nor the law ....................................................... 52 
`Conclusion .................................................................................................... 54 
`
`E. 
`
`V. 
`
`
`
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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 1-15 of U.S. Patent No. 9,890,210 ("the
`
`'210 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, humanized monoclonal anti-CGRP antagonist antibodies. 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 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 their humanized anti-CGRP antagonist antibody 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 anti-
`
`CGRP antibodies and methods of use thereof.
`
`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
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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,
`
`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
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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, as it must under settled law, provide a sufficient
`
`reason why a POSA would have modified Tan 1995's full-length C4.19 antibody.
`
`Indeed, any reason is belied by Tan 1995 itself, which failed to show that the full-
`
`length antibody could engage with the target peptide at its site of action, and made
`
`no suggestion of a therapeutic use. Lilly did not articulate any credible reason that
`
`would have motivated a POSA to ignore these teachings in Tan 1995 and proceed
`
`to humanize Tan 1995's full-length C4.19, relying instead on supposition. On its
`
`face, this omission exposes Lilly's textbook hindsight analysis.
`
`Next, Lilly tries to sidestep the unfavorable aspects of Tan 1995 by
`
`suggesting that Wimalawansa provides a reason to humanize the full-length
`
`antibody. Lilly is wrong. Wimalawansa, and other references Lilly cites, focus on
`
`targeting CGRP receptors, as opposed to CGRP, and predominantly concentrate on
`
`small molecule receptor antagonists as opposed to antibodies. More to the point,
`
`Lilly failed to identify where in any of these references the art provided data
`
`addressing the concerns expressed by Wimalawansa, and admitted by Lilly, that
`
`"[c]learly, 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
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`in humans." EX1096, 567.
`
`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
`
`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
`
`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
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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.
`
`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. EX1024, 420; EX2017. BIBN4096BS
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`performed well in pre-clinical studies and ultimately eight clinical trials
`
`were performed. 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.
`
`EX2018, 2:65-3:2. Despite success during pre-clinical experiments and
`
`investigation in 16 clinical trials, 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
`
`antagonists. 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." EX2015, 2:6-7.
`
`5) In 2005, Bristol-Myers Squibb filed a patent application directed to
`
`bicyclic and tricyclic CGRP receptor antagonists and methods of using
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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. 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
`
`small molecules.
`
`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, one being the difficulty of administering large molecules, such
`
`as antibodies, as non-oral formulations (injections) to patients. A POSA simply did
`
`not consider targeting CGRP, or 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 receptor. But there were
`
`other reasons behind the focus on antagonizing the receptor.
`
`In the cardiovascular system, CGRP is responsible for (i) increasing heart
`
`rate, force of cardiac contraction, coronary blood flow and microvascular
`
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`Patent No. 9,890,210
`permeability; (ii) mediating cardioprotective effects through preconditioning
`
`induced by brief ischemia; and (iii) producing vasodilation in capacitance blood
`
`vessels and regulating vascular tone and angiogenesis. EX1031, 317-18. One
`
`reason researchers focused overwhelmingly on targeting the CGRP receptors was
`
`because they understood that blocking CGRP, one of the most potent vasodilators
`
`known (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 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
`
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`before the '210 patent were those offered by, for example, Wimalawansa—one of
`
`Lilly's primary references—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., 5671. 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 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 in the
`
`field, the therapeutic efficacy of a humanized monoclonal anti-CGRP antagonist
`
`antibody by showing activity in a therapeutically-relevant headache model.
`
`EX1001, 70:42-71:20. The inventors also demonstrated the efficacy of a
`
`
`1 Emphasis added throughout unless otherwise noted.
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`humanized monoclonal anti-CGRP antagonist antibody compared to a small
`
`molecule CGRP receptor antagonist positive control (olcegepant, also known as
`
`BIBN4096BS). Id., 71:12-20. 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, olcegepant. Id.
`
`Recognizing the innovative contribution to the art, the USPTO has rightly
`
`awarded the inventors the '210 patent, along with several others, that are now
`
`before the Board in co-pending IPR proceedings.
`
`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 arguments and art that were already considered and
`
`overcome during prosecution. What's more, each of the primary references in
`
`Lilly's proposed ground—Tan 1995, Wimalawansa, 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
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`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).
