UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ELI LILLY AND COMPANY
`v.
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`
`Case IPR2018-01422 (Patent No. 9,340,614)
`Case IPR2018-01423 (Patent No. 9,266,951)
`Case IPR2018-01424 (Patent No. 9,346,881)
`Case IPR2018-01425 (Patent No. 9,890,210)
`Case IPR2018-01426 (Patent No. 9,890,211)
`Case IPR2018-01427 (Patent No. 8,597,649)*
`
`ELI LILLY TRIAL DEMONSTRATIVES
`
`November 22, 2019
`
`Demonstrative Exhibits – Not Evidence
`
`(*unless indicated otherwise, citations to papers refer to IPR2018-01422)
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ELI LILLY AND COMPANY
`v.
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH
`
`Case IPR2018-01422 (Patent No. 9,340,614)
`Case IPR2018-01423 (Patent No. 9,266,951)
`Case IPR2018-01424 (Patent No. 9,346,881)
`Case IPR2018-01425 (Patent No. 9,890,210)
`Case IPR2018-01426 (Patent No. 9,890,211)
`Case IPR2018-01427 (Patent No. 8,597,649)*
`
`ELI LILLY TRIAL DEMONSTRATIVES
`
`November 22, 2019
`
`Demonstrative Exhibits – Not Evidence
`
`(*unless indicated otherwise, citations to papers refer to IPR2018-01422)
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`
`Eli Lilly Trial Demonstratives
`
`I.
`
`Summary of Case
`
`II. Overview of Challenged Patent Claims
`
`III. Overview of Asserted References
`
`IV. Additional Motivation from Prior Art
`
`V.
`
`Teva Failed to Rebut Motivation
`
`VI. Reasonable Expectation of Success
`
`VII. Alleged Secondary Considerations
`
`VIII. Teva’s Affinity Claims Are Obvious
`
`IX. Detailed Analysis
`
`X. Motion to Strike
`
`XI. Motion to Exclude
`
`3
`
`4
`
`5
`
`11
`
`19
`
`38
`
`40
`
`46
`
`49
`
`114
`
`118
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`
`
`Summary of Case
`
`•
`
`•
`
`Teva’s patents broadly claim any humanized anti-CGRP antagonist antibody
`with known or routinely achievable features
`
`Tan 1995 describes an anti-CGRP antagonist antibody effective in vivo and
`provides guidance to improve immunoblockade
`
`• Wimalawansa expressly teaches that humanized anti-CGRP antibodies
`“should be explored” to treat human diseases
`
`•
`
`•
`
`The prior art is replete with reports providing additional motivation to make
`a humanized anti-CGRP antagonist antibody
`
`Teva conceded it was routine to make a humanized antibody
`
`• Neither Tan 1995 nor Teva’s purported safety concerns teach away from the
`claimed subject matter
`
`•
`
`Teva’s purported secondary considerations lack nexus and are insufficient to
`overcome obviousness
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`
`
`The Breadth of Teva’s Claims
`
`Ex. 1001 (’614 Patent), 101:31-4
`
`Ex. 1001 (’649 Patent), 101:37-41
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`
`
`Tan 1995 (Ex. 1022) Shows MAb C4.19 Was Effective In Vivo
`
`Ex. 1022, 570; Ex. 1008, ¶71; Pet., 17
`
`Ex. 1022, 572; Ex. 1009, ¶76; Pet., 31
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`
`
`Tan 1995 (Ex. 1022) Shows MAb C4.19 Was Effective In Vivo
`
`Ex. 1022, 569; Ex. 1008, ¶57; Pet., 17-18; Reply, 20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`6
`
`
`
`Tan 1995 (Ex. 1022) Provided Guidance to
`Improve Immunoblockade
`
`Ex. 1022, 571; Ex. 1008, ¶122; Ex. 1305, ¶¶24-29; Pet., 39-42; Reply, 20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`
`
`Teva Followed Tan’s Express Guidance
`
`Ex. 1001, 55:7-10; Ex. 1008, ¶¶91-98; Pet., 42-43; Reply, 20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`
`
`Wimalawansa (Ex. 1096): Humanized Anti-CGRP Antagonist
`Antibodies “Should Be Explored”
`
`Ex. 1096, 567; 1008, ¶74; Pet., 19
`
`Ex. 1096, 570; 1008, ¶74; Pet., 19; Reply, 2.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`
`
`Doods (Ex. 1024): Motivation to Make an Anti-CGRP
`Antagonist Antibody
`
`Ex. 1024, 422; Ex. 1008, ¶113; Pet., 26
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`10
`
`
`
`Salmon (Ex. 1027) Disclosed Anti-CGRP Antagonist Antibodies
`for Therapeutic Use
`
`Ex. 1027, ¶[0039]; Ex. 1008, ¶110; Pet., 25
`
`Ex. 1027, claim 8; Ex. 1008, ¶110; Pet., 25; Reply, 12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`
`
`Sveinsson (Ex. 1026) Disclosed Anti-CGRP Antagonist
`Antibodies for Therapeutic Use
`
`Ex. 1026, claims 2 and 7; Ex. 1008, ¶109; Pet., 24-25; Reply, 12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`
`
`The ’438 Patent (Ex. 1028) Disclosed Anti-CGRP Antagonist
`Antibodies for Therapeutic Use
`
`Ex. 1028, 2:7-10; Pet., 25
`
`Ex. 1028, 3:21-22; Ex. 1008, ¶111; Pet., 25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`
`
`Motivation to Make a Humanized Antibody
`
`Dr. Ferrari’s cross-examination:
`
`Q: Hypothetically speaking, as an expert in the field, if a reference stated that an anti-CGRP
`antagonist antibody was to be administered to a human to treat a chronic human disease,
`would that have been understood as a reference to a humanized antibody?
