UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ELI LILLY AND COMPANY
`
`V.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`
`Case IPR2018-01710 (Patent No. 8,586,045)
`
`Case IPR2018-01711 (Patent No. 9,884,907)
`
`Case IPR2018-01712 (Patent No. 9,884,908)*
`
`ELI LILLY TRIAL DEMONSTRATWES
`
`January 8, 2020
`
`% {*unleee indicated etherwiee, eitatiene in papers referto IPR2U1B-U1i1fl)
`
`Demonstrative Exhibits — Net Evidence
`
`

`

`The Breadth of Teva’s Claims
`
`The ’045 Patent:
`
`The ’908 Patent:
`
`We claim:
`We claim:
`1.131 method for reducing incidence ot‘orm 1* A ”13‘th for— in an individual,
`comprising:
`_in an individual, comprising admin-
`administer-in to the individual an efi'ective amount of a
`”wherein sand ant1-CGRPanta otust anti-
`
`.
`.
`.
`.
`.
`.
`istenng to the individual an efiective amount o
`
`o y is a uman monoclonal antibody or a
`
`mono-
`
`comprising:
`
`two human IgG heavy chains, each heavy chain compris-
`ing three complementarity determining regions {CDRs]
`and four flamework regions, wherein portions of the
`two heavy chains together fon'n an Fc region; and
`two light chains, each light chain comprising three CDRs
`and four framework regions;
`wherein the CDRs impart to the antibody specific binding
`to a CGRP consisting of amino acid residues ] to 37" of
`
`clonal antibody.
`
`
`Ex. 1001 {'045 Patent), 99:15."r
`
`SEQ ID N015 or SEQ ID NO: 43, and wherein the
`
`antibody binds to the CGRP with a binding affinity
`
`{KB} of about 10 11M or less as measured by surface
`
`plasmon resonance at 3?“ C.
`
`;
`
`DEMDNSTRATWE EKHEBIT- NUT EVIDENCE
`
`2
`
`Ex. 1001 {'908 Patent}, 99:54-6?, 1fl0:54-58
`
`

`

`I
`
`The Combination of Olesen, Tan 1995, and Queen
`
`Renders Teva’s Claims Obvious
`
`I
`
`Olesen 2004
`
`(Ex.1025)
`
`Tan 1995
`
`(Ex. 1022)
`
`Combination
`
`claimed methods
`
`with a reasonable
`expectation of
`
`achieves the
`
`success
`
`Queen 2001
`
`(Ex.1023)
`
`
`
`Pet, 24-25
`
`;
`
`DEIIIUNETRATWE EKHIBIT- NUT EVIDENCE
`
`3
`
`

`

`I A POSA in 2005 Expected CGRP Antagonists to Treat Migraine I
`
`Doods (Ex.1024):
`
`"Since several lines of evidence indicate that CGRP might be a kev factorIn the initiation of
`
`migraine headache ..
`
`Lassen 2002(Ex.1047):
`
`factor in several diseases, including migraine”
`
`"Evidence is accumulating that inappropriate release of CGRP is a potential causative
`
`-
`
`5
`
`DEMONSTRATWE EKHIBIT- NUT EVIDENCE
`
`4
`
`Ex. 1096, 56?, 5'30; Ex. 1D14,1]116;Pet.,29
`
`

`

`I A POSA in 2005 Expected CGRP Antagonists to Treat Migraine I
`
`Olesen (Ex. 1025):
`
`Arndt 2004 (Ex. 1030):
`
`Multicenter, double-biind, randomized
`
`ciinical trial of BIBN4OQEBS
`
`126 patients with migraine
`Intravenous administration
`"Proof of concept was thus established .”
`Conciusion: "The
`,:
`
`4095 BS was
`
`'=
`
`.
`
`Olesen’s data "demonstrate the ..-:_-;.
`
`:-"
`
`,
`
`'
`
`If.
`
`."_-_';:
`
`I":
`
`[1 511.354. IIBVing 3 HDVEI WHY IE:
`
`:1 5:.r
`
`attacks of
`
`_
`
`'
`
`Ex. 1030, 129; Ex. 1014, 111169, 116; Pet, 15, 30
`
`Dr. Charles:
`
`Ex. 1025, 1104, 1103-1109; Ex. 1014,1m31-34; Pet, 25-26
`
`Ex. 1014, 11109; Pet, 25-26
`
`5
`
`DEMONSTRATWE EKHIBIT- NUT EVIDENCE
`
`5
`
`

`

`I A POSA in 2005 Expected CGRP Antagonists to Treat Migraine I
`
`Dr. Ferrari in 2005:
`
`'-
`
`“Olesen and colleagues evaluated the effectiveness of the CGRPfiantagonist BIBN4OQSBS
`
`.
`.
`Dr. Ferran In 2007:
`
`Ex.1290,65?;Ex.133B,
`
`113
`
`9; Re I ,5
`P?
`
`for acute migraine treatment....There were no serious adverse events”
`important new emerging treatment principle for acute migraine.”
`
`Olesens studv “firmlv establish[ed] 7.5
`
`::'::-:..f-.5:':-:-
`
`"T
`
`T.- -='-51'
`
`:.::.i:i.'.‘.
`
`as a novel and
`
`Dr. Rapoport in 2005:
`
`Ex. 1332, 443; Ex. 1333,1129; Reply, 5
`
`Olesen’s studvrsuggests that
`
`.Preventive drugs might be developed on the same principle.”
`
`;.:; .
`
`2; ; " --
`
`'-
`
`'
`
`5
`
`DEMDNSTRATWE EKHEBIT- NUT E‘III'IDENCE
`
`6
`
`Ex. 129T, 3119; Ex. 1338,1129; Reply, 5
`
`

`

`I
`
`Well-Known Advantages of Humanized Antibodies
`
`I
`
`for Chronic Treatment
`
`Long Half-Lives to Treat Chronic
`
`Migraine Conditions
`
`Ex. 1041, 1013; Ex. 1014,1111124-126; Ex. 1015,1155; Pet, 31; Reply, 14
`
`Lower Toxicity and Fewer Side-
`
`Effects Compared to Small
`
`Molecules
`
`
`
`Ex. 1014,1112'r'; Ex. 1015,1155; Ex. 133?,111ITT-i'9; Pet, 32
`
`Ex. 1014.1132; Ex. 1015. 1155; Ex. 1266, 521; Pet, 32; Remy, 20
`
`Reduced Immunogenicity in
`
`Human Patients
`
`Ex. 1023, 1:44—4?; Ex. 1015,111193-95; Ex. 1014,11120; Pet, 33-34
`
`Ex. 10?3, 120; Ex. 1014,11119; Ex. 1015, 111141, 93, 93; Pet, 33
`
`;
`
`DEMONSTRATWE EXHIBST- NUT E‘IfiDENCE
`
`7
`
`

