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 IPR2018-01422 (Patent 9,340,614 B2)
`Case IPR2018-01423 (Patent 9,266,951 B2)
`Case IPR2018-01424 (Patent 9,346,881 B2)
`Case IPR2018-01425 (Patent 9,890,210 B2)
`Case IPR2018-01426 (Patent 9,890,211 B2)
`Case IPR2018-01427 (Patent 8,597,649 B2)1
`
`_____________________
`
`PATENT OWNER’S DEMONSTRATIVES
`
`
`
`
`
`
`
`
`
`1 A word-for-word identical copy of this paper is filed in each proceeding
`
`identified in the caption.
`
`
`
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ELI LILLY AND COMPANY,
`Petitioner,
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner.
`
`_____________________
`
`Case IPR2018-01422 (Patent 9,340,614 B2)
`Case IPR2018-01423 (Patent 9,266,951 B2)
`Case IPR2018-01424 (Patent 9,346,881 B2)
`Case IPR2018-01425 (Patent 9,890,210 B2)
`Case IPR2018-01426 (Patent 9,890,211 B2)
`Case IPR2018-01427 (Patent 8,597,649 B2)1
`
`_____________________
`
`PATENT OWNER’S DEMONSTRATIVES
`
`
`
`
`
`
`
`
`
`1 A word-for-word identical copy of this paper is filed in each proceeding
`
`identified in the caption.
`
`
`
`
`
`IPR2018‐01422
`IPR2018‐01423
`IPR2018‐01424
`IPR2018‐01425
`IPR2018‐01426
`IPR2018‐01427
`
`Eli Lilly and Company
`v.
`Teva Pharmaceuticals International GmbH
`
`November 22, 2019
`
`1
`
`
`
`A POSA would not have had a reason to humanize anti‐CGRP antibodies
`with a reasonable expectation of success POR, 4‐5, 10‐12, 19‐22, 36‐40 , 46‐51
`
`• Tan 1995’s full‐length antibody did not achieve immunoblockade:
`– “only the Fab’ fragment was found to be an effective tool for blockade ” in rats. EX1022, 570; POR, 39; EX2054, ¶51.
`
`• Wimalawansa’s reference to anti‐CGRP antibodies is inconclusive:
`– “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.” EX1096, 567; POR, 4, 7, 10‐11, 19‐22; EX2137, ¶¶80‐85; EX2054, ¶¶56‐59; EX2141, ¶¶25, 72.
`– “These data warrant further studies in an animal model of sepsis to determine whether blocking CGRP
`receptors with specific antagonists or monoclonal antibodies has beneficial effects on the outcome.” EX1096,
`568; POR, 10‐11, 49; EX2054, ¶58; EX2241, ¶86.
`
`• The decade between Tan/Wimalawansa and Teva’s invention:
`– Salmon, Sveinsson, and the ‘438 patent mention anti‐CGRP antibodies in passing and provide no data. POR, 34‐
`36; EX1026, 7:19; EX1027, ¶[0038]; EX1028, 2:17‐55.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`
`
`Before Teva’s invention, the industry focused on receptor antagonists
`and triptans POR, 10‐11, 49
`
`• Wimalawansa:
`– “CGRP antagonists can be used in the late phase [of migraine]. However, 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; POR, 11, 20, 49; Institution Decision, 15; EX2241, ¶86
`– “These data warrant further studies in an animal model of sepsis to determine whether blocking CGRP
`receptors with specific antagonists or monoclonal antibodies has beneficial effects on the outcome.” EX1096,
`568; POR, 10‐11, 49; EX2054, ¶58
`• Arulmani:
`– “An important breakthrough in the field of CGRP receptors is the development of potent CGRP receptor
`antagonists.” EX1031, 323; POR, 49; EX2141, ¶23
`• Olesen:
`– “BIBN 4096 BS is a nonpeptide CGRP‐receptor antagonist with an extremely high affinity and specificity for the
`human CGRP receptor.” EX1025, 1105; POR, 49; EX2141, ¶22
`• Arulmohzi:
`– “The last decade has witnessed the advent of Sumatriptan and the ‘triptan’ class of 5‐HT1B/1D receptor
`agonists which have well established efficacy in treating migraine.” EX1040, 176; POR, 49; EX2141, ¶21
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`
`
`Teva’s invention led to breakthrough migraine therapy POR, 52‐56
`• Lilly admits that the claimed antibodies satisfied a long‐felt, unmet need:
`– Humanized anti‐CGRP antibodies are a: “[s]afe, effective and well tolerated treatment for
`the prevention of migraine” that satisfied this “enormous unmet medical need.” EX2161, 6; POR,
`55‐56; EX2165, ¶¶25‐44
`
`• The Industry praised the claimed antibodies:
`– “an enormous step forward” EX2172, 1‐2; POR, 52‐55; EX2165, ¶50
`– “a game changer” EX2179, 4; POR, 52‐55; EX2165, ¶52
`– a “breakthrough in migraine” EX2174 ,707; POR, 52‐55; EX2165, ¶49
`
`• Lilly’s expert, Dr. Charles, also praised the claimed antibodies as:
`– “radical concept” EX2053, 23; POR, 52‐55; EX2165, ¶57
`– “very exciting and compelling” EX2182, 207; POR, 9; EX2165, ¶57
`– “absolutely life‐changing” EX2186, 4; POR, 52‐53; EX2165, ¶57
`– “spectacular” EX2186, 4‐5; POR, 52‐53; EX2165, ¶57
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`
`
`Lilly has failed to meet its burden
`to show obviousness
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`
`
`Lilly’s hindsight arguments are driven by the solution Teva’s
`invention provided POR, 46‐51
`• Lilly impermissibly uses the claimed invention as a roadmap. POR, 46‐51
`– Instead of following the art suggested approaches (receptor antagonists and triptans) Lilly
`impermissibly “use[s] the inventions to define the problem that the invention solves” to
`argue obviousness.