`
`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
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`Patent No. 9,890,210
`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. For
`
`example, Lilly acknowledges that Teva cited each of Tan 1995, Wimalawansa, and
`
`Queen to the examiner. Petition, 55. Yet 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 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
`'210 patent and its parent '649 patent
`
`The '210 patent issued from U.S. Patent Application No. 15/588,432 ("the
`
`'432 application"), which claims priority to November 14, 2005, through a chain of
`
`continuation applications and a provisional application as shown in the following
`
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`Case IPR2018-01425
`Patent No. 9,890,210
`family tree2. EX1001, EX2024-EX2032.
`
`
`
`Examiners Saoud and Lockard examined all the applications in this family
`
`tree from U.S. Patent No. 8,586,045 ("the '045 patent") onward. See, e.g., EX1001,
`
`EX2025-EX2032, face page. In addition, prosecution of parent applications is
`
`
`2 This tree shows IPR proceedings involving patents in the '210 patent family.
`
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`Patent No. 9,890,210
`relevant to prosecution of a child application and is considered part of the file
`
`history of the child application. 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 '210 patent; and Examiners Saoud and Lockard
`
`would have been familiar with such arguments and art.
`
`B. All of the Becton Dickinson factors strongly favor denying
`institution under § 325(d)
`
`Lilly asserted, in a single, short paragraph, that the "evidence identified in
`
`this Petition was either not before the Examiner or not fully considered during
`
`prosecution." Petition, 55. But Lilly's Petition addressed only Information
`
`Disclosure Statements submitted during prosecution of the '210 patent. Lilly did
`
`not address the prosecution of any of the patents related to the '210 patent by
`
`priority despite that prosecution being considered part of the file history of the '210
`
`patent. Omega Eng'g, Inc., 334 F.3d at 1333. Moreover, Lilly did not address how
`
`the teachings relied upon in the Petition are not cumulative to those relied upon in
`
`rejections, discussed on the record, and overcome during prosecution of the '210
`
`patent family. Indeed, Lilly did not address any of the Becton Dickinson factors,
`
`which, as shown below, weigh in favor of the Board exercising its discretion to
`
`deny institution.
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`Patent No. 9,890,210
`1.
`Each of the primary references—Tan, Wimalawansa, and
`Queen—is the same or substantially the same as the art that
`was overcome during examination
`Tan 1995. During prosecution, Applicant submitted a complete copy of Tan
`
`1995 to the Office, and the examiner fully considered it at least in four different
`
`respects: First, Tan 1995 was cited in an IDS in every application throughout the
`
`priority chain of the '210 patent (both parent and child applications). And, in every
`
`application, the examiner considered Tan 1995 as evidenced by the examiner's
`
`filing of a copy of the IDS with the examiner's signature and noting the date on
`
`which the cited references were considered. EX2005, 295; EX2033, 442; EX2034,
`
`480; EX2035, 212; EX2036, 269; EX2037, 364; EX2038, 369; EX2039, 370;
`
`EX2040, 362; EX2041, 344; EX2042, 200; EX2043, 199; EX2044, 201; EX2045,
`
`212.
`
`Second, Tan is cited multiple times in the '210 specification. For example,
`
`the '210 patent expressly cites Tan 1995 when acknowledging that "[a]nti-CGRP
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`antagonist antibodies are known in the art. See, e.g., Tan et al., Clin. Sci. (Lond).
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`89:565-73, 1995." EX1001, 26:28-30 (citing EX1022). Tan is again cited in
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`Example 3, when describing the rat saphenous nerve assay. See id., 57:27-31.
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`There is no question that the examiner would have been aware of Tan 1995's anti-
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`CGRP antagonist antibodies and rat saphenous nerve assay—the disclosures from
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`Tan 1995 that are central to Lilly's challenge—when reading the '210 specification.
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`Patent No. 9,890,210
`Third, the patent prosecution record of U.S. Patent No. 8,597,649 ("the '649
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`patent") (a parent patent of the '210 patent) explicitly discussed Tan 1995. EX2005,
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`182. In a response to an Office Action, Applicant directed the examiner to Tan
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`1995, explaining how it gave a POSA no motivation to humanize an anti-CGRP
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`antibody. Id. Thus, Tan 1995 itself was squarely in front of, and has been
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`considered before, by the same examiner in a parent to the '210 patent. And,
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`prosecution of parent applications is considered part of the file history of the child
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`application. Omega Eng'g, Inc., 334 F.3d at 1333.
