`IPR2018‐01711
`IPR2018‐01712
`
`Eli Lilly and Company
`v.
`Teva Pharmaceuticals International GmbH
`
`January 8, 2020
`
`(* ‐ unless otherwise indicated, all citations to papers refer to IPR2018‐01710)
`
`1
`
`
`
`A POSA would not have had a reason to treat migraine with anti‐CGRP
`antibodies with a reasonable expectation of success
`• A POSA would not have extended Olesen’s small‐molecule receptor “CGRP
`antagonists” to anti‐CGRP ligand antibodies
`– Olesen: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine. EX1025, Abstract
`– Dr. Ferrari: “A POSA reviewing Olesen would not have drawn a conclusion that clinical trials using BIBN4096BS
`would translate broadly to all ‘CGRP antagonism’ being effective in treating migraine.” EX2268, ¶98; EX1040, 182; EX2265,
`60‐62; POR, 12‐13, Surreply, 6
`
`• Tan’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; EX2265, ¶51.
`
`• Active research of anti‐CGRP antibodies stopped with Tan
`– In the decade between Tan and Teva’s invention, multiple companies developed small‐molecule, short half‐life,
`receptor antagonists. POR 8‐9, EX2268, ¶52; EX2014, Abstract; EX2071, Abstract; EX2009, 617; EX2003, 910; EX2009, 617; EX2012, 769; EX2015; EX2016.
`
`• A POSA would not have reasonably expected an anti‐CGRP antibody to successfully treat
`migraine POR, 3‐4, 8, 19‐20, 35‐36, 38‐42, 45‐47; Surreply, 17‐25; EX2265, ¶¶60‐68, 88‐90, 134; EX1022, 565‐566, 571, Abstract; EX2268, ¶¶25‐38, 42, 56‐57, 75, 88‐
`90; EX1096, 567; EX2161, 6; EX2335, 1; EX2306; EX2291, 4; EX2296, 1452; EX2222, Abstract; EX2310, 5881; EX2223, 2; EX2306, 789.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`
`
`Teva’s invention led to breakthrough migraine therapy POR, 7, 32, 56‐59; Surreply, 27‐29
`• Lilly admits that Emgality® satisfied a long‐felt, unmet need:
`– “[A] Lilly co‐authored publication acknowledged that humanized anti‐CGRP antibodies were a ‘[s]afe,
`effective and well tolerated treatment for the prevention of migraine’ that satisfied this ‘enormous unmet
`medical need.’” POR, 59, EX2161, 890; EX2262, ¶40
`• “LY2951742 was effective and generally well tolerated for the preventive treatment of migraine in patients with frequent
`attacks.” EX2161, 890
`• “Safe, effective, and well tolerated treatment for the prevention of migraine represents an enormous unmet medical need.”
`EX2161, 890
`• The Industry praised the claimed methods of treatment:
`– “an enormous step forward” EX2172, 1‐2; POR, 56‐58; EX2260, ¶54
`– “a game changer” EX2179, 4; POR, 56‐58; EX2262, ¶56
`– a “breakthrough in migraine” EX2174 ,707; POR, 56‐58; EX2262, ¶53
`• Lilly’s expert, Dr. Charles, also praised the claimed methods of treatment as:
`– “radical concept” EX2053, 23; POR, 7, 32; EX2262, ¶61
`– “very exciting and compelling” EX2182, 207; POR, 56; EX2262, ¶61
`– “absolutely life‐changing” EX2186, 4; POR, 56; EX2262, ¶61
`– “spectacular” EX2186, 4‐5; POR, 56; EX2262, ¶61
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`
`
`Skepticism surrounded development of anti‐CGRP antibodies for treating
`migraine POR, 61‐62; Surreply, 28
`
`• Inventor Jaume Pons:
`– “Key Opinion Leaders (“KOL”) frequently expressed skepticism that an antibody like fremanezumab
`would be able to treat migraine because it could not cross the BBB. EX2331, ¶6
`– “Pfizer expressed the same concerns over fremanezumab’s ability to treat migraine due to its
`inability to enter the CNS.” EX2331, ¶7
`– “After Pfizer acquired Rinat, work on RN307 [fremanezumab] was halted for several years because
`Pfizer did not think that the molecule would treat migraine.” EX2331, ¶8
`– “Several of the [venture capital firms] expressed skepticism that treatment of migraine was
`possible with a drug that could not enter the CNS.” EX2331, ¶11
`
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`
`4
`
`
`
`Claim Construction
`
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`5
`
`
`