`Mintz v. Dietz Watson, Inc., 679 F.3d 1372, 1377 (Fed. Cir. 2012); Ortho‐McNeil Pharma., Inc. v. Mylan Labs, Inc., 520 F.3d 1358, 1364
`(Fed. Cir. 2008); POR, 49‐50
`
`• Overwhelming objective indicia arguments expose Lilly’s hindsight. POR, 51‐61
`– The strong objective indicia evidence here are “powerful tools for courts faced with the
`difficult task of avoiding subconscious reliance on hindsight.”
`Mintz v. Dietz & Watson, Inc., 679 F.3d 1372, 1378 (Fed. Cir. 2012); POR, 51
`– Lilly’s arguments fail because the “intervening time between the prior art’s teaching [and
`the invention] speaks volumes to the nonobviousness of the…patent.”
`Leo Pharm v. Rea, 726 F.3d 1346, 1359 (Fed Cir. 2013); POR, 48‐49
`
`• Lilly’s hindsight is exposed by its expert, Dr. Charles, stating in 2018 that “[t]he notion
`that we would be using antibodies to treat migraine is really quite a radical concept.”
`EX2053, 23; POR, 9, 46; EX2165, ¶57
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`6
`
`
`
`Lilly argued motivation to humanize for “therapeutic use” in humans and
`must show reasonable expectation of clinical utility POR, 13‐15; Surreply, 3‐5
`
`• ’211 Patent, Claim 1:
`
`• Lilly’s Petition:
`– A POSA would have been specifically motivated to humanize an anti‐CGRP antagonist antibody for
`human use…[in] chronic conditions requiring repeated administration of therapeutic agents.”
`Petition, 35
`
`EX1001, 103:32‐45
`
`• Phigenix, Inc. v. ImmunoGen, Inc., IPR2014‐00676, Paper 39 at 16, 21 (PTAB October 27, 2017); Surreply, 3‐4
`– “when asserting that an ordinary artisan would have had a reason to … prepare [the
`claimed] immunoconjugate, Petitioner relies on the position that an ordinary artisan
`would have expected such an immunoconjugate to work clinically to treat tumors in
`humans upon reading the cited references.” Phigenix, Paper 39 at 16
`– “Petitioner does not persuade us that a preponderance of the evidence establishes that
`a skilled artisan would have had a reasonable expectation of success in 2000 that [the
`claimed] immunoconjugate would be useful in the treatment of breast tumors in
`humans.” Phigenix, Paper 39 at 21
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`
`
`Lilly’s obviousness argument lacks particularity POR, 47‐49; Surreply, 24‐25
`• The Board noted that “Petitioner is not necessarily arguing that a person of ordinary
`skill would have started with Tan’s antibodies (MAb C4.19) and simply humanized
`them.” Inst. Dec. at 24.
`• And, Lilly’s expert, Dr. Charles, admitted that “[he is] not sure that humanization of 4.19
`would result in all of the features that are described in claim 1.” EX2192, 154:14‐20; Surreply, 25
`• Lilly’s argument “fails to comply with the particularity and specificity
`required of supporting evidence under our governing statute and rules.”
