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 DEMONSTRATIVES
`January 8, 2020
`
`Demonstrative Exhibits – Not Evidence
`(*unless indicated otherwise, citations to papers refer to IPR2018-01710)
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`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 DEMONSTRATIVES
`January 8, 2020
`
`Demonstrative Exhibits – Not Evidence
`(*unless indicated otherwise, citations to papers refer to IPR2018-01710)
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`
`The Breadth of Teva’s Claims
`
`The ’045 Patent:
`
`The ’908 Patent:
`
`Ex. 1001 (’045 Patent), 99:1-7
`
`Ex. 1001 (’908 Patent), 99:54-67, 100:54-58
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`
`
`The Combination of Olesen, Tan 1995, and Queen
`Renders Teva’s Claims Obvious
`
`Olesen 2004
`(Ex. 1025)
`
`Antagonized the CGRP
`pathway to successfully
`treat migraine patients
`
`Tan 1995
`(Ex. 1022)
`
`Used an anti-CGRP
`antibody to antagonize
`the CGRP pathway in vivo
`
`Queen 2001
`(Ex. 1023)
`
`Humanized antibodies
`for therapeutic use
`
`Combination
`achieves the
`claimed methods
`with a reasonable
`expectation of
`success
`
`Pet., 24-25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`
`
`A POSA in 2005 Expected CGRP Antagonists to Treat Migraine
`
`Doods (Ex. 1024):
`“Since several lines of evidence indicate that CGRP might be a key factor in the initiation of
`migraine headache, we expect that CGRP antagonists will be effective anti-migraine drugs.”
`Ex. 1024, 422; Ex. 1014, ¶139; Pet., 37
`
`Lassen 2002 (Ex. 1047):
`•
`“CGRP caused headache in virtually all migraine sufferers, whereas placebo did not.”
`•
`“This finding greatly increases the likelihood that a CGRP antagonist may be effective in
`the treatment of migraine attacks.”
`
`Wimalawansa (Ex. 1096):
`•
`“Evidence is accumulating that inappropriate release of CGRP is a potential causative
`factor in several diseases, including migraine”
`“The role of CGRP antagonists and humanized monoclonal antibodies should be
`explored”
`
`•
`
`Ex. 1047, 59, 60; Ex. 1014, ¶¶29, 139; Pet., 11, 37
`
`Ex. 1096, 567, 570; Ex. 1014, ¶116; Pet., 29
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`
`
`A POSA in 2005 Expected CGRP Antagonists to Treat Migraine
`
`Olesen (Ex. 1025):
`
`• Multicenter, double-blind, randomized
`clinical trial of BIBN4096BS
`• 126 patients with migraine
`•
`Intravenous administration
`•
`“Proof of concept was thus established.”
`• Conclusion: “The CGRP antagonist BIBN
`4096 BS was effective in treating acute
`attacks of migraine.”
`
`Ex. 1025, 1104, 1108-1109; Ex. 1014, ¶¶31-34; Pet., 25-26
`
`Arndt 2004 (Ex. 1030):
`Olesen’s data “demonstrate the validity of
`the CGRP concept paving a novel way in
`migraine pain treatment.”
`Ex. 1030, 129; Ex. 1014, ¶¶69, 116; Pet., 15, 30
`Dr. Charles:
`Olesen’s study “encouraged the
`development of additional agents to treat
`migraine by blocking the CGRP pathway.”
`Ex. 1014, ¶109; Pet., 25-26
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`
`
`A POSA in 2005 Expected CGRP Antagonists to Treat Migraine
`
`Dr. Ferrari in 2005:
`•
`“Olesen and colleagues evaluated the effectiveness of the CGRP-antagonist BIBN4096BS
`for acute migraine treatment….There were no serious adverse events”
`“CGRP antagonists … seem promising, new antimigraine drugs without vascular side
`effects.”
`
`•
`
`Dr. Ferrari in 2007:
`
`Ex. 1290, 657; Ex. 1338, ¶89; Reply, 5, 12
`
`Olesen’s study “firmly establish[ed] blockade of the CGRP pathway as a novel and
`important new emerging treatment principle for acute migraine.”
`
`Dr. Rapoport in 2005:
`Olesen’s study “suggests that antagonising the effect of CGRP may provide acute relief of
`migraine headache. Preventive drugs might be developed on the same principle.”