`

`I
`
`Long Half-Life Desired for Chronic Migraine Treatment
`
`I
`
`Dr. Charles:
`
`- Episodic Nature of Migraine: Motivated a POSA "to target long-term approaches for
`
`- Duration of Attack "Because a migraine attack can last anywhere between
`H a POSA would have been motivated to look for
`.2;
`'-
`
`i?
`
`”
`
`for longer periods of time.
`
`
`Dr. Vasserot:
`
`56 1
`
`Ex. 1281, 3'36; Ex. 1294, Abstract; Ex. 1266, 521; Ex. 1338.1]1118-19; Reply, 14
`DEMONSTRATI‘U'E EXHIBST - NUT EVIDENCE
`8
`
`

`

`I
`
`Teva Admitted CGRP’s Involvement in Migraine
`
`I
`
`Teva Theory:
`
`Teva Patents:
`
`' Gcadsby 111111. AnnNeurcl 2311337 1990.1111111" 1.111
`
`1.1.1177 i"""-.'H“l
`
`rialu ularvein .'
`
`.1
`
`-
`
`-
`
`-'
`
`intheexter—
`
`Ex. 1flfl1 [”345 Patent}, 2:19; Reply, 6
`
`that Inhibit relesae fGRP (e.g., sumatripnta), antagcnize at
`the CGRP receptcr (e1g1, dipeptide derivative BIBN4096BS
`(Bcerhringer Ingelheim); CGRP (8-3 7)), cr interact with cne
`cr more of receptcr-asscciated proteins, such as, receptcr
`activity membrane protein (RAMP er rece tcr ccm enent
`
`iretein iRCP), both cfwhich
`
`lil'nili.
`
`541.
`
`I”11117131113111|'1.1_=.__'-i1.‘1':l H1133-
`
`11"1 1'Il..
`
`'!'i'1:i|1i~1 ii':
`
`I
`
`5
`
`DEMDHSTRATWE EKHEBIT- NUT EVIDENCE
`
`9
`
`Ex. 1001 {1145 Patent), 2:14-23; Pet, T
`
`

`

`I
`
`Spare Receptor Theory and Ligand Cross-Binding
`
`Did Not Deter Researchers
`
`I
`
`Teva Theories:
`Sheykhzade 2004 (Ex. 2065):
`_ "In our study, approximately «:=:.::'-‘
`occupied by CGRP to
`.
`-
`*
`_-_
`indicating the presence of a relatively small CGRPl-receptor
`reserve poolIn the human subcutaneous arteries.”
`
`
`
`Dr. Charles:
`
`Ex. 2055, 1cm; Ex. 133?, 1145; Reply, 13-19
`
`"[T] here is no indication that it would be necessary to 'sequester
`99,999 ligands’ out of 100,000 (i.e., 99.999943 of all CG RP
`
`molecules) to preyent anti C-G RP antagonist antibodies from
`
`;
`
`DEMONSTRATI‘II'E EXHIBST- NUT EVIDENCE
`
`1 0
`
`

`

`I
`
`Extensive Prior-Art Evidence Demonstrates Treatment of
`
`Migraine Through Peripheral CGRP Antagonism
`
`I
`
`Teva Theory:
`
`Triptans:
`
`
`
`. support a central site of action for the role ofEGRP in promoting migraine, as well
`.
`cf. Leg: "These findings .
`as the antimigraine effect of CERF antagonism.” (Ex. 2293, 204]
`
`E 5
`
`DEMDNSTFMTWE EEHIBIT - MDT EVIDENCE
`
`Ex. 1338, 111] 36-53; Reply, '.-’-1fl; Pet, 32-33
`
`1 1
`
`Arulmani 2DD4: BIEN _.__-..-_-.-;!--
`
`,
`
`.
`
`Dr. Foord’stestlmon__
`
`'
`
`-
`
`activitylEx. 23D?, 2125 1126}
`Fischer: "Blockade of CERF receptors, possiblyr at central -':'-~--:
`to decrease nociceptive transmission." (Ex. 2310, Abstract}
`
`;_
`
`.-
`
`'--':-':'
`
`'-
`
`'
`
`

`

`I
`
`Teva’s Theories Did Not Deter Development of
`
`I
`
`Anti-CGRP Antibodies
`
`1993
`
`Wong
`
`Teaching "specific blocking of endogenous CGRP either at the receptor level
`
`using specific CGRP antagonists, or bv neutralizing endogenous peptide with a
`specific antibodv." (Ex. 1933, 95}
`
`1994
`
`Tan Thesis
`
`"There seems to be no reason whv anti-peptide MAbs should not be
`
`investigated as therapeutic agents” for "migraine" (Ex. 123?, 24?}
`
`1995
`
`Tan 1995
`
`"immunoblockade" as "an alternative strategy" or "complementarv" to the
`
`use of receptor antagonists. {EL 1922, 599, 521}
`
`1999
`
`Wimalawansa
`
`"The role of CGHP antagonists and humanized monoclonal antibodies should
`
`be explored" (Ex. 1999, 59?, 529}
`
`2992
`
`Salmon
`
`Compositions can include anti-CERF "monoclonal antibodies for the
`
`modulation of” "neurogenic inflammatoryr pain" {Ex 192?, [9939]}
`
`2992
`
`“439 patent
`
`Disclosing and claiming "anti-CERF antibodies" for therapeutic use
`
`(Ex. 1929, claim 2}
`
`2994
`
`Sveinsson
`
`Disclosing and claiming "anti-CGRP antibodies" for therapeutic use
`
`(Ex. 1929, claim 2}
`
`
`
`2995
`
`Arulmozhi
`
`"[l]nhibition of CERF or antagonism of CERF receptors could be a viable
`
`therapeutic target for the pharmacological treatment of migraine.” (Ex. 1949,
`192}
`
`Ex. 1914, W111, 116-11?;Pet.,26- 2T;Rep|1.r,fi, 15
`
`;
`
`DEMONS'I'RATWE EIHIBlT- NUT EVIDENCE
`
`1 2
`
`