`Whole Space Indus. Ltd. v. Zipshade Indus. (B.V.I.) Corp., IPR2015‐00488, Paper 14 at 13 (PTAB July 24, 2015) (citing 35 U.S.C. §
`312(a)(3))
`• “‘Generic motivations with no specificity’ fall short of the articulated
`rationale required.” Agilent Tech. Inc. v. Bio‐Rad Labs. Inc., IPR2019‐00268, Paper 8 at 19 (PTAB May 16, 2019)
`• The Board preliminarily found that “Petitioner has made an adequate
`showing that a person of ordinary skill … would have sought to humanize
`Tan’s antibodies,” but this is not supported by the complete record. Inst. Dec. at
`19.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`
`
`Tan 1995 is not clinically relevant and its
`anti‐CGRP monoclonal antibody
`fails to immunoblockade
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`
`
`Tan 1995 is not related to any clinical or therapeutic use POR, 15‐16
`• Lilly’s expert, Dr. Charles’ declaration:
`– Misrepresents Tan 1995 as providing “guidance to a POSA to use anti‐CGRP antagonist antibodies,
`including full‐length antibodies, to treat vasomotor symptoms, which include migraine.” EX1002, ¶121;
`Petition, 30‐33; EX2054, ¶53; POR, 15‐16
`• But in Dr. Charles’ deposition:
`– He admitted that Tan 1995 “is talking about experiments, not actually treating any disease.” EX2192,
`156:2‐9; POR, 3‐4
`
`• Other experts agree that Tan 1995 is not related to clinical or therapeutic use:
`– Lilly’s expert, Dr. Vasserot: Tan 1995 is silent as to the “efficacy of administering an anti‐CGRP
`antagonist antibody to humans to treat a disease.” EX2191, 122:16‐123:15; POR, 3‐4, 17‐18
`– Dr. Foord: “Tan 1995…draws no therapeutic or clinical conclusions.” EX2054, ¶50; POR, 15‐16
`– Dr. Tomlinson: “Tan 1995 does not contain any discussion of diseases.” EX2137, ¶86; POR, 15‐16
`– Dr. Ferrari: “Tan 1995 is a basic research paper and did not test clinical use of anti‐CGRP antibodies
`or mention such a clinical use.” EX2141, ¶61; POR, 15‐16
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`10
`
`
`
`Tan 1995 concludes: a full‐length anti‐CGRP antibody does not block CGRP
`activity in vivo POR, 17, 25‐26, 39‐43
`
`EX1022, 569; POR, 25‐26, 41‐43; EX2054, ¶51
`
`EX1022, 571; POR, 42; EX2054, ¶15
`
`EX1022, 570; POR, 25‐26, 39‐40; EX2054, ¶51
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`
`
`Lilly’s mischaracterization of Tan 1995’s findings does not undermine Tan
`1995’s ultimate conclusion regarding full‐length antibody POR, 16‐18, 42
`• Lilly’s expert, Dr. Charles:
`– “Tan 1995 confirmed that…the full‐length IgG antibody MAb C4.19 generates
`immunoblockade and abolishes the effects of CGRP.” EX1002, ¶53, citing EX1022, 568‐569
`
`• But Tan 1995’s actual finding is:
`– “Further nerve stimulation performed at 2 h after 3 mg/rat MAb produced an AUC
`which was slightly smaller compared with baseline stimulation, but not by more
`than 16% (n=2).” EX1022, 569; POR, 16‐17, 41‐42; EX2054, ¶52; EX2137, ¶88
`
`• Lilly’s expert, Dr. Vasserot, cautions against relying on Tan 1995’s 16% data:
`– “[Tan 1995’s 16% result is] something that I would take with caution and would
`need to repeat.” EX2191, 118:21‐119:1; POR, 16‐17
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`
`
`Lilly resorts to mischaracterizing Teva’s expert’s testimony Surreply, 7
`
`• On Reply, Lilly, citing to Dr. Ferrari:
`– “Tan’s MAb C4.19…antagonized CGRP in vitro and in vivo.” Reply, 3; EX1303, 160:2‐9, 162:12‐22
`
`• Dr. Ferrari was discussing Fab’ fragments, not IgGs:
`
`EX1303, 160:2‐9; Surreply, 7
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`EX1303, 162:12‐15; Surreply, 7
`
`
`
`Lilly’s belated “carcass” data fails to support Tan 1995’s speculation Surreply, 2‐3, 8‐10
`
`• Because Tan 1995's C4.19 IgG failed to block endogenous CGRP activity, Lilly is forced
`to rely on Tan 1995's speculation. POR, 41‐43; EX2141, ¶¶60‐64
`
`• Tan 1995 speculates:
`– “Covell et al. showed that the time to reach steady‐state interstitial to plasma
`concentration ratio in the carcass (including muscle and skin) was 14 times more
`rapid for Fab' fragments than for whole lgG….The slow distribution of whole IgG to
`the site of immunoblockade could be overcome by the alternative strategies of