`“effective amount” is “an amount sufficient to effect beneficial or desired
`results” as defined in the specification POR, 10‐11; Surreply, 3‐4
`• The Board: “‘Effective amount’ is an amount sufficient to effect beneficial or desired
`results,’ including the results of prophylactic or therapeutic use, as those terms are
`used in the ’045 patent.” Decision, 12; POR, 10‐11
`• ’045 specification:
`
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`EX1001, 18:38‐57
`
`6
`
`
`
`“effective amount” is not an amount sufficient to inhibit cAMP activation
`without identifiable clinical change POR, 10‐11; Surreply, 3‐4
`
`• Surreply:
`– “[T]he specification unambiguously ties biochemical or histological symptoms to
`clinical results.” EX1001, 18:41‐44; Surreply, 4
`
`• Lilly’s Dr. Charles:
`– A physician treating migraine would want “to administer an effective amount that
`will help you achieve that clinical response.” EX2336, 66:1‐5; Surreply, 4
`– cAMP activation “can change without any effect on symptoms of a disease.” EX2336,
`57:13‐15; Surreply, 4
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`
`
`A POSA would not have had a reason to
`combine Olesen, Tan, and Queen
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`
`
`The art as a whole, which teaches MAb’s failure to immunoblockade and
`extensive safety concerns, provides “reasons not to combine” POR, 4‐6, 24‐33;
`
`Surreply, 28
`
`• 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.” Id. 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.” Id. at 1360
`
`• Lilly’s obviousness challenge failed to consider the art as a whole and failed to
`consider safety concerns. POR, 4‐6, 24‐33; EX2268, ¶¶103‐143; EX2271, ¶¶69‐84
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`9
`
`
`
`Nothing in the art suggests Lilly’s broad extension of “CGRP antagonists”
`to anti‐CGRP antibodies POR 12‐13; Surreply, 6
`• Dr. Foord:
`– “Olesen does not discuss or lead a POSA to anti‐CGRP antagonist antibodies.” EX2265,
`¶¶60‐62
`
`• Dr. Ferrari:
`– “A POSA reviewing Olesen would not have drawn a conclusion that clinical trials
`using BIBN4096BS would translate broadly to all ‘CGRP antagonism’ being effective
`in treating migraine.” EX2268, ¶98
`– Arulmozhi cites to Edvinsson (EX2009), which “only refers to two classes of
`compounds: CGRP receptor antagonists and triptans (5HT receptor inhibitors that
`inhibit CGRP release).” EX2268, ¶98; EX1040, 182; EX2009, 617‐618
`
`• Lilly’s assertion that Teva’s experts agree in their own publications is baseless:
`– EX1332 (post‐filing), EX1290 and EX1297 all discuss only BIBN4096BS as “CGRP
`antagonists.” Surreply, 6
`
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`
`10
`
`
`
`The field was focused on small‐molecule receptor antagonists POR, 8‐9
`
`• Dr. Ferrari confirms: before November 14, 2005, the field focused on “CGRP receptor
`antagonists [that] are all small molecules with a short half‐life appropriate for acute
`treatment of migraine, but not preventative treatment” EX2268, ¶ ¶ 50‐52
`– Olesen (EX1025); Doods (EX1024)—BIBN4096BS, a CGRP receptor antagonist
`– Chiba (EX2004); Brain and Grant (EX2003)—CGRP8‐37, a CGRP receptor antagonist
`– Merck: multiple families of CGRP receptor antagonists. EX2014, Abstract; EX2071, Abstract
`– Boehringer Ingelheim: CGRP receptor antagonist “compound 1.” EX2009, 617
`– SmithKline Beecham Pharmaceuticals: CGRP receptor antagonist SB‐273779. EX2003,
`911; EX2012, 769
`– Grunenthal GmbH and Bristol‐Myers Squibb: receptor antagonists. EX2015; EX2016
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`
`
`Lilly’s reasons to combine the cited art based on the alleged “therapeutic
`advantages” of targeting CGRP over its receptor fail POR, 24‐35, 60; Surreply, 6‐8, 13‐14
`
`Lilly Alleged That…
`“a POSA would have known that small molecule receptor
`antagonists are often not sufficiently specific for a given receptor.”