`

`I
`
`Teva’s Theories Did Not Deter Development of
`
`Anti-CG RP Apta mers
`
`I
`
`Pendergrast (Ex. 1309):
`
`
`Healy (Ex. 1310):
`
`Ex. 1309, Abstract; Ex. 1333,1124; Ex. 133?,1fl] 5?, 60; Reply, 13
`
`Tova Theorles:
`
`primary headaches.”
`
`Efficacy: "Neurogenic blood flow increases in the meninges are
`reduced by binding of the released CGRP to the Spiegelmer"
`
`Safety: “Basal blood flow and systemic arterial pressure were
`
`unchanged."
`
`“The Spiegelm er may open a -.;=._.r.~-
`
`i.ii---.-:.~.::-:-;s;.-
`
`..
`
`.
`
`I
`
`;
`
`DEMONSTRATWE EXHIBST- NUT EVIDENCE
`
`1 3
`
`Ex. 1240, 923; Ex. 1014,1162; Pet, 2?
`
`

`

`I
`
`Teva’s Purported Safety Concerns Were Resolved by
`
`November 2005
`
`I
`
`£1.10?!) w m
`E" mail
`‘ .. lentil“:
`CERF”?
`Winn!
`“5 “Pfuuflsh
`"E effect"
`
`
`
`
`BlBHdflQEBS
`without m
`
`eardimscular
`CGRP--Aptan1er
`
`side-effects"
`“unchanged"
`
`sIsIII-Inssss
`"E statistically
`significant effect"
`
`slsnwssss
`“E a
`uasuennstrictnr"
`
`
`
`2005
`
`Emennus
`{SEEP
`
`Emenulll
`{SEEP
`
`Elngennus
`CERF
`
`Capsaicln
`
`FIRM-409655
`“did not affect”
`
`BlBHflflQfiB
`“did nut aflect"
`
`BIB "469635
`“did not alter”I
`
`BIBMDBEES
`“nu efiett"
`
`Dr. Charles:
`
`"There were multiple studies in humans that indicate that,
`in fact, it was safe to therapeutically target CG RP, and
`animals also.”
`
`Ex. 1338,1mei-3i; Reply, 16-13
`
`Tmmh"
`
`I
`
`;
`
`Ex. 2333, 40:11-20
`
`DEMONSTRATI‘III'E EIHIBiT- HUT E‘III'JDENCE
`
`14
`
`

`

`I
`
`Anti-CGRP Antibodies Did Not Raise Safety Concerns
`
`I
`
`Tan 1995 (Ex. 11122):
`
`MAP gradually recovered within "u” for full-length IgG and Fab’ fragment
`
`Tan’s contemporaneous statements:
`
`Ex. 1022, 563; Ex. 1333, 111191 4-13; Ex. 133T, mlfi2-EE; Reply, 14
`
`"There seems to be
`
`.
`
`-'.-:--:-.::'-:
`
`or their fragment5_
`
`-
`
`.2
`
`:'
`
`1.:
`
`-..'i-::
`
`Wong (Ex. 1033):
`
`Ex. 1237.241; Reply, a, 15
`
`"The monoclonai antibody had "r..-
`
`:"=—"-
`
`1'
`Ex. 1533, 1111; Ex. 1338,1192;Ex. 133?,111163-T0;Repl1.r, 15 I
`
`"
`
`Andrew (Ex. 1055):
`
`’filthough the immunized rats had high levels of circulating antibodies to rat CG RP, they .
`
`Ex. 1055, 93; Ex. 1333,1193; Ex. 1331,1171; Reply, 15
`
`5
`
`DEMDNSTRATWE EKHEBIT- NUT EVIDENCE
`
`1 5
`
`

`

`I
`
`Teya’s Patents Do Not Identify or Solve the Problems
`
`Teya Raises in this Litigation
`
`I
`
`Alcoa Research, Ltd. v. Apotex into, 637 F.3d 1362,. 1369 (Fed. Cir. 2012) (affirming
`obyiousness where purported safety concerns were not addressed in the invalidated
`patent)
`
`
`
`Reply, 4
`
`Teya Theories:
`
`Dr. Ferrari:
`
`.
`
`.
`
`“There is no text mentioning data from safety studies."
`
`“The patents do not disclose studies in humans."
`
`Ex. 1303, 56:4-11; Reply, 3
`
`Teya‘s patent examples “will never satisfy concerns about safety and
`
`
`
`efficacy.”
`
`Dr. Ferrari:
`
`
`- Teya‘spatentexamplesare“notaimedatstudyingtheblood—brain
`
`barrier."
`
`Ex. 1345, 61:5-65:2; Reply, 4
`
`I
`
`3
`
`DEMONS'I'RATWE EIHIBlT- NUT EVJDENCE
`
`1 6
`
`

`

`I
`
`Tan 1995 (Ex. 1022]: lmmunoblockade of CGRP
`
`Was Effective In Vivo
`
`I
`
`Tan 1995 (Ex. 1022):
`
`Block hggotensive effect:
`“This studyr has clearly demonstrated the ability of MAb {34.19 IgG and its Fab’ fragment to block
`
`hypotensive effects of exogenous rat oCGRP in vivo.
`
`Rat saghenous nerve effect:
`“Further nerve stimulation performed at 2 h after 3 mgfrat MAb produced an AUC which was slightly
`smaller compared with baseline stimulation, but not by more than 15% (n=2}.”
`
`
`
`Provided Guidance:
`
`*
`
`*
`
`“The data of Covell et al. suggest that much larger doses and longer distribution times are required
`
`for successful immunoblockade with IgG."
`
`“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."
`
`.
`
`“With repeated administration, IgG should eventually distribute into interstitial space and achieve
`
`the sufficiently high concentrations required for immunoblockade.”
`
`Dr. Charles:
`
`Ex. 1022, 559-5?1; Pet, 4545; Reply, 10-11
`
`“A PDSA would have been motivated to follow Tan’s recommendations because they are consistent
`
`with how a PDSA would have wanted to reduce incidence of or chronically treat migraine, i.e., with
`
`therapeutic agents having high specificity and long half-lives.”
`
`
`5 ga;
`Ex.1fl14,1]136;F'et.,46-4?
`
`DEMONSTRATNE EEHIBIT - noT EVIDENCE
`
`1 7
`
`