`active immunization with CGRP or chronic administration of IgG.” EX1022, 571; Surreply, 2, 8‐
`9; POR, 42‐43
`
`• But the prior art teaches that “assignment of a site, or sites, of antibody localization
`was not possible” in carcass experiments like those referenced in Tan 1995. EX2270, 3045;
`EX2273, 92:14‐16; Surreply, 2, 8‐9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`
`
`Lilly failed to articulate an apparent reason to modify Tan; its reliance on
`Sanofi is misplaced Surreply, 3‐7; POR, 36‐38
`
`Tan’s MAb C4.19 IgG
`A ligand antibody but the field was focused on
`antagonists “extremely specific to the CGRP
`receptors.” EX1096, 568; see also EX1031, 323; POR, 11, 20,
`52; EX2141, ¶¶21‐26
`
`Sanofi’s promising antibody candidate
`A receptor antibody and the field identified
`targeting receptors as “more promising” than
`targeting their ligands (cytokines), and “several
`companies” were seeking to do just that. Sanofi at
`20; Surreply, 5‐6
`Receptor antibody could immunoblock two
`complementary targets (IL‐4 and IL‐13) by binding
`to the single receptor—an approach validated in
`the art. Sanofi at 18; Surreply, 5‐6
`Sanofi‐Aventis U.S. LLC. v. Immunex Corp., IPR2017‐01884, Paper 96, 17 (P.T.A.B. Feb. 14, 2019)
`
`Tan’s “MAb C4.19 IgG … did not block the skin
`blood flow response to antidromic nerve
`stimulation.…” EX1022, 569; POR, 25; EX2137, ¶66; EX2141,
`¶60
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`
`
`Wimalawansa does not provide motivation:
`it focuses on receptor antagonists and
`teaches that “[c]learly more data from
`carefully designed studies” are needed
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`
`
`Wimalawansa focuses on receptor antagonists POR, 10‐11, 20
`
`• Lilly’s expert, Dr. Charles:
`– “Wimalawansa’s discussion of using a compound for migraine that is ‘extremely
`specific’ would have naturally led a POSA to use anti‐CGRP antagonist antibodies.”
`EX1002, ¶63, citing Wimalawansa, EX1096, 568
`
`• But, Wimalawansa teaches extreme specificity to CGRP receptors:
`– “[T]he 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; POR, 10‐11, 20; EX2141, ¶86
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`
`
`Wimalawansa teaches that “carefully designed” studies were needed before
`evaluation as therapeutic agents POR, 4, 10‐11, 19‐22; EX2137, ¶¶80‐85; EX2054, ¶¶56‐59; EX2141, ¶¶25, 72
`
`• Wimalawansa:
`– “Clearly, more data from carefully designed studies are necessary before …
`humanized anti‐CGRP monoclonal antibodies … can be evaluated as therapeutic
`agents in humans.” EX1096, 567; POR, 4, 10‐11, 19‐22; EX2137, ¶¶80‐85; EX2054, ¶¶56‐59; EX2141, ¶¶25, 72
`
`• Dr. Tomlinson testifies that such studies are a prerequisite to humanization:
`– “Broadly, a POSA would have required a series of experiments relating to the basic
`function of a candidate antigen before having a reason to proceed with
`humanization.” EX2137, ¶¶38‐40; POR, 19, 26
`– “[W]hen discussing the wide range of CGRP activities, Wimalawansa concludes that
`further investigation was necessary before there could be reason to pursue
`humanized anti‐CGRP antibodies.” EX2137, ¶80; POR, 19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`18
`
`
`
`Cited art does not provide the “carefully designed studies” that might
`motivate a POSA to consider anti‐CGRP antibodies for human use POR, 34‐36
`
`• Dr. Ferrari:
`– “A careful examination of the art, however, reveals that anti‐CGRP antibodies were mentioned only in the
`context of being a theoretical possibility that still required further validation before clinical use—and that there
`had been no analysis or testing of whether it would be a good idea to make clinical use of anti‐CGRP
`antibodies in view of the expected side effects.” EX2141, ¶¶71‐75 (discussing EX1026, EX1027; EX1028); POR, 34‐36
`
`• Lilly’s expert, Dr. Charles, agrees that the cited references contain no safety or efficacy data regarding anti‐CGRP
`antibodies:
`
`Reference
`
`EX1026 (Sveinsson)
`
`EX1027 (Salmon)
`
`EX1028 (’438 patent)
`
`Lilly’s expert, Dr. Charles:
`Did not identify any “safety data” or “efficacy data” in his declaration.