`Petition, 28
`
`BUT
`
`“Monoclonal antibodies have the ‘inherent advantage of defined
`specificity’” compared to “small molecule receptor antagonists.”
`Petition, 28, citing to EX1022, 572 (Tan)
`
`“A POSA also would have chosen antibodies to avoid the known
`side effects of existing small‐molecule migraine drugs.” Petition, 32
`
`“The prior art had embraced humanized antibodies for treating
`human patients to reduce immunogenicity” Petition, 33.
`
`“[A] POSA would have been motivated to use a longer acting drug,”
`e.g., “humanized monoclonal antibody.” Petition, 31
`
`“Olesen’s clinical study demonstrated that blocking CGRP pathway
`[with BIBN4096BS] effectively treats migraine in human patients.”
`Petition, 24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`a POSA Would Have Known That…
`
`Olesen’s BIBN4096BS was a “highly” and “extremely” specific CGRP receptor antagonist. EX1025,
`Abstract, 1105; POR, 33
`
`Tan (EX1022) touts inherent advantages over polyclonal antibodies, not small molecules: “An
`advantage of goat polyclonal anti‐CGRP Fab fragment over IgG in blocking capsaicin‐induced
`inflammatory responses has been demonstrated after intradermal injection into rabbit skin … The
`present investigations have been performed with an MAb with inherent advantages of defined
`specificity, known affinity, reproducibility, and unlimited availability.” POR, 34; EX2265, ¶¶92‐94
`
`“Blocking [CGRP’s] 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).” EX2268, ¶105; POR, 30
`
`“Because antibodies have long half‐lives and accordingly long durations of action, a POSA would have
`had to account to the risk of [cardiovascular and cerebrovascular] side effects over a period of
`weeks, months, or longer.” EX2268, ¶¶12, 104‐105; EX2265, ¶120; EX2271, ¶¶76‐80; POR, 30
`
`“[O]nly the Fab' fragment was found to be an effective tool for blockade of the increased hind paw
`skin blood flow after antidromic stimulation of the saphenous nerve.” EX1022, 570; POR, 60
`
`12
`
`
`
`Alleged higher specificity of Abs over small molecules provided no
`motivation to use an anti‐CGRP Ab to treat migraine POR, 20‐21, 33‐34; Surreply 7‐8
`• Olesen’s BIBN4096BS was “extremely” specific:
`– “BIBN 4096 BS is a nonpeptide CGRP‐receptor antagonist with an extremely high affinity and
`specificity for the human CGRP receptor.” EX1025, 1105; EX2265, ¶78; POR, 6, 33
`
`• CGRP ligand antagonism with an Ab does not guarantee a more specific
`pharmacological effect because CGRP also cross‐reacts with other receptors:
`– “[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.” EX2265, ¶¶32‐40, 66‐68; POR, 20‐21
`
`• Lilly’s argument that “inherent advantages” of anti‐CGRP antibodies provided
`motivation mischaracterizes Tan’s discussion of anti‐CGRP sera vs. monoclonal
`antibodies:
`– Tan: “An advantage of goat polyclonal anti‐CGRP Fab fragment over IgG in blocking capsaicin‐
`induced inflammatory responses has been demonstrated after intradermal injection into rabbit skin
`… The present investigations have been performed with an MAb with inherent advantages of
`defined specificity, known affinity, reproducibility, and unlimited availability.”EX1022, 572; POR, 34; EX2265,
`¶¶92‐94
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`
`13
`
`
`
`Toxicity concerns negated motivation to use full‐length anti‐CGRP Abs to
`treat migraine POR, 5, 30; Surreply, 5, 8‐10
`• A POSA would have expected an unacceptable level of cardiovascular and
`cerebrovascular toxicity in migraine patients with anti‐CGRP antibodies. POR, 5; EX2265, ¶¶112‐
`133; EX2268, ¶¶119‐136; EX2157, 533; EX2086, 15; EX2088, 63; EX2158, S24‐S25.