`
`Ex. 1332, 443; Ex. 1338, ¶29; Reply, 5
`
`Ex. 1297, S119; Ex. 1338, ¶29; Reply, 5
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`6
`
`
`
`Well-Known Advantages of Humanized Antibodies
`for Chronic Treatment
`
`Long Half-Lives to Treat Chronic
`Migraine Conditions
`Ex. 1041, 1073; Ex. 1014, ¶¶124-126; Ex. 1015, ¶55; Pet., 31; Reply, 14
`
`Lower Toxicity and Fewer Side-
`Effects Compared to Small
`Molecules
`Ex. 1014, ¶127; Ex. 1015, ¶55; Ex. 1337, ¶¶77-79; Pet., 32;
`Reply, 18
`Reduced Immunogenicity in
`Human Patients
`
`Ex. 1023, 1:44-47; Ex. 1015, ¶¶93-96; Ex. 1014, ¶120; Pet., 33-34
`
`High Affinity and Specificity –
`“Perfect Tool” for “Disrupting
`Ligand-Receptor Interactions”
`Ex. 1014, ¶132; Ex. 1015, ¶55; Ex. 1266, 521; Pet., 32, 33;
`Reply, 20
`Humanized IgG Antibodies Were
`a “Clinically Well-Validated
`Technology”
`Ex. 1073, 120; Ex. 1014, ¶119; Ex. 1015, ¶¶41, 93, 98; Pet., 33
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`
`
`Long Half-Life Desired for Chronic Migraine Treatment
`
`Dr. Charles:
`• Episodic Nature of Migraine: Motivated a POSA “to target long-term approaches for
`migraine treatment, i.e., a POSA would have looked for drugs that persist in the body
`long enough to reduce incidence of future migraine attacks.”
`• Duration of Attack: “Because a migraine attack can last anywhere between 4 hours and 3
`days, a POSA would have been motivated to look for other drugs that persist in the body
`for longer periods of time.”
`Ex. 1014, ¶¶124-126; Pet., 31
`Dr. Vasserot:
`•
`Less-Frequent Administration: “Full-length antibodies for chronic treatment are desirable
`because they have longer half-lives and as such would require fewer administrations.”
`• Widely Adopted Drug Format: “[B]y 2005, the discovery and development of therapeutic
`antibodies had outpaced small molecule drug discovery and development.”
`Ex. 1015, ¶¶55, 99; Pet., 32, 34
`Teva’s Experts:
`• Dr. Ferrari: “short plasma half-life” was a “[m]ain disadvantage” of sumatriptan
`• Dr. Rapoport: advocated daily triptan administration for a full year
`• Dr. Tomlinson: long half-life of antibodies provides a “favorable pharmacokinetic profile””
`
`Ex. 1281, S76; Ex. 1294, Abstract; Ex. 1266, 521; Ex. 1338, ¶¶ 18-19; Reply, 14
`8
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Teva Admitted CGRP’s Involvement in Migraine
`
`Teva Patents:
`
`Teva Argument:
`CGRP not a
`“biomarker”
`
`Ex. 1001 (’045 Patent), 2:7-9; Reply, 6
`
`Ex. 1001 (’045 Patent), 2:14-23; Pet., 7
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`
`
`Teva Arguments:
`Spare Receptor
`
`Cross-Binding
`
`Spare Receptor Theory and Ligand Cross-Binding
`Did Not Deter Researchers
`Sheykhzade 2004 (Ex. 2065):
`“In our study, approximately 27% of all receptors must be
`occupied by CGRP to elicit a half-maximal response (EC50),
`indicating the presence of a relatively small CGRP1-receptor
`reserve pool in the human subcutaneous arteries.”
`Dr. Charles:
`Ex. 2065, 1071; Ex. 1337, ¶46; Reply, 18-19
`“[T]here is no indication that it would be necessary to ‘sequester
`99,999 ligands’ out of 100,000 (i.e., 99.999% of all CGRP
`molecules) to prevent anti-CGRP antagonist antibodies from
`eliciting a full clinical response. Rather, clinical evidence indicated
`that merely normalizing CGRP levels can successfully treat
`migraine.”
`Ex. 1338, ¶117; Ex. 1044, Abstract; Reply, 18-19
`Dr. Charles:
`•
`“[C]ross-binding of CGRP to these other receptors was
`understood to be poor before November 2005.”
`“The anti-CGRP ligand aptamers had been shown to inhibit
`neurogenic blood flow increases in the rat cranial dura (Ex.
`1240, 923) just as BIBN4096BS did in Doods (Ex. 1024, 422).”
`Ex. 1338, ¶¶121-124; Ex. 2059, Table 1; Ex. 1240, 923; Reply, 19
`10
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`•
`
`
`
`Extensive Prior-Art Evidence Demonstrates Treatment of
`Migraine Through Peripheral CGRP Antagonism
`Teva Argument:
`Triptans:
`Blood-Brain
`Dr. Ferrari: “Important pharmacological actions of sumatriptan are (i) poor penetration
`of the blood-brain barrier suggesting a peripheral point of action”
`Barrier
`Ex. 1281, S73; Ex. 1338, ¶18; Reply, 9
`Aptamers:
`Healy: “None of the aptamer conjugates or compositions showed a propensity to traverse the blood/brain barrier.”