`EX2192, 85:6‐13; POR, 34‐35; EX2141, ¶73
`Could not “recall” and “certainly [did] not include[]” any safety data in
`his declaration. EX2192, 79:1‐80:2; POR, 35; EX2141, ¶74
`Is not “aware” of and did not “include” any safety or efficacy data in his
`declaration. EX2192, 82:11‐83:19; POR, 35‐36; EX2141, ¶75
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`19
`
`
`
`Safety concerns would have dissuaded a
`POSA from therapeutic use of anti‐CGRP
`antibodies
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`
`
`The safety concerns about CGRP provide reason to not combine, but Lilly
`does not address them POR, 21‐22, 36‐37
`
`• Arctic Cat Inc. v. Bombardier Recreational Prods. Inc., 876 F.3d 1350 (Fed. Cir. 2017)
`– “Evidence suggesting reasons to combine cannot be viewed in a vacuum apart
`from evidence suggesting reasons not to combine.” Artic Cat, 876 F.3d at 1363
`– “As our precedent reflects, prior art need not explicitly ‘teach away’
`to be relevant to the obviousness determination. Implicit in our
`discussion of the ‘degree’ of teaching away is an understanding that
`some references may discourage more than others.” Artic Cat, 876 F.3d at 1360
`
`• Lilly’s obviousness challenge failed to consider the art as a whole and failed to
`consider safety concerns. POR, 21‐22, 36‐37; EX2141, ¶¶27‐66; EX2137, ¶¶60‐78
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`21
`
`
`
`CGRP was known to regulate blood pressure and to prevent
`hypertension‐related health problems POR, 23‐24; EX2141, ¶¶38‐41, 48‐54
`
`• Brain and Grant (EX2003):
`– Because of its potent vasodilation properties, CGRP plays a “pivotal role” in the “physiology and
`pathophysiology of cardiovascular regulation.” EX2003, 923; EX2054, ¶23; Inst. Dec. (Paper 14), 3‐4, 12‐14; EX2141, ¶36;
`POR, 10, 23
`– “[I]nfusion of CGRP is beneficial in increasing cardiac output and lowering blood pressure in
`patients with congestive heart failure.” EX2003, 919; EX2141, ¶39; POR, 23‐24
`• Edvinsson (EX2215):
`– “[B]lockade of a strong endogenous vasodilator such as CGRP carries the inherent risk of causing
`unwanted side effects such as local vasoconstriction.” EX2215, 72; EX2141, ¶48; POR, 23‐24
`• Petersen (EX2019):
`– “One potential concern of CGRP antagonism could be cerebral vasoconstriction, if CGRP exerts a
`tonic influence on the cerebral arteries.” EX2019, 139‐140; EX2141, ¶48; POR, 23‐24
`• Supowit (EX2011):
`– “[D]eletion of the α‐calcitonin gene‐related peptide gene makes the heart and kidneys more
`vulnerable to hypertension‐induced end organ damage.” EX2011, Abstract; EX2141, ¶48; POR, 23‐24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`
`
`CGRP was known to protect against escalation of ischemic events POR, 9‐10, 23‐24
`• Juul (EX2139):
`– CGRP is “involved in a reflex mechanism to counterbalance cerebrovascular constriction.” EX2139, 68‐69; EX2141, ¶45;
`POR, 10, 23‐24
`
`• Brain and Grant (EX2003):
`– “The local release of CGRP from cardiac and coronary tissues is thought to counteract the effects of ischemic
`episodes leading to a cardiac protective effect.” EX2003, 919; EX2141, ¶39; POR, 23‐24, 27
`
`• Edvinsson (EX2009):
`– “CGRP was known as ‘a potent cerebral vasodilator’ and was thought to play a role in a ‘protective
`mechanism…[that] may have considerable pathological significance.’” EX2141, ¶40 (quoting EX2009, 614‐615); POR, 23‐24, 27
`
`• Wimalawansa (EX1096):
`– Low CGRP levels in early morning “may well be associated with vasomotor instability and the tendency of the
`elderly to experience cerebrovascular episodes.” EX1096, 543; EX2141, ¶43; Inst. Dec. (Paper 14), 12‐14; POR, 24‐25
`• Dr. Ferrari:
`– Inadequate CGRP during an ischemic attack heightened the risk for transient mild ischemic events turning into full‐
`blown infarctions. EX2141, ¶¶28, 42‐47; POR, 23‐24
`– CGRP‐induced vasodilation allows more blood to enter affected tissues, countering the lack of an adequate blood
`supply that is the defining feature of ischemia. EX2141, ¶42 (citing EX1096, 536; EX2003, 915); POR, 23‐24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`