`• Dr. Ferrari:
`– “Blocking [CGRP’s] 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).” EX2268, ¶105; POR, 30; see also EX2268, ¶¶12, 104‐105; POR, 30
`• Dr. Foord:
`– “[T]he long half‐life of full‐length antibodies could further exacerbate or cause adverse
`side effects discussed above because administration of full‐length anti‐CGRP antagonist
`antibodies would functionally deplete CGRP for weeks or months.” EX2265, ¶120; POR, 30
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`14
`
`
`
`Full‐length anti‐CGRP Abs were shown not to be efficacious POR, 3‐4, 14‐15, 35‐36, 60
`
`• Tan:
`– “[O]nly the Fab' fragment was found to be an effective tool for blockade of the
`increased hind paw skin blood flow after antidromic stimulation of the saphenous
`nerve.” EX1022, 570; POR, 60
`
`• Dr. Foord:
`– “Tan showed that administration of an anti‐CGRP antagonist antibody was not
`effective in an assay attempting to functionally deplete endogenous CGRP at its
`sites of action.” EX2265, ¶82
`
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`15
`
`
`
`Tan is not clinically relevant and its
`anti‐CGRP monoclonal antibody
`fails to immunoblockade
`
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`
`16
`
`
`
`Tan is not related to any clinical or therapeutic use POR, 4, 14‐15
`• Lilly’s expert, Dr. Charles’ declaration:
`– “Grossly mischaracterizes” Tan as providing “guidance to a POSA on how to use full‐length
`antibodies” “to reduce incidence of or chronically treat migraine” EX1014, ¶134‐136; Petition, 38‐40; EX2265,
`¶86‐91; POR, 4, 14‐15
`• But in Dr. Charles’ deposition:
`– He admitted that Tan “is talking about experiments, not actually treating any disease.” EX2192, 156:2‐9;
`POR, 4
`• Other experts agree that Tan is not related to clinical or therapeutic use:
`– Lilly’s expert, Dr. Vasserot: Tan does not provide “any clinical evidence regarding efficacy of
`administering an anti‐CGRP antagonist antibody to humans to treat a disease.” EX2191, 122:16‐123:15; POR,
`4, 15
`– Dr. Foord: “Tan … draws no therapeutic or clinical conclusions.” EX2265, ¶82‐83; POR, 14‐15
`– Dr. Tomlinson: “Tan does not contain any discussion of diseases.” EX2271, ¶89‐91; POR, 14‐15
`– 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.” EX2268, ¶137‐141; POR, 14‐15
`
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`17
`
`
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`Tan 1995 concludes: a full‐length anti‐CGRP antibody does not block CGRP
`activity in vivo POR, 27, 35‐36, 60; Surreply, 18
`
`EX1022, 569; POR, 27, 60; EX2265, ¶84; EX2268, ¶137
`
`EX1022, 571; POR, 35‐36
`
`EX1022, 570; POR, 60
`
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`18
`
`
`
`Tan’s statement that further nerve stimulation with longer incubation time with a full‐
`length anti‐CGRP antibody “produced an AUC which was slightly smaller compared
`with baseline stimulation, but not by more than 16% (n=2)” is “ambiguous” POR, 3‐4, 16, 35‐
`36; Surreply, 18
`
`• Lilly’s expert, Dr. Charles:
`– “Tan 1995 confirmed that (1) administering CGRP to rats suppresses mean arterial pressure
`and increases heart rate; and (2) the full‐length IgG antibody MAb C4.19 generates
`immunoblockade and abolishes the effects of CGRP.” EX1014, ¶55, 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, 35‐36; EX2265, ¶85; EX2271, ¶91
`
`• 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, 3‐4, 16; Surreply, 18
`
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`19
`
`
`
`Safety concerns would have dissuaded
`a POSA from therapeutic use of
`anti‐CGRP antibodies
`
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`20
`
`
`
`Lilly admits that a POSA would have considered side‐effects in developing
`human treatment methods with antibodies but then ignores serious, art‐
`known side‐effects Petition, 32, 34; POR, 24; Surreply, 4‐5
`
`• Lilly’s Petition:
`– “A POSA also would have chosen antibodies to avoid the known side effects of existing
`small‐molecule migraine drugs.” Petition, 32
`– “a POSA would have been motivated to make humanized anti‐CGRP antagonist antibody to
`minimize the risk of immunogenicity,” e.g., “serum sickness and other harmful effects.”