`Ex. 1310, 2244; Ex. 1338, ¶24; Reply, 9
`BIBN4096BS:
`•
`Peterson 2004: “The present study strongly suggest that the clinically effective migraine drug BIBN4096BS
`(Olesen et al., 2004) does not cross the BBB.” (Ex. 1090, 703)
`•
`Peterson 2005: BIBN “prevents or treats headache predominantly in an extracerebral manner.” (Ex. 1333, 211)
`•
`Edvinsson 2005: BIBN “does not appear to pass the blood-brain barrier freely” (Ex. 2215, 75)
`•
`Arulmani 2004: BIBN “does not seem to penetrate the blood-brain barrier” (Ex. 1031, 326)
`• Dr. Foord’s testimony: “it would be unlikely” that BIBN crosses the BBB (Ex. 1343, 76:12-77:8)
`•
`Storer: Peripherally administered BIBN “resulted in a dose-dependent inhibition of” trigeminocervical nucleus
`activity (Ex. 2307, 1175-1176)
`Fischer: “Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way
`to decrease nociceptive transmission.” (Ex. 2310, Abstract)
`-----------------------------------------------------------------------------------------------------------------------------------------------------------
`•
`cf. Levy: “These findings . . . support a central site of action for the role of CGRP in promoting migraine, as well
`as the antimigraine effect of CGRP antagonism.” (Ex. 2298, 704)
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1338, ¶¶ 36-53; Reply, 7-10; Pet., 32-33
`
`11
`
`
`
`Development of Anti-CGRP Antibodies
`
`1993
`
`1994
`
`1995
`
`1996
`
`2002
`
`2002
`
`2004
`
`2004
`2005
`
`Wong
`
`Tan Thesis
`
`Tan 1995
`
`Wimalawansa
`
`Salmon
`
`’438 patent
`
`Sveinsson
`
`Olesen
`Arulmozhi
`
`Teaching “specific blocking of endogenous CGRP either at the receptor level
`using specific CGRP antagonists, or by neutralizing endogenous peptide with a
`specific antibody.” (Ex. 1033, 95)
`“There seems to be no reason why anti-peptide MAbs should not be
`investigated as therapeutic agents” for “migraine” (Ex. 1287, 247)
`“Immunoblockade” as “an alternative strategy” or “complementary” to the
`use of receptor antagonists. (Ex. 1022, 566, 571)
`“The role of CGRP antagonists and humanized monoclonal antibodies should
`be explored” (Ex. 1096, 567, 570)
`Compositions can include anti-CGRP “monoclonal antibodies for the
`modulation of” “neurogenic inflammatory pain” (Ex. 1027, [0039])
`Disclosing and claiming “anti-CGRP antibodies” for therapeutic use
`(Ex. 1028, claim 2)
`Disclosing and claiming “anti-CGRP antibodies” for therapeutic use
`(Ex. 1026, claim 2)
`“Proof of Concept was thus established” (Ex. 1025, 1109)
`“[I]nhibition of CGRP or antagonism of CGRP receptors could be a viable
`therapeutic target for the pharmacological treatment of migraine.” (Ex. 1040,
`182)
`
`Ex. 1014, ¶¶111, 116-117; Pet., 26- 27; Reply, 6, 15
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`
`
`Teva’s Concerns Did Not Deter Development of
`Anti-CGRP Aptamers
`Pendergrast (Ex. 1309):
`“[A]ptamers can be thought of as nucleic acid analogs to antibodies.”
`Ex. 1309, Abstract; Ex. 1338, ¶24; Ex. 1337, ¶¶ 57, 60; Reply, 13
`
`Healy (Ex. 1310):
`“None of the aptamer conjugates or compositions showed a propensity
`to traverse the blood/brain barrier.”
`
`Teva Arguments:
`Blood-Brain
`Barrier
`
`Safety Concerns
`
`Spare Receptor
`
`Cross-Binding
`
`Ex. 1310, 2244; Ex. 1338, ¶24; Reply, 9
`
`Messlinger (Ex. 1240):
`•
`Tested “a new high-affinity CGRP-binding RNA-Spiegelmer, which is a
`biostable aptamer”
`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 Spiegelmer may open a new therapeutic strategy in diseases
`that are linked to excessive CGRP release such as migraine and other
`primary headaches.”