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`Fourth, the very disclosure in Tan 1995 upon which Lilly relies in the
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`Petition, was already before the examiner and raised in a rejection during
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`prosecution of the parent '649 patent in the form of Frobert (EX1032). Lilly relies
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`upon Tan 1995 for teaching mouse monoclonal antibodies that block CGRP from
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`binding to its receptor. Petition, 16-17, 22. Frobert provides the same teachings,
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`which as Lilly admits, the examiner considered during prosecution. EX2050, 10-
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`11. According to the examiner, "Frobert teaches agonists/antagonists that compete
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`with ligands to the CGRP receptors such as monoclonal antibodies to human
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`CGRP I or CGRP alpha, including residues 25-37 of CGRP (See pg. 277, right
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`column; Table 1 at pg. 276)." EX2005, 162 (citing EX1032). Thus, the examiner
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`already considered the knowledge in the art relating to mouse monoclonal
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`antibodies that block CGRP binding to its receptor in the form of Frobert. Tan
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`1995 is not materially different.
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`Wimalawansa. As with Tan 1995, the examiner also already considered
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`Lilly's Wimalawansa arguments during prosecution.
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`First, Wimalawansa was cited in an IDS, and, the examiner considered
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`Wimalawansa as evidenced by the examiner's filing of a copy of the IDS with the
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`examiner's signature and noting the date on which the cited references were
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`considered. EX2043, 320.
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`Second, Lilly advances Wimalawansa for the sole reason that it allegedly
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`"proposes using humanized anti-CGRP monoclonal antagonistic antibodies as
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`therapeutic agents for CGRP-related diseases." Petition, 22. But the record
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`demonstrates that the examiner already considered the issue of humanization of
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`anti-CGRP antibodies on the record during prosecution of the parent '649 patent.
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`For example, in one office action rejection, the examiner considered and relied
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`upon Pisegna, which states that "[f]or certain therapeutic applications, humanized
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`antibodies are desirable." EX2049, ¶[0125]; EX2005, 162-63. In a September 5,
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`2013 Response to Office Action, Applicant pointed the examiner to that disclosure
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`and explained that despite that disclosure, "one skilled in the art would in fact have
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`had no motivation whatsoever to humanize an anti-CGRP antibody . . . [and]
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`would have had no reasonable expectation that a humanized antibody would have .
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`. . a therapeutic application." EX2005, 182. Accordingly, the examiner was well
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`aware of the issue of humanization of anti-CGRP antibodies necessary for
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`therapeutic use, and fully considered that issue before allowing the application.
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`Lilly does not refute this.
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`Wimalawansa's remaining disclosures are also cumulative to what was
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`before the examiner. Lilly cites Wimalawansa in summarizing CGRP's known
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`biological effects as a neuropeptide. See, e.g., Petition, Section IV.A.
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`Wimalawansa provides an "overview of [CGRP's] molecular genetics, structure-
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`activity, and receptors." EX1096, 534. Substantially similar disclosures regarding
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`CGRP's function were present in references cited by the examiner, e.g., in Tan
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`(EX1022), Frobert (EX1032), and Pisegna (EX2049) during prosecution of the
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`parent '649 patent. EX2005, 162-164. For example, Frobert summarized how
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`CGRP activity "suggest[s] the physiological and possibly the physiopathological
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`importance of CGRP." EX1032, 275. Lilly apparently agrees that Wimalawansa
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`and Frobert contain similar disclosures about CGRP biological effects, given that
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`Lilly cites both papers in parallel multiple times in summarizing CGRP's function.
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`Petition, 10. The examiner, therefore, was also well aware of the field's knowledge
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`of CGRP and fully considered that issue during prosecution.
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`Queen. As with the other two primary references, even though the examiner
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`did not specifically cite Queen in a rejection, the examiner nevertheless considered
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`the same disclosure from Queen during prosecution. The Petition advances Queen
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`Patent No. 9,890,210
`for generalized teachings on humanizing antibodies. Petition, e.g., 15, 22, 28, 29,
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`33-35, 43. But, even as the Petition itself acknowledges, the '210 patent
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`specification cites Queen to explain humanizing antibodies. Id., 7-8. Indeed, the
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`Petition confirms that the contents of the '210 specification disclose how to
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`humanize antibodies: "The '210 patent states that preparing humanized and human
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`antibodies from non-human antibodies, such as murine antibodies, was 'known' and
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`'conventional.'" Id., 7, citing EX1001 at 28:10-16, 32:4-8, 32:51-52, 36:24-25,
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`38:8-12; see also id., cols. 28-30 (Queen is cited at 29:36).
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`Also, Pisegna, which the examiner considered during prosecution of the
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`parent '649 patent, states that "[f]or certain therapeutic applications, humanized
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`antibodies are desirable." EX2049, ¶[0125]. That same paragraph also cites to
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`multiple references that provide "details on human