`

`I
`
`Teva’s Synaptic Cleft Size Arguments Are Meritless
`
`I
`
`Wrong Synaptic Cleft Size:
`' Teva relies on a 20 nm cleft in CNS tissues (Ex. 2280, 333)
`
`' Cleft size in tissues relevant to migraine: 100 to several hundred nm (Ext. 1349, 275-217)
`
`E11. 2255, 1195; FOR, 37; Ex. 1337,1135; Reply, 11
`
`Wrong Antibody Type and Antibody Size:
`'1
`Teva relies on an lgE antibody having 15 nm in its longest direction {£111. 2281, 1967)
`
`s
`
`Ignored Mobility 81 Three-Dimensional Nature of Antibodies
`'1
`Dr. Balthasar: an antibody may be "rotated or folded such that it has a profile significantly
`
`E11.2255,1190; FOR, 37; Ex. 1337,1132; Reply, 11
`
`narrower than 15 nm wide" (Ex. 133?, 1l36}
`
`'1
`
`
`Size of lgG antibodies: "8-10 nm (Ex. 1347, 7184}
`Even lgE antibodies are only 5 nm in profile (Ex. 2281, 1967)
`lllPas deferens tissues have 20 nm synaptic cleft size (Ex. 1348, 5}
`
`Ex. 2255,1155; FOR, 3?; Reply, 11
`
`Tan Demonstrates Access to Synaptic Cleft
`'1 MAb lgG £4.19 "reached equilibrium in the synaptic cleft after 45 min[utes]" (Ex. 1021, 109}
`
`'1
`
`Dr. Foord’s Admission:
`
`'51 1331 “33? RENE 10'“
`
`[Y]ou’re not an expert in the dynamics of an antibody and how they behave in the synaptic cleft?
`
`That is correct.
`
`
`53
`Ex. 1343, 15:4-5; Reply, 11
`
`DEMONSTRATWE EXHIBIT - HOT EVIDENCE
`
`1 8
`
`

`

`I
`
`Tan Teaches that Anti-CGRP Antibodies Were Expected
`to Access the Synaptic Cleft
`
`I
`
`Tan 1995 (EI- 1022):
`
`Covell (Ex. 1247):
`
`
`
`a] ,
`(:1
`Covcll
`the time to reach steady-stale
`showed that
`[14]
`interstilial
`to plasma concentration ratio in
`the
`carcass [including muscle and skin] was
`l4 times
`more rapid for Fab' fragments than for whole IgG.
`
`Ex. 1022, 5?1; Err. 133?,1129;Rep|1r, 10
`
`Table 3 Steady-flare inmirinkplm antibody member H?) and lime in
`”“hmmm-tm'”)
`WM"
`PM”:
`
`Orrin
`er
`“I."
`er
`Gut
`1154
`I
`.
`{1.53
`Live:
`ear
`.
`ears
`5"”
`33:;
`-
`31:
`Kidne
`.
`P, m “E! m
`I113
`0.11
`
`' Calculated by model simulation.
`* calculated as r. - (V, + Fares.
`
`
`appropriate just as Tan 1995 repeatedlyr recommended”
`
`Dr. Balthasar:
`
`Ex. 124?, 39T2; Ex. 133T, 1123; Reply, 10
`
`[a] POSA would have readily appreciated that permitting a
`"Consistent with Covell’s data,
`longer time for distribution, as well as higher doses or chronic administration, was
`
`1‘! fl
`
`Ex. 133111112129; Reply, 10
`
`I
`
`;
`
`DEMONSTRATWE EXHIBIT- NUT EVIDENCE
`
`19
`
`

`

`Teva Followed Tan’s Express Guidance
`
` lmfl-flhfl'fl:
`L's Emu-Is a:
`-l|.l| m.- m:
`...-. United States Patent
`m. on “Hill:
`1.4mm;
`w. l'!. ms
`
`nu wllnunuwuum nun-nu
`nmannr Jun-mu:
`
`
` -3"- Inn-Mr- Jun-5m m kill-.115 ----- :Ii
`u.
`
`Ion-1.5.1.. “Lu—w. n
`
`
`.:.m1.u-uu.flu.
`lu-
`
`“min-AA. tun—h...
`"-'
`Example 3
`“In. I Mus. min”...
`
`
`“-me m1 “mun.-
`
`
`l-ril‘I-I-I Wind-Ir l'tll‘l
`
`m: Jun-w Imwhh.-nmw~1'l
`"mm"
`um:-
`n.
`.-. -_
`
`
`
`m..- huuth—nmwmm. m.“ .. . v.4.
`mu.m«ummv mum“.
`
`
`
`Effect ofAnti-CGRP Antagonist Antibodies on Skin
`Ilsi LII-Ine- Ilam
`‘
`
`Ifll
`I"! Ii!
`”(II—Ill-
`
`
`I
`'I
`Ilkld
`HILIIII
`,1
`_
`Vasodilatation Induced by Stimulation of Rat
`
`
`
`
`
`
`W" ”m
`‘-"‘"""7f~'-:=-==1'“
`Saphenous Nerve
`Inn mum—Inn.
`
`
`
`'. lhhnol mum na- uounu mu :- w
`I
`«pm-“K.- l'I'l Ilw-oalaI-rm : :u'n
`,,
`--
`. .
`“i" L' "In-"V"
`mu m pew-Idle]
`
`lhan-Mwh'd-ifih some"! madam.
`"
`no:
`I..¢au.mum'mm-.L:m:ul:1..n Wat-I‘m-
`H.”
`IIIM'rJ
`hand—Ln"...
`..
`. ..
`
`
`IFII ”it
`h.
`I IL‘OIMII'II'HZ“
`Imfll
`INI IF"!
`“Mimi-"IV
`.mm
`uflflw
`" "kl-“W
`
`
`
`
`
`mnm'lfrflr'“
`“1: null
`.pnn.
`'h" 'hiL
`u—uu Luau-u.
`For e
`law
`was unto. m l'|'|-l
`434”” ~m1|.smur1.suum I
`3:. mm mm ”mm. fl antibody 7D11_ or vehicle control
`
`mm}.
`
` Ill-I I'IH flimm
`
`
`
`
`-- Mm:
`""9"“?!- .T
`(PBS with 0.01% Tween 20 was administered intra erito-
`
`
`
`‘: if“?
`'
`.
`neally (IP)
`
`
`eriments shown in FIGS. 2A and 213, antibody 4901
`
`noun-s
`--
`For
`-
`1wmmm --
`now ....:....1 Jail-huh.— u.-.u “nu...
`
`
`
`mumsfissmmwm
`Ex. 1001, 55:61-64; Ex. 1014.111133-95; Pet, “-48; Roply', 11
`“""m’"
`
`
`
`
`3 v “53
`‘m"*""*...r..;tt.:cr:.rssrm"
`c;
`evasion“ 12;:
`.ms
`"is...”
`..
`
`
`
`5
`
`DEMDNSTRATWE EXHIBIT- MDT EVIDENCE
`
`20
`
`