`
`•
`
`•
`
`•
`
`Ex. 1240, 923; Ex. 1014, ¶62; Pet., 27
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`
`
`Teva’s Purported Safety Concerns Were Resolved by
`November 2005
`
`Ex. 2151
`Ex. 2154
`Ex. 2070
`Ex. 2089
`Observational
`
`1990
`
`Ex. 2209
`Exogenous
`CGRP/capsaicin
`
`Ex. 2152
`CGRP8-37
`“no effect”
`
`Ex. 1283
`CGRP8-37
`“no effect”
`
`Ex. 1284
`BIBN4096BS
`“no statistically
`significant effect”
`
`Ex. 1025
`BIBN4096BS
`“not a
`vasoconstrictor”
`
`Ex. 1042
`BIBN4096BS
`“without
`cardiovascular
`side-effects”
`
`Ex. 1240
`CGRP-Aptamer
`“unchanged”
`
`1995
`
`2000
`
`2005
`
`Exogenous
`CGRP
`Ex. 2079
`
`Exogenous
`CGRP
`Ex. 2058
`
`Exogenous
`CGRP
`Ex. 2139
`
`Capsaicin
`Ex. 2150
`
`BIBN4096BS
`“did not affect”
`Ex. 1318
`
`BIBN4096B
`“did not affect”
`Ex. 1285
`
`BIBN4096BS
`“did not alter”
`Ex. 1263
`
`BIBN4096BS
`“no effect”
`Ex. 2019
`
`Dr. Charles:
`“There were multiple studies in humans that indicate that,
`in fact, it was safe to therapeutically target CGRP, and
`animals also.”
`
`Lilly Exhibit
`
`Teva Exhibit
`Ex. 1338, ¶¶67-87; Reply, 16-18
`
`Ex. 2338, 40:11-20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`
`
`Anti-CGRP Antibodies Did Not Raise Safety Concerns
`
`Tan 1995 (Ex. 1022):
`
`MAP gradually recovered within “10 to 15 min” for full-length IgG and Fab’ fragment
`
`Tan’s contemporaneous statements:
`“There seems to be no reason why anti-peptide MAbs or their fragments should not be
`investigated as therapeutic agents.”
`
`Ex. 1022, 568; Ex. 1338, ¶¶91-93; Ex. 1337, ¶¶62-66; Reply, 14
`
`Ex. 1287, 247; Reply, 6, 15
`
`Wong (Ex. 1033):
`“The monoclonal antibody had no significant effect on MAP and heart rate (n=6).”
`Ex. 1033, 101; Ex. 1338, ¶92; Ex. 1337, ¶¶68-70; Reply, 15
`
`Andrew (Ex. 1055):
`POR, 5, 14-15
`“Although the immunized rats had high levels of circulating antibodies to rat CGRP, they did
`not show any signs of physical or behavioral abnormality.”
`Ex. 1055, 93; Ex. 1338, ¶98; Ex. 1337, ¶71; Reply, 15
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`
`
`Teva’s Patents Do Not Identify or Solve the Problems
`Teva Raises in this Litigation
`
`Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012) (affirming
`obviousness where purported safety concerns were not addressed in the invalidated
`patent)
`Reply, 4
`Teva Arguments:
`Blood-Brain
`Safety Concerns
`Barrier
`Dr. Ferrari:
`•
`“There is no text mentioning data from safety studies.”
`•
`“The patents do not disclose studies in humans.”
`Dr. Foord:
`
`Spare Receptor
`
`Cross-Binding
`
`Ex. 1303, 56:4-11; Reply, 3
`
`Teva’s patent examples “will never satisfy concerns about safety and efficacy.”
`
`Dr. Ferrari:
`Teva’s patent examples are “not aimed at studying the blood-brain barrier.”
`
`Ex. 1300, 174:5-11; Reply, 3
`
`Ex. 1345, 61:5-65:2; Reply, 4
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`
`
`Tan 1995 (Ex. 1022): Immunoblockade of CGRP
`Was Effective In Vivo
`
`Tan 1995 (Ex. 1022):
`Block hypotensive effect:
`“This study has clearly demonstrated the ability of MAb C4.19 IgG and its Fab’ fragment to block
`hypotensive effects of exogenous rat αCGRP in vivo.
`Rat saphenous nerve effect:
`“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).”
`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, 569-571; Pet., 45-46; Reply, 10-11
`“A POSA would have been motivated to follow Tan’s recommendations because they are consistent
`with how a POSA would have wanted to reduce incidence of or chronically treat migraine, i.e., with
`therapeutic agents having high specificity and long half-lives.”