`Petition, 34
`
`• Lilly, in effect, argues that a POSA would only consider side‐effects that help its
`position, and ignores other side‐effects that were expected with anti‐CGRP antibodies.
`POR, 24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`21
`
`
`
`CGRP was known to regulate blood pressure and to prevent
`hypertension‐related health problems POR, 24‐28; EX2268, ¶¶115‐118, 125‐131; Surreply, 15
`
`• 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; EX2265, ¶26;
`EX2268, ¶113; POR, 7‐8
`– “[I]nfusion of CGRP is beneficial in increasing cardiac output and lowering blood
`pressure in patients with congestive heart failure.” EX2003, 919; EX2268, ¶116; POR, 8, 25
`• 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; EX2268, ¶125; POR, 24‐25
`
`• 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; EX2268, ¶125; POR, 24‐25
`
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`
`22
`
`
`
`CGRP was known to protect against escalation of ischemic events POR, 5‐7, 24‐26;
`
`Surreply 15‐16
`
`• Juul (EX2139): CGRP is “involved in a reflex mechanism to counterbalance cerebrovascular constriction.”
`EX2139, 68‐69; EX2268, ¶122; POR, 5, 24‐26
`
`• 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; EX2268, ¶¶116, 120;
`POR, 8, 2
`
`• 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.’” EX2268, ¶117 (quoting EX2009,
`614‐615); POR, 8, 25
`
`• 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; EX2268, ¶¶119‐120; POR, 26
`
`• Dr. Ferrari:
`– Inadequate CGRP during an ischemic attack heightened the risk for transient mild ischemic events
`turning into full‐blown infarctions. EX2268, ¶¶105, 119‐124; POR, 24‐26
`– 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. EX2268, ¶119 (citing EX1096, 536; EX2003, 915); POR,
`24‐26
`
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`23
`
`
`
`The risk of side effects from CGRP antagonism is particularly pertinent to
`migraineurs because of the link between migraine and stroke POR, 5, 25‐27; Surreply
`
`15‐16
`
`• 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; EX2268, ¶¶125‐136; POR, 25
`
`• 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.” EX2268, ¶132‐136; POR, 5, 25‐27
`
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`24
`
`
`
`Long‐term blockade of CGRP activity would have been expected to have
`unacceptable side effects POR, 4‐6, 24‐32; Surreply, 9‐17
`
`• Lilly’s expert, Dr. Vasserot:
`– “Antibodies also were known to have prolonged half‐lives, typically on the order of weeks.” EX1015,
`¶55 (citing EX1070, 18); POR, 29‐30
`
`• 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).” EX2268, ¶105; 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. EX2265, ¶120; EX2271, ¶¶54‐59; EX1059,
`143, Figure 4.16; POR, 29‐30
`
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`25
`
`
`
`Lilly’s Reply is wrong:
`The concerns regarding targeting CGRP
`still existed by November 2005
`
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`26
`
`
`
`Lilly’s “more recent” references are not informative
`as to the safety of anti‐CGRP antibodies Surreply, 12
`
`CGRP vasoprotective activity
`
`Short half‐life CGRP receptor antagonist
`
`Short half‐life aptamer
`
`Ex. 2152
`CGRP (8‐37)
`
`Ex. 2209
`CGRP (8‐37)
`
`Ex. 1283
`CGRP (8‐37)
`
`Ex. 1284
`BIBN4096BS
`
`Ex. 2019
`BIBN4096BS
`Ex. 1042
`BIBN4096BS
`Ex. 1263
`BIBN4096BS
`Ex. 1025
`BIBN4096BS
`Ex. 1285
`CGRP (8‐37)
`Ex. 1318
`BIBN4096BS
`
`Ex. 1240
`Aptamer
`
`1990
`
`1991
`
`1992
`
`1993
`
`1994
`Ex. 2139
`CGRP “may reverse significantly the
`vasoconstriction seen after SAH”
`Ex. 2058
`CGRP “delays the onset of myocardial
`ischaemia during treadmill exercise”
`Ex. 2089
`Age‐related changes in CGRP levels “may contribute to
`the increased incidence of cardiovascular episodes.”