`

`Teva’s Secondary Considerations Are Not Commensurate with
`
`the Scope of the Challenged Claims
`
`Headache Types
`
`Ex. 1304, Y4:1?-75:12; Ex. 1001, 20:25-
`
`40; Pet., 62; Reply, 21-22
`
`Binding Affinityr
`
`2 pM-ZSO nM
`-
`’045 patent claims 4 8t. 20 [50 HM
`or less]
`
`-
`
`’903 patent (about 10 nM or less}
`
`Ex. 1301, 102:1-103:15, 1D4:T-19; Ex.
`1001, 5:35-46; Reply, 23
`
`Fab; Fab', F{ab’]2 : F“;
`single chain [ScFvL fusion proteins
`
`Ex. 1301, 21125-2325; Ex. 1001, 12:51-
`55; Pet, 23-24; Reply, 23
`
`IEA; ISD. '35; '35, ISM
`
`EX. 1301, 3T:16-39:11; Ex. 1001, 12:29-
`3?; Reply, 23
`
`Antibody Format
`[ggu fragments}
`{”045 patent]
`
`AntibodyI Class
`{'045 patent]
`
`
`
`“1:" in re Koo, 639 F.3d 1057, 1063 (Fed. Cir. 2011) (“Evidence of secondaryr considerations
`must be reasonably commensurate with the scope of the claims”).
`
`Sam;
`
`DEMONSTRATWE EKHIBIT- NUT EVIDENCE
`
`RBP'Y. 23
`
`21
`
`

`

`I
`
`TeIIa Failed to Rebut EIIidence Showing Lack of Nexus
`
`I
`
`
`. LI? '
`“Neither the district court nor appellees explain the nexus between [secondary consideration
`
`eIIidence].and the broad scope of ’029 patents.claimedinvention.”
`.
`.
`.
`.
`as compounds with Cl-amidegroups in order to establish that
`
`
`eIIidence of [secondaryr considerations]is commensurate with the scope of the claims.”’
`
`Reply, 23
`
`Dr. Tomlinson’s testimony:
`
`human therapeutic against that target"{EII. 1501 154:14-25; ReplII,25}
`
`Fremanezumab and galcanezumab
`104: ?- 19; ReplII, 23}
`
`.
`
`.
`
`-
`
`-
`
`' "
`
`"Ithinkits-prettyclearthat.ii-'-
`
`- .-
`
`:.-
`
`--
`
`.
`
`_.
`
`5
`
`DEMONSTRATWE EKHIBIT- NUT EVIDENCE
`
`22
`
`

`

`I
`
`Teva Failed to Rebut Evidence Showing Lack of Nexus
`
`I
`
` in the claim,
`
`...i;'.-".'-':._.-i.'r:;'. o the merits of the claimed invention 3’)
`
`15:1;
`
`Dr. Rapoport’s cross-examination:
`
`Reply, 23
`
`Cl:
`
`So it’s your opinion that the antibodies that you have indicated met a long-felt need
`
`is based on their characteristic that theyr block the CG RP pathway, correct? A: Correct.
`
`Ex. 1304, 142:1-3; Reply, 23-24
`
`5
`
`DEMONSTRATI‘U'E EXHIBST- NUT EVIDENCE
`
`23
`
`

`

`Teva’s Evidence of Industry Acclaim ls Deficient
`
` Teva’s arguments:
`
`rim, Lilly'scxpaLEk. Mahashinndfpniacdfluhummflodaui-
`
`CGRP magnum min-ochre used in Ihccllhnod ntfioch—rcpcflodlg—as:
`
`W"
`drug based on monoclonal anthodIes to prevent migraine”
`
`wmnbewmwwmmmommm"
`smaller percentage have shown complete remission whichIs
`
`
`“aboohteljr Hie-changing"
`
`
`
`having 11:“! ‘Wm'fil'fl to Emilia-m condition] aloud: to aim
`“deluxe-net hemlock? and.
`
`..
`l
`
`
`
`
`E20132. 10?; moms, 4; was; 1; E22152, 1161.61
`
`I
`
`;
`
`DEMONSTRATWE EIHIBIT- NUT EVIDENCE
`
`24
`
`Ex. 2052, 1; Ex. 1338, 11131; Reply, 24-25
`
`

`

`I
`
`Teva’s Evidence of Industry Acclaim ls Deficient
`
`I
`
`UCLA U Magazine (Ex. 2053):
`
`-
`
`"Researchers have found that serum concentrations of CG RP become elevated
`
`during migraine attack, and they normalize when the attack resolves.
`
`Small
`
`molecule drugs binding to the CGRP receptor were able to abort migraine
`attacks.”
`
`-
`
`"It was this bodv of evidence that led researchers to suspect that by blocking
`
`CG RP receptors, or targeting the neuropeptides itself, a migraine attack could be
`prevented. According to results from late-stage clinical trials of grgnuma,_‘ea;qg;
`
`and other anti-CGRP antibodies, the researchers were right.”
`
`during a migraine attack.”
`
`"The notion that would be using antibodies for treating migraine is reallv quite I
`-...This is a verv different approach because, in contrast to other
`treatments that we’ve used in the past, which often have been developed for other
`
`reasons and we’ve borrowed them as migraine treatments, this has been developed
`based on our understanding of the chemistrv of migraine and what is going on
`
`;
`
`DEMONSTRATNE EXHIBIT- NOT EVIDENCE
`
`25
`
`Ex. 2053, 23; Ex. 1333, 1”] 131, 135; Reply, 24-25, 2?
`
`