`
`•
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1014, ¶136; Pet., 46-47
`
`17
`
`
`
`Teva’s Synaptic Cleft Size Arguments Are Meritless
`
`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 (Ex. 1349, 275-277)
`Ex. 2265, ¶90; POR, 37; Ex. 1337, ¶38; Reply, 11
`
`Wrong Antibody Type and Antibody Size:
`•
`Teva relies on an IgE antibody having 15 nm in its longest direction (Ex. 2281, 1967)
`•
`Size of IgG antibodies: ~8-10 nm (Ex. 1347, 7184)
`
`Ex. 2265, ¶90; POR, 37; Ex. 1337, ¶37; Reply, 11
`Ignored Mobility & Three-Dimensional Nature of Antibodies
`• Dr. Balthasar: an antibody may be “rotated or folded such that it has a profile significantly
`narrower than 15 nm wide” (Ex. 1337, ¶36)
`Even IgE antibodies are only 5 nm in profile (Ex. 2281, 1967)
`
`•
`
`Ex. 2265, ¶90; POR, 37; Reply, 11
`
`Tan Demonstrates Access to Synaptic Cleft
`• MAb IgG C4.19 “reached equilibrium in the synaptic cleft after 45 min[utes]” (Ex. 1021, 709)
`• Vas deferens tissues have 20 nm synaptic cleft size (Ex. 1348, 5)
`Ex. 1337, ¶38; Reply, 10-11
`Dr. Foord’s Admission:
`Q:
`[Y]ou’re not an expert in the dynamics of an antibody and how they behave in the synaptic cleft?
`A:
`That is correct.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1343, 70:4-9; Reply, 11
`18
`
`
`
`Tan Teaches that Anti-CGRP Antibodies Were Expected
`to Access the Synaptic Cleft
`
`Tan 1995 (Ex. 1022):
`
`Covell (Ex. 1247):
`
`Ex. 1022, 571; Ex. 1337, ¶29; Reply, 10
`
`Dr. Balthasar:
`“Consistent with Covell’s data,” “[a] POSA would have readily appreciated that permitting a
`longer time for distribution, as well as higher doses or chronic administration, was
`appropriate just as Tan 1995 repeatedly recommended”
`
`Ex. 1247, 3972; Ex. 1337, ¶28; Reply, 10
`
`Ex. 1337, ¶¶27-29; Reply, 10
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`19
`
`
`
`Teva Followed Tan’s Express Guidance
`
`Ex. 1001, 55:61-64; Ex. 1014, ¶¶88-95; Pet., 47-48; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`
`
`Teva’s Secondary Considerations Are Not Commensurate with
`the Scope of the Challenged Claims
`
`Headache Types
`
`Sequence Mutations
`
`250
`
`20220
`
`Binding Affinity
`
`Antibody Format
`(e.g., fragments)
`(’045 patent)
`Antibody Class
`(’045 patent)
`
`2 pM-250 nM
`•
`’045 patent claims 4 & 20 (50 nM
`or less)
`•
`’908 patent (about 10 nM or less)
`Fab, Fab', F(ab’)2 , Fv,
`single chain (ScFv), fusion proteins
`
`IgA, IgD, IgE, IgG, IgM
`
`Ex. 1304, 74:17-75:12; Ex. 1001, 20:25-
`40; Pet., 62; Reply, 21-22
`Ex. 1301, 92:8-10; Ex. 2217, 8-9; Reply,
`22
`Ex. 1301, 102:1-103:15, 104:7-19; Ex.
`1001, 5:35-46; Reply, 23
`
`Ex. 1301, 27:25-28:6; Ex. 1001, 12:61-
`65; Pet., 23-24; Reply, 23
`
`Ex. 1301, 37:16-39:11; Ex. 1001, 12:29-
`37; Reply, 23
`
`In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011) (“Evidence of secondary considerations
`must be reasonably commensurate with the scope of the claims.”).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 23
`
`21
`
`
`
`Teva Failed to Rebut Evidence Showing Lack of Nexus
`
`•
`
`Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 963 (Fed. Cir. 2014)
`•
`“Neither the district court nor appellees explain the nexus between [secondary consideration
`evidence] and the broad scope of ’029 patent’s claimed invention.”
`“The district court needed to have found that other embodiments falling within the claim will
`behave in the ‘same manner’ as compounds with C1-amide groups, in order to establish that
`evidence of [secondary considerations] ‘is commensurate with the scope of the claims.’”
`Reply, 23
`
`Dr. Tomlinson’s testimony:
`•
`Selected mutations were made to fremanezumab “[t]o increase binding affinity” and “to prevent
`antibody dependent cell cytotoxicity, ADCC, and complemental dependent cytotoxicity, CDC.” (Ex.
`1301, 115:9-116:21; Ex. 2217, 8-9; Reply, 22)
`Fremanezumab and galcanezumab “do not cover or represent the full range of affinities” (Ex. 1301,
`104:7-19; Reply, 23)
`“I think it’s pretty clear that an unformatted antibody fragment is not going to be effective as a
`human therapeutic against that target.” (Ex. 1301, 134:14-25; Reply, 23)
`
`•
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`
`
`Teva Failed to Rebut Evidence Showing Lack of Nexus
`
`In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011) (“Where the offered secondary
`consideration actually results from something other than what is both claimed and
`novel in the claim, there is no nexus to the merits of the claimed invention.”)