`Ex. 2070
`Evaluated circadian variation in plasma
`concentrations of CGRP
`Ex. 2154
`CGRP levels were “reduced” after
`subarachnoid haemorrhage (SAH)
`Ex. 2079
`CGRP “improves myocardial contractility in
`patients with congestive heart failure”
`Ex. 2151
`CGRP “may be acting as a local mediator in the
`pathophysiology of [acute myocardial infarction]”
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1995
`
`1996
`
`1997
`
`1998
`
`1999
`
`2000
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`Ex. 2150
`CGRP is possibly involved in “protection
`of the myocardium during ischemia.”
`
`Ex. 2003
`CGRP plays a “pivotal role” in the “physiology and
`pathophysiology of cardiovascular regulation.”
`
`Ex. 2005
`CGRP protects against “hypertension‐induced” organ
`damage and from “ischemia/reperfusion injury”
`
`27
`
`
`
`BIBN4096BS studies would not have assuaged concerns regarding
`anti‐CGRP antibody safety POR, 6‐9, 20‐23, 28‐31; Surreply, 6‐8, 13‐14
`
`• Olesen:
`– “[O]ur data base was too small for us to assess cardiovascular safety.” EX1025, 1109; POR, 29; EX2268,
`¶¶50, 101; Surreply, 13‐14
`
`• 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 along with
`BIBN4096BS during a time frame measured in hours.” EX2265, ¶65 (citing EX1042, 645); POR, 29
`
`• Dr. Ferrari:
`– The BIBN4096BS studies in Iovino (EX1042) and Petersen (EX2019) were done in “healthy
`volunteers,” which would not assess whether BIBN4096BS would “block rescue
`mechanisms in the times of ischemia.” Surreply, 13; EX1303, 87:5‐17, 89:21‐90:3; EX2268, ¶¶113‐144; EX2193, 222;
`EX2157, 533; EX1025, 1108; EX1042, 647; EX2019, 144; EX2338, 83:22‐84:13; POR, 7‐8, 24‐25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`
`
`CGRP receptor and ligand antagonism are not alternative or
`complementary strategies POR, 20‐23; Surreply, 6‐8
`
`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 or complementary strategies” for blocking the
`CGRP pathway.” EX2265, ¶¶32‐40, 66‐68; POR, 20‐21
`– “[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.” EX2265, ¶¶17, 41‐45, 69‐76; POR, 22‐23
`– “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 ligand
`antagonist antibody.” EX2265, ¶¶ 64‐81; Surreply, 7‐8
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`
`29
`
`
`
`Triptans, Aptamers, and CGRP8‐37 are not informative as to the safety of a
`humanized anti‐CGRP antibody POR, 8‐9, 44‐45; Surreply, 10‐15
`
`• Triptans:
`– Short half‐life of, e.g., sumatriptan, is only “about two hours.” EX1282, 7; EX2338, 99:1‐4; Surreply, 14
`– Different mechanism of action than anti‐CGRP antibodies: triptans agonize 5‐HT
`receptors and inhibit CGRP release. EX1040, 180‐181; EX2268, ¶49; EX2338, 99:20‐100:1; Surreply, 14
`
`• Aptamers:
`– Short half‐life—“hours to days.” EX1309, Abstract; EX2338, 114:6‐115:5; EX2265, ¶¶110‐111; Surreply, 14‐15