`

`I
`
`Teya Failed to Establish Unexpected Results
`
`or Industry Skepticism
`
`I
`
`Teva’s Argument:
`
`Dr. Rapoport in 2003:
`
`"[S]ome of the patients stopped overusing acute care
`
`medication during the [naratriptan] study”
`
`Dr. Pens:
`
`Ex. 1294, 43?; see also Ex. 1295, Table 1; Ex. 1333, 1”] 13?-143; Reply, 25-26
`
`"Labrys was created s-eeificall
`
`rn
`
`to move forward on
`....._._ ,I
`'«l
`
`Ex. 1346, 4222-432; Reply, 26
`
`Pfizer "decided that migraine was not an area it wanted to
`pursue.”
`
`Ex. 2331,1113; Reply, 26
`
`5 a2:;
`
`DEMONSTRATWE EKHIBlT - NUT eyJeENoE
`
`Ex. 216?, 118-119 [quoting Dr. Pens}; Reply, 26
`
`26
`
`

`

`I Teya’s Purported Evidence of Licensing, Long-Felt Need, and
`
`Commercial Success Do Not Support Patentability
`
`I
`
`Teva's Arguments:
`
`Dr. Stoner:
`
`C1:
`
`[I]f all of the challenged claims were canceled, Alder Bio would
`
`still owe the same considerations to Toys for the same reason,
`
`that they had admitted infringement of all of the 1?9 additional
`
`patents, correct?
`
`A:
`
`That appears to be a reasonable interpretation of this paragraph
`
`Dr. Charles:
`
`Ex. 1302, 1?9:14-130:19; Reply, 26-2?
`
`
`13?).”
`
`
`
`“The fact that researchers have been working on the CGRP pathway
`more than 25-30 years is consistent with my previous testimony that {1)
`it was well known that the CGRP pathway is important in migraine
`pathophysiology (Est. 1014, 111126-33, 10?~113}, and (2} the prior art
`
`would have motivated a PDSA to use a humanized anti—CGRP antagonist
`antibody for treating or reducing incidence of migraine (id, 111110?-
`
`* NO eyidence of any commercial sales
`
`* N0 eyidence of market share
`
`DEMONS'I'RATWE EXHIBIT - NUT EVJDENCE
`
`Ex. 1333,11135; Reply, 2?
`
`Reply, 26
`
`27
`
`

`

`I
`
`Teva’s Affinity Claims Were Obvious
`
`I
`
`Dr. Tomlinson in 2004:
`
`“would have the following qualities: it would have
`
`and exquisite specificity for its target”
`
`Ex. 1233, 521; E11. 133?, 1137; Reply, 23
`
`Tan 1994 (Ex. 1021):
`
`Dr. Vasserot:
`
`I. (Ex. 1055, 92]"
`
`“The dissociation constants (Kd} of MAb
`C4. 19 for rat uCGRP and BCGRP were very
`.
`.
`=
`respectivelyl.’
`
`Andrew5 antibodies “against :-
`.;-.-:'-.-
`alreadyr shown to have affinities of about
`
`.-.:.
`
`Ex. 1321.133; Ex. 1315,11113; Pet, 52
`
`Ex. 1315,11115; Pet, 52
`
`Tova’s Argument:
`
`“The art teaches a disconnect between binding and activity.
`[T]he anti-CGRP antibodyr MAb R150
`‘clearly showed the greatest [binding] activity’ among the tested antibodies to rat oICGRP, yet it
`
`‘blocked rat aCGRP poorly.”
`
`Bur-reply, 24-25
`
`Tan 1994 (Ex. 1021):
`
`
`
`,7
`
`DeuousmTwE ExI-IIEIIT- HoT EVIDENCE
`
`28
`
`Ex. 1021, 70?; Ex. 133T, 1131; Reply, 19-20
`
`

`

`I
`
`Teva’s Claims Do Not Require A Clinical Response
`
`I
`
`Claim Terms:
`
`Teva Patents:
`
`We claim:
`1. A method for I headache in an individual,
`
`comprising:
`
`administering to the individual an eflective amount of a
`htunanizod monoclonal antivfalcitonin GeneuRelated
`
`EK- 1001. 1713133; EK- 1014111132; Pet, 2‘3
`
`Ex. 1001100? patent), 1032005
`
`Peptide (CERF) antagonist antibody. comprising:
`ticular individual. antagonist antibody, wherein said anti-CGRP antagonist anti-
`Eit. 1001, 1T:01-05; Ex. 1014,11103; Pet, 21
`
`We claim:
`ii or“ at least
`.-:
`0-.
`I. A method For -:'..~'I
`one vasomotor symptom in an individual, comprising admin-
`
`istering to the individual an efiective amount ofan anti-CUR?
`
`“method of_h-dache in an individual"
`reflects administering the anti-CERF antagonist antibody
`reasonable expectation that such administration
`cause such a reduction in incidence in that par-
`
`body is a human monoclonal antibody or a humanized mono-
`clonal antibody.
`
`Ex. 1001 1015 patent), 001-?
`
`Novartis Pharm. Corp. v. Actavis, line, No. 12-cv-366, 2013 WL 6142747, at *11lD. Del.
`Nov. 21, 2013) (construing "treating” as merely an "attempt to cause a therapeutic
`improvement,” relying on "the term’s use in the patent”).
`
`I
`
`;
`
`DEMONSTRATWE EXHIBIT- NUT EVIDENCE
`
`Pet, 20
`
`29
`
`

`

`I
`
`Teva’s Claims Do Not Require A Clinical Response
`
`I
`
`Claim Terms:
`
`Teva Patents:
`
`As used herein, an “effective dosage"_
`-ofdrug, compound, or pharmaceutica compost 1on
`
`is an amount suflicient to effect beneficial or desired results.
`
`'
`
`-
`
`'
`
`.'
`
`clonal antibody. '
`Ex. 1001(045 patent), 99:14r
`within an individual human for treatment are
`let alone anyr response.”
`
`We claim:
`
`1. A method tbr reducing incidence of or treating at least
`one vasomotor symptom in an individual comprising admin-
`
`isteringto theindividual anmat"ananti-CGRP
`
`antagonist anti-
`antagonist antibody, wherein sa1 ant1-
`body is a human monoclonal antibody or a humanized mono-
`
`We claim:
`1. A method for treating headache in an individual,
`comprising:
`
`administering to the individual an“of a
`
`humanized monoclonal anti-Ca citomn
`
`ie- eated
`
`i"L- fixture-M
`:-:'
`-.'.-_'-.-.-I-.-|'.||':t'-!I
`|'-i't----.-i'u!:n_- ~|'.|:'i|l:'
`* beneficial or desired results include cli
`
`resu ssu
`
`asredncingp'
`._._| -n
`
`Ex. 1331 , 13:33-57; EK. 1333,1I1I7-3; PEL, 22-23; Reply, 2-3
`
`Dr. Foord:
`
`An effect in a cAMP assay "and the effective dose
`
`Peptide (CERF) antagonist antibody. comprising:
`
`Ex. 1001(‘9'3? patent}, 10320-35
`
`16. The method of claim 1, wherein the close of said anti-
`
`CGRP antagonist antibody is at
`
`Ex. 1001 {ms patent}, 100:1-2
`
`;
`
`DEMDNSTRATWE EKHEBIT- NUT EVIDENCE
`
`30
`
`Ex. 1014, 11105; Pet, 22-23
`
`