`Reply, 23
`
`Dr. Rapoport’s cross-examination:
`Q: … So it’s your opinion that the antibodies that you have indicated met a long-felt need
`is based on their characteristic that they block the CGRP pathway, correct?
`A: Correct.
`
`Ex. 1304, 142:1-8; Reply, 23-24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`
`
`Teva Failed to Establish A Presumption of Nexus
`
`Fox Factory, Inc. v. SRAM, LLC, 2019 WL 6884530 (Fed. Cir. Dec. 18, 2019)
`
`•
`
`•
`
`•
`
`•
`
`“[N]exus can only be presumed where the evidence of secondary
`considerations is tied to a specific product that ‘is the invention disclosed and
`claimed.’” (id. at *8)
`
`“We reject SRAM’s attempt to reduce the coextensiveness requirement to an
`inquiry into whether the patent claims broadly cover the product that is the
`subject of the evidence of secondary considerations.” (id. at *8)
`
`“[W]hen the thing that is commercially successful is not coextensive with the
`patented invention … the patentee is not entitled to a presumption of nexus.”
`(id. at *5)
`
`“[B]ecause there are one or more features not claimed by the [] patent that
`materially impact the functionality of the [commercial] products,” “nexus may
`not be presumed.” (id. at *7)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`24
`
`
`
`Teva Failed to Establish A Presumption of Nexus
`The instant case
`Fox Factory
`Rejected changing the coextensiveness
`Teva: “Ajovy® and Emgality® are covered by the claims.” (Sur-reply, 27;
`requirement to an inquiry into whether
`POR, 55-56)
`the patent claims broadly “cover” the
`Dr. Tomlinson: claims “cover administration of at least one of” Ajovy® and
`product.
`Emgality®. (Ex. 2271, ¶127)
`No presumed nexus when the product
`Sequence and Mutations: 20220
`•
`has one unclaimed feature that
`Ajovy® and Emgality® have optimized amino acid sequences with specific
`mutations to modify their functionalities (Reply, 22)
`“materially impacts” functionality
`•
`Ajovy®: targeted mutations at residues 99, 100, 330, 331 (Ex. 2217,
`(>80% gap filling)
`8-9; Ex. 2216, 17 (Emgality® mutations)
`•
`Teva does not dispute in sur-reply
`Binding affinity:
`•
`Tomlinson: Low pM affinities of Ajovy® and Emgality® do not cover or
`represent the full range of affinities claimed. (Ex. 1301, 104:7-19
`(“They’re just two antibodies within that range.”); Reply, 23)
`Antibody fragments:
`•
`Tomlinson: “an unformatted antibody fragment is not going to be
`effective as a human therapeutic” (Ex. 1301, 134:14-25; Reply, 23)
`Antibody class (IgG3, IgA, IgM, IgD, IgE):
`•
`Tomlinson: could not identify any marketed drug within these classes (Ex.
`1301, 111:7-115:1; 34:9-35:1, Reply, 23; Reply (’908 patent), 23)
`Indication:
`•
`Rapoport: there are 250 different types of headache (Ex. 1304, 74:17-
`75:12; Reply, 21-22)
`
`Additional unclaimed features that
`materially impact functionality further
`demonstrate no entitlement to
`presumption of nexus:
`—tooth tips
`—hook features
`—mud clearing features
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`
`
`Teva’s Evidence of Industry Acclaim Is Deficient
`
`Teva’s arguments:
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`“First up will likely be erenumab (Aimovig)”.
`“[A]t least one prophylactic GGRP-antagonizing small
`molecule (and several others for acute treatment) might not
`be far behind.”
`“‘These are really the first therapies, ever, that have been
`designed based on a specific laboratory understanding of the
`mechanisms of migraine,’ says Andrew Charles…‘That, to me,
`very exciting and compelling.’”
`Ex. 2182, 207; Ex. 1338, ¶131; Reply, 24-25
`“In fact, the [FDA] this May approved ereunumab-aooe, the
`first drug based on monoclonal antibodies to prevent
`migraine.”
`“‘A smaller percentage have shown complete remission,
`which is unlike what we’ve seen with other therapies.’”
`Ex. 2053, 26; Ex. 1338, ¶131; Reply, 24-25
`“’[T]hese therapies have the possibility to transform our
`clinical approach to migraine and cluster headache,’ said
`Charles, from the University of California, Los Angeles.”
`“Charles noted having treated approximately 500 patients
`with erenumab (Aimovig), following its approval in May 2018.
`He said that response to erenumab were consistent or often
`better than reported in clinical trials, with a majority of
`patients responding.”