`– Have many characteristics that are similar to small‐molecules and are not “analogs to
`antibodies” as Lilly asserts. EX1309, Abstract; EX2265, ¶¶110‐111; Surreply, 14‐15
`
`• CGRP8‐37:
`– Short half‐life / receptor antagonist. Surreply, 10‐12; POR, 8‐9, 20‐23; EX2268, ¶51
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`30
`
`
`
`Cited art does not provide the “carefully designed studies” that might
`motivate a POSA to consider anti‐CGRP antibodies for treating migraine
`POR, 42‐45
`• 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, 13, 44‐47; EX2265, ¶¶104‐107; EX2268, ¶¶54, 149
`• Lilly’s expert, Dr. Charles, agrees that the cited references contain “no data” on
`treating migraine with anti‐CGRP antibodies.
`Dr. Charles agrees: “No evidence is presented” on “therapeutic efficacy of treating migraine with anti‐
`CGRP antibodies.” EX2277, 53:17‐54:1; POR, 43‐44; EX2268, ¶150
`
`“The only reference to headache or migraine in Sveinsson is at page 7, line 8, in a paragraph referring to
`antibodies to the CGRP receptor, not CGRP.” POR, 43; EX1026, 7:5‐12.
`Dr. Charles agrees: no “data regarding the administration of an anti‐CGRP antibody.” EX2277, 72:4‐8; POR, 44;
`EX2265, ¶¶108, 129; EX2268, ¶151.
`
`“Salmon (EX1027) mentions only in passing that CGRP antagonists could be used to inhibit the effect of
`CGRP in inflammatory pain or opiate withdrawal” POR, 44; EX2265, ¶¶108, 129; EX2268, ¶151; EX2277, 72:4‐8.
`
`EX1026
`(Sveinsson)
`
`EX1027
`(Salmon)
`
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`
`
`
`A POSA would not have had a
`reasonable expectation of success
`
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`
`
`
`Federal Circuit precedent demands finding of non‐obviousness based
`on lack of a reasonable expectation of success POR, 8, 19‐20, 35‐36, 38‐42, 45‐47; Surreply, 17,
`
`21‐25
`• Novartis Pharmaceuticals Corp. v. West‐Ward Pharmaceuticals Int’l Ltd., 923 F. 3d 1051 (Fed. Cir. 2019)
`
`Novartis v. West‐Ward
`Method of Treatment claims
`
`Current Proceedings
`Method of Treatment claims
`
`The prior art lacked an “express disclosure” that the everolimus
`“would be effective in treating” cancer. Reply, 20; Surreply, 25
`
`Tan’s antibody failed to immunoblockade in vivo. POR, 35‐36; Surreply, 25;
`EX2265, ¶134; EX1022, 565, 571
`
`No “preclinical or clinical data showing any antitumor activity of
`everolimus.” POR, 46
`
`Lilly could only point to Phase II clinical data with BIBN4096BS, not with an
`IgG. Reply, 21; Surreply, 25
`
`Phase I data with temsirolimus came from “small sample sizes,”
`and therefore had “diminished weight.” POR, 46
`
`Olesen’s BIBN4096BS “data base was too small.” EX1025, 1109; POR, 47
`
`Temsirolimus and everolimus are “pharmacologically different.”