`

`Detailed Analysis
`
`31
`
`

`

`I
`
`Novartis v. West-Ward ls lnapposite
`
`I
`
`
`
`
`
`Teva’s patents broadlv cover using anv humanized
`anti-CGRP antagonist antibodv, with no structural
`limitations, for the aspirational goal of treating
`
`migraine.
`
`NofPhaSell dataLexiSt'ed for
`evérolim'u‘s' .o-rv‘a'nv other "rhTO R—
`inhibitor.
`
`Olesen published a Phase II clinical trial, establishing
`that blocking the CGRP pathwav effectively treats
`migraine.
`
`BIBN.
`
`Multiple effective CGRP-pathwav inhibitors were
`known to treat migraine, including sumatriptan and
`
`No-prioriartc‘disclosureth’ati
`e’vérolimuswoul'd be:effe¢t-ive in
`treating— the claimed. diSease.
`
`_ The prior art disclosed: “we expect that CGRP
`antagonists will be effective anti*migraine drugs.”
`
`;
`
`DEMONSTRATWE EIHIBlT- NUT E‘v’lDENCE
`
`Replv, 20-21
`
`32
`
`

`

`5. Ala. v. Gnosis S.p.A., Affirming Absence of Nexus for Alleged
`
`Industry Praise, ls Highly Analogous
`
`Patentee relied on purported praise of five
`drug products including an active ingredient
`
`Teva relies on purported praise of only two antibodv
`drug products, fremanezumab [Ajovv‘] and
`
`and specific vitamin(s}.
`
`galcanezumab [Emgalitv'I'L
`
`Patentee’s claims encompassed a broad
`
`Teva‘s claims broadlv encompass a genus of any
`
`genus of methods and compositions.
`
`humanized anti-CGRP antagonist antibodv.
`
`Combinations of the active ingredient and
`specific vitamins were not recited in the
`
`The specific antibodies and other formulation
`components are not recited in Teva’s claims.
`
`claims.
`
`Patentee failed to demonstrate that “other
`
`Other embodiments within the claims would not
`
`embodiments falling within the claim will
`
`behave in the same manner as Ajovv" or Emgalitv"
`
`behave in the same manner."
`
`{e.g., due to different mutations, different tvpes of
`
`fragments, different antibodv classes, and different
`affinities).
`
`;
`
`DEMONSTRATNE EXHIBIT— NOT EVIDENCE
`
`Reply, 24
`
`33
`
`

`

`I
`
`Known Anti-CGRP Pathway Antagonists Were Reported
`to Be Safe and Effective
`
`I
`
`Triptans: FDA-approved anti-
`
`migraine drugs advocated for daily
`
`administration
`
`Ex. 1282. 1521; Ex. 1294, Abstract; Ex. 1338,1fi119.93; Reply, 13
`
`BIBN4OQBBS: "caused only minor
`
`adverse events and had no constrictor
`
`effect"
`
`Ex. 1025 {Gleam}, 1103; Ex. 1333.132; Reply, 12
`
`CGRP-binding "biostable aptamer”:
`
`"Basal blood flow and systemic arterial
`
`pressure were unchanged"; "a new
`
`therapeutic strategy in diseases
`
`such
`
`as migraine"
`
`3'
`
`DEMONSTRATWE EXHIBIT — NOT EVIDENCE
`
`34
`
`Ex. 1240. 923; Ex. 1032, Abstract, 2; Ex. 1338, 1130; Reply, 13
`
`

`

`I
`
`Tan 1995 Offers Express Guidance to
`I mprove lmmunoblockade
`
`I
`
`ennui-Inn: I vu :-'I Mod r ir- Im-I-I
`admin wanted peptide as an magma
`II.n..-,.1i[';|:.cue immunohlocklde Indies in rim with
`“flakitoningenefihtedpepfidemmdmm.
`am Fab We“
`a...“ r: nu Hum, moon Full-.5] MMIH'VEEI gm; HEW.
`m 1. {13011 I'll.“ ham El N||.Lr
`:J-cl' WIN-Mn L" ' L‘s-"'1'” a" (mi-win film-til Hut my, w_
`5.54% o:_ m:
`-.Ur-:I- Sin-fl mi Du!" mun. Lm_ Wm M
`a.“ l‘g'm_ Emr_ L r:
`
`Pi
`
`Tevals argu ment‘S:
`
`In the Louistoekray experiments, “the antibodies 'leaked’ into the
`
`"I
`.
`f
`.
`.
`.
`Interstitial space due to plasma extrauasatlon.
`
`Bur—Tap“.I 18-19
`l
`
`
`
`I cm pan-Mun pepti- .n:nr. . I: .
`lily-Mind" wh1_-mafl n l mu
`WIN-h- "u'Ir
`'Imliplld I|It Inim- 04' m
`mums-'- .i-amhq-mmihmh
`I'm" an ll mm Imaflllar.
`”kl-II!- III a- "III-l “Rf nun-thul unfit-H:
`fill-h “H [Ll'ull and
`in uh rug-u: .-
`{flirt-Hum! th-In i- Hnd Fri-m -t 4'-
`
`mm
`'
`.mJ-n- .‘N'II-J'WUIJ'
`;
`.‘ukrl us. m I
`
`
`
`“Fri-Irmhhl'm-hfwlhhms
`MI" 14
`'IIrr-r-II-
`rIr IUiIll'
`rIHiHI'I
`III-
`'Ihh W aim-mi
`In 1m L-L“ lfl.‘
`'IPH-
`IIIII-rIu-bh- “I
`lab
`[Inna-III
`
`Tan 1995 (Ex. 2022):
`
`éi‘tez'siiiial space lfr‘t' {Masai-5.1 £311th asstion ('3: The
`short stimulation period and mild stimulation para-
`
`
`EEiE":fii'—fii3: gin-7m; meters used in the present
`investigation would not
`
`
`t 4
`"-
`have caused plasma extravasation [9].
`m
`"ws.
`
`
`The slow distribution of whole I_ G to the site of
`
` live strateies of
`
`
`1n
`IH
`H'
`m.-
`rh gum-Imi-
`era-Emu!
`”in-hm I H"
`'
`ran-"M m" ‘M'
`""III N hL' run—— mr 1.5.- “ inn—-
`
`.
`r-rum-HM I“
`
`‘-
`
`—“up...
`.
`.
`FI_#_H_
`.
`“umuhmpmrwflfl
`:tea:¢&£s
`
`.
`
`0r
`
`
`:2: _E"'[':.|:"'!I_:|:'_‘.
`
`”Eli-J if'r".
`
`:. NIH-.3
`
`-
`
`Ex. 1022, 571; Ex. 133111111539; Reply, 10
`
`;
`
`DEMDHSTRATWE EKHlBIT- NUT EVIDENCE
`
`35
`
`