`
`POR, 56
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 2052, 1; Ex. 1338, ¶131; Reply, 24-25
`26
`
`
`
`Teva’s Evidence of Industry Acclaim Is Deficient
`
`UCLA U Magazine (Ex. 2053):
`•
`“Researchers have found that serum concentrations of CGRP become elevated
`during migraine attack, and they normalize when the attack resolves. Infusion of
`CGRP in patient volunteers provokes migraine attacks that are very similar to
`those that occur spontaneously. Small molecule drugs binding to the CGRP
`receptor were able to abort migraine attacks.”
`“It was this body of evidence that led researchers to suspect that by blocking
`CGRP receptors, or targeting the neuropeptides itself, a migraine attack could be
`prevented. According to results from late-stage clinical trials of erenumab-aoo
`and other anti-CGRP antibodies, the researchers were right.”
`
`•
`
`“’The notion that would be using antibodies for treating migraine is really quite a
`radical concept,’ … ’This is a very 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 chemistry of migraine and what is going on
`during a migraine attack.’”
`
`Ex. 2053, 23; Ex. 1338, ¶¶ 131, 135; Reply, 24-25, 27
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`27
`
`
`
`Teva Failed to Establish Unexpected Results
`or Industry Skepticism
`
`Teva Arguments:
`Medication
`Overuse
`Headache
`
`Industry
`Skepticism
`
`Dr. Rapoport in 2003:
`
`“[S]ome of the patients stopped overusing acute care
`medication during the [naratriptan] study”
`Ex. 1294, 487; see also Ex. 1295, Table 1; Ex. 1338, ¶¶ 137-143; Reply, 25-26
`Dr. Pons:
`Q: So Pfizer conducted five Phase I trials with
`fremanezumab from 2009 to 2012, correct?
`A: Yes.
`
`Ex. 1346, 42:22-43:2; Reply, 26
`“Labrys was created specifically to move forward on
`RN307”: “$31 million in series A financing”
`
`Ex. 2331, ¶13; Reply, 26
`Pfizer “decided that migraine was not an area it wanted to
`pursue.”
`
`Ex. 2167, 118-119 (quoting Dr. Pons); Reply, 26
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`
`
`Teva’s Purported Evidence of Licensing, Long-Felt Need, and
`Commercial Success Do Not Support Patentability
`
`Teva Arguments:
`Licensing
`
`Long-felt but
`Unmet Need
`
`Dr. Stoner:
`
`Q:
`
`[I]f all of the challenged claims were canceled, Alder Bio would
`still owe the same considerations to Teva for the same reason,
`that they had admitted infringement of all of the 179 additional
`patents, correct?
`That appears to be a reasonable interpretation of this paragraph
`A:
`Ex. 1302, 179:14-180:19; Reply, 26-27
`Dr. Charles:
`“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 (Ex. 1014, ¶¶26-38, 107-113), and (2) the prior art
`would have motivated a POSA to use a humanized anti-CGRP antagonist
`antibody for treating or reducing incidence of migraine (id., ¶¶107-
`137).”
`
`Ex. 1338, ¶135; Reply, 27
`
`Commercial
`Success
`
`NO evidence of any commercial sales
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 26
`29
`
`
`
`Teva’s Affinity Claims Were Obvious
`
`Dr. Tomlinson in 2004:
`“An ideal drug would have the following qualities: it would have very high affinity and exquisite
`specificity for its target”
`
`Tan 1994 (Ex. 1021):
`“The dissociation constants (Kd) of MAb
`C4.19 for rat αCGRP and βCGRP were very
`similar (1.9 and 2.5 nM respectively).”
`
`Dr. Vasserot:
`
`Ex. 1266, 521; Ex. 1337, ¶87; Reply, 20
`
`Andrew’s antibodies “against human αCGRP were
`already shown to have affinities of about 4 nM to 40
`nM. (Ex. 1055, 92)”
`
`Ex. 1021, 707; Ex. 1015, ¶113; Pet., 52
`Teva’s Argument:
`“The art teaches a disconnect between binding and activity. … [T]he anti-CGRP antibody MAb R1.50
`‘clearly showed the greatest [binding] activity’ among the tested antibodies to rat αCGRP, yet it
`‘blocked rat αCGRP poorly.’”
`
`Ex. 1015, ¶115; Pet., 52
`
`Tan 1994 (Ex. 1021):
`“The use of RIA and a receptor binding assay as biochemical screens was generally successful in
`predicting blocking MAbs. An interesting exception was MAb R1.50”
`
`Sur-reply, 24-25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1021, 707; Ex. 1337, ¶81; Reply, 19-20
`30
`
`
`
`Teva’s Claims Do Not Require A Clinical Response
`
`Claim Terms:
`
`Teva Patents:
`
`Ex. 1001, 17:37-38; Ex. 1014, ¶102; Pet., 20
`
`Ex. 1001(’907 patent), 103:20-35
`
`Ex. 1001(’045 patent), 99:1-7
`
`Ex. 1001, 17:61-65; Ex. 1014, ¶103; Pet., 21
`
`Novartis Pharm. Corp. v. Actavis, Inc., No. 12-cv-366, 2013 WL 6142747, at *11 (D. Del.