`POR, 46
`
`IgG and BIBN4096BS are pharmacologically different. EX2265, ¶¶60‐65;
`POR, 47
`
`Molecular biology of the claimed cancer was “not fully
`understood.” POR, 46
`
`The art called for “additional experiments.” POR, 46‐47
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Many unknowns in the field (pathophysiology of migraine, site of action of
`anti‐migraine drugs, CGRP being a biomarker for migraine). POR, 8, 19‐20,
`38‐40; EX2268, ¶¶25‐38, 42, 56‐57
`The art called for “more data from carefully designed studies.” EX1096,
`567; POR, 47
`
`33
`
`
`
`In 2005, there was no consensus as to the pathophysiology of migraine
`
`POR, 8; EX2268, ¶¶25‐38
`
`1.
`
`Dr. Ferrari:
`– “As of November 14, 2005, there were three principle theories” (EX2268, ¶27; EX1040, 178‐179 ):
`The vascular theory:
`– “[T]ransient ischemia (shortage of oxygen) and oligemia (reduction in blood volume) induced by
`vasoconstriction caused aura in migraineurs, whilst the headache pain reflected rebound abnormal
`vasodilation and mechanical activation of perivascular trigeminal nerve endings.” EX2268, ¶¶28‐31;
`EX2289, 374‐375
`The central neuronal theory:
`– “[M]igraine involved activation and sensitization (sometimes referred to as hypersensitization) of
`the trigeminovascular pathways.” EX2268, ¶¶32‐33; EX2295, 283; EX2289,373‐375
`The neurogenic inflammation theory:
`– “[A]ctivation of the trigeminal system causes the release of vasoactive peptides (for example
`Substance P, neurokinin A and CGRP) onto dural tissues.” EX2268, ¶¶35‐37; EX2289, 375
`
`2.
`
`3.
`
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`
`
`
`Tvedskov showed that CGRP is not increased during a migraine attack POR, 17‐
`
`20; EX2268, ¶¶56‐57; Surreply, 22‐24
`
`• Tvedskov and Olesen (EX2309) in September 2005:
`– “CGRP is not increased in external jugular blood during attack of migraine without
`aura, nor in peripheral blood.” EX2309, 564‐566
`• Goadsby (EX1043), etc., did not account for the “large interindividual variation of CGRP” caused
`by gender, age, pregnancy, oral contraception, opiate use, arterial hypertension, sample
`collection, or exercise levels. Id.
`• Lilly’s Dr. Charles:
`– Tvedskov and Olesen (EX2309) “was contrary to the generally accepted
`understanding that CGRP levels were elevated as part of a migraine attack.” EX2336,
`77:12‐17
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`
`
`
`In 2005, there was a vigorous debate regarding the site of action of anti‐
`migraine drugs (e.g., BIBN4096BS and triptans): central vs. peripheral POR, 38‐
`
`40; Surreply, 17, 21‐23
`
`• Levy (EX2298, 704): “[O]ur results are consistent with a growing body of evidence suggesting
`that the facilitatory effect of CGRP on discharge of central trigeminovascular neurons results
`from a central, rather than a peripheral, site of action.”
`• Fischer (EX2310, 5881): “[W]e cannot exclude a central site of action of [BIBN4096BS].”
`• Ahn (EX2291, Abstract): As of 2005, “it was not clear whether the antimigraine activity of the
`triptans involves an action only in the periphery or in the CNS as well.”
`• Kaube (EX2306, 791): “[S]umatriptan has no effect on isolated pial vessels when it acts as a
`vasoconstrictor, again suggesting that the blood‐brain barrier must be passed for a significant
`action to be seen.”
`• Araki (EX2282, 127, EX2268, ¶82): “Since the success of sumatriptan, various triptan agents
`have been developed by improving the weak points of sumatriptan (the elimination half‐life in
`the blood is short, crossing the blood‐brain barrier is weak, and the metabolites do not have
`an inhibiting action on migraine).”
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`36
`
`
`
`Transient breaks in the blood‐brain barrier would allow BIBN4096BS to
`cross, adding to the uncertainty about the site of action POR, 41‐42; EX2268, ¶42; Surreply,
`
`22‐23
`
`• Dr. Ferrari:
`– “[T]here are human case reports showing that there is transi