`

`I
`
`Absolute Risk of Stroke and Myocardial lschemia in
`
`Migraine PatIents Was Very Low
`
`I
`
`Bousser (Ex. 2157):
`
`: 18 per 100,000 per year.”
`
`.
`Dr. FerrarI:
`
`Ex. 215?, 535; Ex. 1333, 103; Re I
`1]
`p 5'
`
`, 13
`
`(1: Well, for the percentage of patients that experience migraine without aura, as of 2005
`there was no known association between migraine without aura and ischemic stroke,
`correct?
`
`_
`
`A:
`
`In 2005 there was ._:
`
`:-- .:::...
`
`-- -- -
`
`--.-
`
`Dr. Charles:
`
`Ex. 1303, 193:3-10; Reply, 13
`
`"Clinicians experience withtriptlans led to theunderstanding that (l)—
`._..-
`=
`:-
`'-
`- ----
`-.
`-
`-
`and(2)adrugthatcould
`potentially worsen ischernic episodes
`I
`..
`_.
`:
`_
`__
`.
`1 .--.
`_
`.
`
`Ex. 1333, 11113; Reply, 13
`
`'
`
`I. the ”5" that 3 (We Could worse ischernic episodes would have
`'
`" a
`similar to those that
`-
`'-
`-
`-
`--
`-=
`-
`
`-
`
`;:
`
`: y:-
`
`DEMDNSTRATWE EKHEBIT- NUT EVIDENCE
`
`36
`
`

`

`Prior Art Clinical Evidence Undermines Teva’s Hypothetical
`
`Application of the "Spare Receptor Theory”
`
`The Tfigeminovascuiar System and Migraine:
`Studies Clumcterizing Cerebrovascular and
`Neuropeptitie Changes Seen in
`
`
`
`
`
`- tients man I ndin to subcutaneous sumatrip-
`--.
`:_
`----. ” '
`'
`'
`
`tan administration.th :l: 8 pmoli'liter} were -_
`1 El pmolfliter}.
`manmmuu.WW_MMh.-nan
`
`
`
`——nnun.u—I-r-s—Tnlmp-rmI—n-n-H-hm-wn-mp—h
`"Mi—minim “www.1'thdpdhnhdfinfll
`E11. 1044, Abstract; Ex. 1338, 11116; Raply, 13-19
`0mit"HMflHhtmmhuwIMHJtfiHm-kflflififiln
`MIHMEIIHHETLJMITIIlflfiuulhfllflummmmfim
`mhmquu-I—uj—u—n-u—m-mdu-n—u
`
`
`uri—ud—n—n-kru-u—u-umm Imqur-mmmm—mp
`hflmMCHPMWIIWmu‘d-fihhfihhdfllfl
`.smmtmmmuwuwummm m.uuH—um
`Dr. Charles’s testimony:
`mdmmmmumdwmmmpm
`
`flm‘fl—‘hmmhMH—J-flt
`mun—n.1,. mmwa “an.“nsqqmu
`
`
`nmqmm-mflmmmmumm
`
`mm 1 115. The clinical evidence contradicts Dr. Foortl‘s assettion._
`1m-imh—smmdum “mm—ammo...-
`
`
`Imam-“mun-rm hmmmmlrmnmmh—
`mdmltlmmdbw mdmmtflwu-
`mmna—ummmurumm “HHWHHMH
`
`Wfllmwmiflmwfl
`iflu-Wmli‘ll'k—d-Jh
`mdhflmflhw» bahikmmhdlfilndmmlfijp-nd
`“mammal-um amusomloM-Mwwmiflmfle
`.wm-mm-‘uh H's-I
`I'VTH Immmm
`
`“Mmmmwum mmefiwmmmmllflJlih
`'
`
`mdhmm—md huhmmmhum
`{Ex
`h-nm-fl-ndmmh-hflrrudr
`“flinhmdruhmmdhufihn
`
`-5123 fimh‘i'm‘m“d:
`1'2: "M973“; "$.12? '“ ”" “m "'
`
`3:1:mu: 3:;-fligrw-mw na- urn-3.:3La1.1::
`“$143. Abstract: Ex. 11344. Abstract: see also Ex. 1134 r. 59 {adntuustenng
`h-lnlflwmhmnmllm mmmePIm-[HHJ-udum
`mmwflrmu—lmHLTk mmmumlmmn-hfim
`
`
`mmmum.mm1mlufl
`hhflafl‘l'm.—J-bv-Jh_ldln nun—1:.-
`I‘ll-lirlrI-rr.M—IILI-li-|lF-Dl—fl|-Inilkw
`noun—M :'. 1m
`exogenous CERF “caused migraine in virtuallyF all ntigaine sufferers“): Ex. 113915.
`u.tm|mt.u.m
`Mar—mun“.
`um .
`mm.u—~H...u1.n-L..
`Burnt—‘- "
`
`
`1: (worms-rummaging
`56? (“inappropriate release of CGRP is a potential causative factor in several
`
`
`IFHflISJJL-QI
`Lullrt‘nlmir Isa-Helm
`diseases. including ungaine"): supra §V: Ex. 1014. 9126-33.}
`
`
`
`55
`Ex.1333,1l116;Rep|y,13-19
`
`DEMDNS'IRATNE BEHBIT- NEIT EVIDENCE
`
`37
`
`

`

`Dr.