`Nov. 21, 2013) (construing “treating” as merely an “attempt to cause a therapeutic
`improvement,” relying on “the term’s use in the patent”).
`
`Pet., 20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`
`
`Teva’s Claims Do Not Require A Clinical Response
`
`Claim Terms:
`
`Teva Patents:
`
`Ex. 1001(’045 patent), 99:1-7
`
`Ex. 1001(’907 patent), 103:20-35
`
`Ex. 1001 (’045 patent), 100:1-2
`
`Ex. 1001 , 18:38-57; Ex. 1338, ¶¶7-8; Pet., 22-23; Reply, 2-3
`Dr. Foord:
`An effect in a cAMP assay “and the effective dose
`within an individual human for treatment are
`enormously apart.”
`
`Ex. 1343, 33:24-34:6; Reply, 2-3
`
`Dr. Charles:
`“A POSA would view doses as low as about 3 µg/kg to
`be exceedingly low and likely to be insufficient to
`generate a clinical response, let alone any response.”
`Ex. 1014, ¶105; Pet., 22-23
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`
`
`Detailed Analysis
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`
`
`Novartis v. West-Ward Is Inapposite
`
`Novartis v. West-Ward
`Patent claimed using a specific
`compound (everolimus), defined
`by chemical structure, to inhibit
`tumor growth.
`No Phase II data existed for
`everolimus or any other mTOR
`inhibitor.
`The claimed disease resisted all
`treatment modalities.
`
`No prior art disclosure that
`everolimus would be effective in
`treating the claimed disease.
`
`The instant case
`Teva’s patents broadly cover using any humanized
`anti-CGRP antagonist antibody, with no structural
`limitations, for the aspirational goal of treating
`migraine.
`Olesen published a Phase II clinical trial, establishing
`that blocking the CGRP pathway effectively treats
`migraine.
`Multiple effective CGRP-pathway inhibitors were
`known to treat migraine, including sumatriptan and
`BIBN.
`The prior art disclosed: “we expect that CGRP
`antagonists will be effective anti-migraine drugs.”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 20-21
`
`34
`
`
`
`Known Anti-CGRP Pathway Antagonists Were Reported
`to Be Safe and Effective
`
`Triptans: FDA-approved anti-
`migraine drugs advocated for daily
`administration
`Ex. 1282, 1521; Ex. 1294, Abstract; Ex. 1338, ¶¶19, 93; Reply, 13
`BIBN4096BS: “caused only minor
`adverse events and had no constrictor
`effect”
`Ex. 1025 (Olesen), 1108; Ex. 1338, ¶82; Reply, 12
`CGRP-binding “biostable aptamer”:
`“Basal blood flow and systemic arterial
`pressure were unchanged”; “a new
`therapeutic strategy in diseases … such
`as migraine”
`Ex. 1240, 923; Ex. 1082, Abstract, 2; Ex. 1338, ¶80; Reply, 13
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`
`
`Tan 1995 Offers Express Guidance to
`Improve Immunoblockade
`
`Teva’s arguments:
`In the Louis/Dockray experiments, “the antibodies ‘leaked’ into the
`interstitial space due to ‘plasma extravasation.’”
`
`Tan 1995 (Ex. 2022):
`
`Sur-reply, 18-19
`
`Ex. 1022, 571; Ex. 1337, ¶¶15-39; Reply, 10
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`36
`
`
`
`Absolute Risk of Stroke and Myocardial Ischemia in
`Migraine Patients Was Very Low
`
`Bousser (Ex. 2157):
`The “absolute risk of stroke in young women with migraine is low: 18 per 100,000 per year.”
`Ex. 2157, 535; Ex. 1338, ¶108; Reply, 18
`Dr. Ferrari:
`Q: 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 no known association.
`Dr. Charles:
`“Clinicians’ experience with triptans led to the understanding that (1) the absolute risk of
`suffering from clinical ischemia is low among migraine patients, and (2) a drug that could
`potentially worsen ischemic episodes can be used safely with little or no adverse events
`when patients are appropriately selected.”
`
`Ex. 1303, 193:3-10; Reply, 18
`
`“At most, the risk that a drug could worse ischemic episodes would have amounted to a
`warning or contraindication, similar to those that already existed for triptans and ergots.”
`Ex. 1338, ¶113; Reply,
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