`
`The risk of CGRP side effects from CGRP antagonism is particularly pertinent
`to migraineurs because of the link between migraine and stroke
`
`POR, 26‐28
`
`• Bousser (EX2157): A POSA would have known that there is “a complex bidirectional
`relation between migraine and stroke, including migraine as a cause of stroke,
`migraine as a risk factor for or as a consequence of cerebral ischaemia, and migraine
`and cerebral ischaemia sharing a common cause.” EX2157, 533; EX2141, ¶¶48‐59; POR, 27
`
`• Dr. Ferrari: “[A] POSA would have known that there was a connection between
`migraine and stroke, and that migraine patients were an at‐risk population for the
`occurrence of strokes.” EX2141, ¶58; POR, 6, 26‐27
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`24
`
`
`
`Long‐term blockade of CGRP activity would have been expected to have
`unacceptable side effects POR, 23‐30
`
`• Lilly’s expert, Dr. Vasserot:
`– “Antibodies also were known to have prolonged half‐lives, typically on the order of weeks.” EX1003,
`¶56 (citing EX1070, 18); POR, 30
`
`• Dr. Ferrari:
`– “Blocking [CGRP] function for long periods of time would have been expected to have serious,
`potentially life‐threatening, health risks to patients such as losing CGRP’s vasoprotective effects in
`preventing minor ischemic events (e.g., angina and cerebral transient ischemic attacks) from
`turning into serious events (e.g., myocardial and cerebral infarctions).” EX2141, ¶28; POR, 30
`• Dr. Foord:
`– Lilly’s experts, Drs. Charles and Vasserot, both agreed that the long half‐life of full‐length antibodies
`are advantageous for treatment of chronic diseases, yet did not consider that adverse side effects
`could occur from functionally depleting CGRP for weeks or months. EX2054, ¶76; EX1062, 43; EX2137, ¶¶50‐55;
`EX1059, 143, Figure 4.16; POR, 29‐30
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`
`
`Lilly’s Reply is wrong:
`The concerns regarding targeting CGRP
`still existed by November 2005
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`26
`
`
`
`Lilly’s “more recent” references are not informative as to the safety of
`anti‐CGRP antibodies Surreply, 13‐19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Surreply, 14
`
`27
`
`
`
`BIBN4096BS studies would not have assuaged concerns regarding
`anti‐CGRP antibody safety POR, 6‐7, 22, 28‐34; Surreply, 15‐16
`
`• Olesen:
`– “[O]ur data base was too small for us to assess cardiovascular safety.” EX1025, 1109; POR, 29;
`EX2141, ¶22
`• BIBN is a small molecule with a short half‐life:
`– Dr. Foord: “[T]he half‐life of BIBN4096BS is about 2.5 hours due in part to its small
`molecular weight, which means that it is cleared from the body after less than 24
`hours. And any side‐effects associated with BIBN4096BS would be expected to
`clear after this time.” EX2054, ¶84 (citing EX1042, 645); POR, 29‐30
`• Dr. Ferrari:
`– Any BIBN trials done in “healthy volunteers” “are the wrong experiments to assess
`cardiovascular safety of any drug interacting with CGRP” because they do not study
`whether the antagonist would “block rescue mechanisms in the times of ischemia.”
`Surreply, 16; POR, 28‐29; EX1303, 87:5‐17, 89:21‐90:3; EX2141, ¶¶48‐59; EX2193, 222; EX2157, 533; EX1025, 1108; EX1042, 647; EX2272,
`83:22‐84:13
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`
`
`CGRP receptor and ligand antagonism are not alternative or
`complementary strategies POR, 31‐33; Surreply, 21‐24
`
`Dr. Foord:
`– “[A] POSA would have appreciated the cross‐reactivity of CGRP binding at other receptors
`besides the CGRP receptor and the physiological or pathophysiological activities of CGRP
`binding to these other receptors. This would have prevented a POSA from considering the
`CGRP ligand or receptor as alternative, complementary strategies for blocking the CGRP
`pathway.” EX2054, ¶¶29‐37, 85‐87; POR, 31‐32
`– “[U]nder the spare receptor theory, the CGRP receptors in the microvasculature would
`only need a small amount of CGRP to be fully activated. Therefore, antagonizing the
`comparatively high concentration of CGRP molecules would have been expected to
`result in a different effect than antagonizing the comparatively lower CGRP receptor
`concentration in the microvasculature.” EX2054, ¶¶17, 38‐42; POR, 32‐33
`– “Because CGRP receptor and ligand antagonism are not ‘alternative, complimentary
`strategies,’ any data and conclusions about a small molecule receptor antagonist (e.g.,
`Olesen's BIBN4096S) are not informative to a POSA with regard to an anti‐CGRP antagonist
`antibody.” EX2054, ¶83; Surreply, 23‐24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`29
`
`
`
`Triptans, Aptamers, and CGRP8‐37 are not informative as to the safety of a
`humanized anti‐CGRP antibody Surreply, 13‐19; POR, 52
`
`• Triptans:
`– Short half‐life of only “about two hours.” EX1282, 7; EX2272, 99:1‐4; Surreply, 17
`– Different mechanism of action than anti‐CGRP antibodies: triptans agonize 5‐HT
`receptors. EX1040, 180‐181; EX2141, ¶21; EX2272, 99:20‐100:1; Surreply, 17
`
`• Aptamers:
`– Short half‐life—“hours to days.” EX1309, Abstract; EX2272, 114:6‐115:5; Surreply, 18
`– Have many characteristics that are similar to small‐molecules and are not “analogs
`to antibodies” as Lilly asserts. EX1309, Abstract; Surreply, 18
`
`• CGRP8‐37:
`– Short half‐life / receptor antagonist. Surreply, 16; POR, 28‐34; EX2141, ¶23
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`30
`
`
`
`Strong objective indicia evidence compels
`finding non‐obviousness of the claims
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`
`
`Strong objective indicia evidence compels finding non‐obviousness of
`the claims POR, 54‐64; Surreply, 25‐27
`
`• Nexus: Lilly fails to rebut the presumption of nexus between evidence of objective indicia and products
`encompassed by the claims (Ajovy®/Emgality®). POR, 54‐55, Surreply, 25‐26; EX2266, ¶114
`• Praise: Lilly does not dispute that the claimed invention is praised industry‐wide as, e.g., “an enormous
`step forward” or “a game changer” or “very exciting and compelling.” POR, 55‐57; Surreply, 26; EX2162, 449; EX2174,
`707; EX2172, 1‐2; EX2179, 4; EX2167, 117; EX2182, 207; EX2186, 4; EX2052, 1; EX2165, ¶¶57‐58
`• Long‐felt, but unmet need: Lilly admitted that the claimed antibodies provide a “[s]afe, effective and
`well tolerated treatment for the prevention of migraine” that satisfied an “enormous unmet medical
`need.” EX2161, 6; POR, 58‐59; Surreply, 26‐27; EX2165, ¶37‐38; EX2172, 1‐2; EX2174, 707
`• Commercial acquiescence to validity via licensing (AlderBio) and commercial success (market analyst
`conclusions) support nonobviousness. POR, 61‐64; Surreply, 27; EX2123; ¶¶15‐26
`• Skepticism: The claimed antibodies faced industry skepticism regarding potential side effects and lack of
`efficacy. POR, 61; EX2162, 447; EX2189, 3; EX1096, 568; EX2241, ¶¶85‐86
`• Unexpected results: the claimed antibodies are unexpectedly safe and achieve surprising efficacy in
`medication overuse headaches. POR, 59‐61; Surreply, 26; EX2162, 448‐449; EX2163, 543; EX2161, 891; EX2241, ¶¶81‐84;
`EX2165,¶¶15, 65‐69
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`
`
`The prior art would not have led a POSA to
`the claimed affinity of anti‐CGRP antibodies
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`
`
`Lilly did not prove that a humanized anti‐CGRP antibody with the claimed
`affinity would have been obvious POR, 44‐48; Surreply, 24
`
`• Tan 1994 does not disclose an affinity for human CGRP. EX2137, ¶¶108‐112; POR, 44‐48
`– Dr. Tomlinson: Tan 1994’s affinity data is not informative of affinity for human
`CGRP because it improperly used of a mix of rat and human CGRP in RIA. EX2137, ¶¶108‐
`112
`
`• The affinity of other antibodies is not relevant to anti‐CGRP antibodies. POR, 44‐47
`– Dr. Tomlinson: the affinity required for any given antibody to have biological or
`therapeutic effects is specific for the particular antigen. EX2137, ¶¶114‐115; POR, 44‐47
`
`• Tan 1994 demonstrates no correlation between higher affinity and better activity.
`POR, 44‐45; EX2137, ¶114
`– Tan 1994: the anti‐CGRP antibody MAb Rl.50 “clearly showed the greatest
`[binding] activity” to rat CGRP among all antibodies tested, yet it “blocked rat
`
`(cid:2009)CGRP poorly.” EX1021, 707; POR, 44‐45
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`34
`
`
`
`A POSA would not have had a reason to
`humanize anti‐CGRP Fab’ fragments
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`
`
`Lilly’s alleged rationales for humanization do not apply to Fab'
`fragments POR, 38‐41
`
`Lilly’s Argument
`Lilly’s experts, Dr. Charles and Dr. Vasserot:
`“[T]he longer half‐life of full‐length IgG antibodies (i.e.,
`on the order of weeks) would have been a preferred or
`desirable feature to a POSA seeking therapeutic
`treatments for chronic diseases.” EX1012, ¶136; EX1013,
`¶¶23, 110
`
`Lilly’s experts, Dr. Charles and Dr. Vasserot:
`“[E]liminating or minimizing undesired immunogenic
`responses was a strong motivating reason for
`humanizing antibodies.” EX1002, ¶132; Ex. 1003 ¶¶95‐96
`
`Fab’ Fragment
`
`Knight (EX2051):
`“Monoclonal antibody Fab fragments possess limited
`therapeutic utility because of their rapid disappearance
`from circulation.” EX2051, 415; EX2137, ¶55; EX2090, 72‐73;
`EX1301, 134:18‐25; IPR2018‐01427 POR, 39‐40
`Lilly’s expert, Dr. Vasserot:
`“Fab' fragments were generally only preferred in
`specific cases where a short serum half‐life was
`desired.” EX1003, ¶58 (citing EX1068, 361; EX1070, 18)
`
`Khazaeli (EX1072):
`“The Fab fragment of murine monoclonal reagents
`appears to be less immunogenic than the intact
`molecule.” EX1072, 45; EX2137, ¶¶102‐105; EX2107, 434; EX2131,
`286, 272; EX1062, 43; IPR2018‐01427 POR, 40
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`36
`
`
`
`Many challenged claims do not encompass Fab fragments
`
`Claims 16 and 17
`(IPR2018‐01422)
`POR, 37
`
`Claims 15 and 16
`(IPR2018‐01423)
`POR, 37
`
`Claims 15 and 16
`(IPR2018‐01424)
`POR, 38
`
`All Claims
`(IPR2018‐01425)
`Surreply, 7
`
`All Claims
`(IPR2018‐01426)
`Surreply, 7
`
`Claims 5 and 6
`(IPR2018‐01427)
`POR, 38‐39
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`
`
`Outstanding Motions
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`38
`
`
`
`Exhibit 1287 should be stricken or excluded from these proceedings
`
`Mot. to Strike, 2‐3; Mot. To Exclude, 2‐7
`
`• Exhibit 1287 was introduced in Reply to rehabilitate a hole in Lilly’s motivation argument. Mot. to Strike, 2‐3
`– 37 C.F.R. § 42.23; Henny Penny Corp. v. Frymaster LLC, No. 2018‐1596, slip. op. at *9 (Fed. Cir. Sept. 12, 2019)
`Paper 43, 1‐2
`• A Reply is for rebuttal, not to rehabilitate flawed theories in a Petition or
`introduce new arguments and evidence.
`
`• Lilly has not shown EX1287 was publicly available to a POSA before November 2005. Mot. To Exclude, 2‐7
`– “We do not have the paperwork with the date of deposit of the thesis in the University Library.”
`EX1307, 300; Mot. To Exclude, 6‐7
`– Kayak Software Corp. v. International Business Machines Corp., CBM2016‐00076, Paper 16, at 8 (PTAB December
`15, 2016)
`• “Determining public accessibility of a thesis for prior art purposes requires a showing
`of both shelving and meaningful indexing/cataloging” at a library. Kayak Software, Paper 16 at 8
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`
`
`Patent Claims
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`40
`
`
`
`IPR2018‐01422 (U.S. Patent No. 9,340,614)
`
`Challenged Claims: 1‐7, 15‐20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`41
`
`
`
`IPR2018‐01423 (U.S. Patent No. 9,266,951)
`
`Challenged Claims: 1‐6, 14‐19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`
`
`IPR2018‐01424 (U.S. Patent No. 9,346,881)
`
`Challenged Claims: 1‐6, 14‐19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`43
`
`
`
`IPR2018‐01425 (U.S. Patent No. 9,890,210)
`
`Challenged Claims: 1‐15
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`44
`
`
`
`IPR2018‐01426 (U.S. Patent No. 9,890,211)
`
`Challenged Claims: 1‐2, 7‐14
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`45
`
`
`
`IPR2018‐01427 (U.S. Patent No. 8,597,649)
`
`Challenged Claims: 1‐9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`46
`
`
`
`
`
`
`
`CERTIFICATE OF SERVICE (37 C.F.R. § 42.6(e))
`
`The undersigned hereby certifies that the “Patent Owner’s Demonstratives”
`
`was served in its entirety on November 15, 2019, via electronic mail upon the
`
`following counsel for Petitioner:
`
`Sanjay M. Jivraj
`
`
`William B. Raich
`Mark J. Stewart
`
`
`Erin M. Sommers
`Eli Lilly and Company
`
`
`Pier D. DeRoo
`
`Yieyie Yang Lilly Corporate Center Patent Dept.
`John Williamson
`
`
`
`Indianapolis, IN 46285
`Finnegan, Henderson, Farabow,
`jivraj_sanjay@lilly.com
`Garrett & Dunner, LLP
`
`
`stewart_mark@lilly.com
`901 New York Avenue, NW
`
`
`Washington, DC 20001
`william.raich@finnegan.com
`erin.sommers@finnegan.com
`pier.deroo@finnegan.com
`yieyie.yang@finnegan.com
`john.williamson@finnegan.com
`
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
`
`
`Deborah A. Sterling, Ph
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