`
`A:
`
`I think that, and, again, I’m not an antibody expert, but by 2005 it was well-known that
`you would significantly reduce the risk of immunological side effects to an antibody by
`humanizing it. So developing an antibody at that time without including humanization
`would not mean – would not be useful to use in patients.
`
`Ex. 1303, 49:1-20; Reply, 3
`
`Dr. Tomlinson’s cross-examination:
`
`Q: As of 2005, by the time that an antibody in drug development reached a Phase 1 clinical
`study for dosing in humans, it would likely be a human or humanized antibody, correct?
`
`A:
`
`In 2005, yes.
`
`Q: And then as of 2005 in a clinical trial program, it would not have been acceptable for a
`person of ordinary skill to have administered a murine antibody to a human for chronic
`use without first humanizing it, correct?
`
`A:
`
`I would say that was quite very unlikely.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`Ex. 1301, 211:2-15; Reply, 3
`
`
`
`Lassen 2002 (Ex. 1047): Motivation to Make an Anti-CGRP
`Antagonist Antibody
`
`Ex. 1047, 59; Ex. 1008, ¶113; Pet., 26
`
`Ex. 1047, 60; Ex. 1008, ¶113; Pet., 26
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`
`
`Olesen (Ex. 1025): Motivation to Make an Anti-CGRP
`Antagonist Antibody
`
`Ex. 1025, 1105; Pet., 10-11
`
`Ex. 1025, 1108-1109; Ex. 1008, ¶¶41-44, 113; Pet., 10-11, 24, 26
`
`Ex. 1025, 1104; Ex. 1008, ¶¶41-44, 113; Pet., 10-11, 24, 26
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`
`
`Targeting CGRP and Its Receptor Were Alternatives
`
`Dr. Rapoport’s statements in 2018:
`
`Ex. 2169, 915; Ex. 1306, ¶86; Opp. Mot. Excl., 12
`
`Arulmozhi 2005:
`
`Ex. 1040, 182; Ex. 1008, ¶116; Pet., 27; Reply, 9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`
`
`Targeting CGRP and Its Receptor Were Alternatives
`
`Ex. 1022, 566, 571; Ex. 1008, ¶114; Ex. 1305, ¶37; Reply, 9
`
`Ex. 1033, 95; Ex. 1305, ¶37; Reply, 9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`18
`
`
`
`Teva’s Patents Do Not Address Safety
`
`Alcon Research Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir. 2012)
`
`“Although Alcon argues that Kamei would not give a skilled artisan an expectation of success
`because it does not teach that olopatadine is safe for the human eye, we find this
`contention to be without merit. While it is true that [the prior art] does not expressly
`disclose that olopatadine would be safe for use in human eyes, neither does the ’805 patent.
`The patent is not based on testing in humans; instead it reports only in vitro tests.”
`Reply, 4-5
`
`Dr. Ferrari’s cross-examination:
`
`Q:
`
`A:
`
`Q:
`
`A:
`
`[Y]ou would agree that the ’614 patent does not disclose any safety studies at all,
`correct?
`
`There is no text mentioning data from safety studies.
`
`Teva’s patents do not disclose any studies in humans at all, correct?
`
`The patents do not disclose studies in humans.
`
`… Q
`
`: …And you would agree with me Teva’s patents do not mention cardiovascular effects
`resulting from anti-CGRP antagonist antibodies, correct?
`
`A:
`
`The same answer, yes.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1303, 56:4-57:19; Reply, 4
`
`19
`
`
`
`Teva’s Patents Do Not Address Safety
`
`Dr. Foord’s cross-examination:
`
`Q:
`
`[W]ould a description of a successful use, whether a statistically significant efficacy
`was shown of an anti-CGRP antibody in a rat saphenous nerve assay, have adequately
`resolved the concerns you identify in your declaration about safety and efficacy?
`
`A: No.
`
`Q: Would the description of the successful use of anti-CGRP antibodies in the rat closed
`cranial window assay have adequately resolved the concerns you identified about
`safety and efficacy?
`
`A: No. These are preclinical animal experiments that will never satisfy concerns about
`safety and efficacy, until that agent goes into man.
`
`Ex. 1300, 173:20-174:11; Reply, 4
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`
`
`Teva’s Purported Safety Concerns Were Resolved by
`November 2005
`
`Ex. 2151
`Ex. 2154
`Ex. 2070
`Ex. 2089
`
`Observational
`
`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”
`
`1990
`
`1995
`
`2000
`
`2005
`
`Exogenous
`CGRP
`
`Exogenous
`CGRP
`
`Exogenous
`CGRP
`
`Ex. 2079
`
`Ex. 2058
`
`Ex. 2139
`
`Capsaicin
`
`Ex. 2150
`
`BIBN4096BS
`“did not affect”
`
`BIBN4096B
`“did not affect”
`
`BIBN4096BS
`“did not alter”
`
`BIBN4096BS
`“no effect”
`
`Ex. 1318
`
`Ex. 1285
`
`Ex. 1263
`
`Ex. 2019
`
`Lilly Exhibit
`
`Teva Exhibit
`
`Ex. 1306, ¶¶20-38; Reply, 7-9, 13-14
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`21
`
`
`
`Sumatriptan, FDA-Approved for Treating Migraine, Was
`Understood to Inhibit CGRP Release
`
`Ex. 1282, 1520; Ex. 1306, ¶64; Reply, 7
`
`Dr. Rapoport’s cross-examination:
`
`Q:
`
`So as of 2005, a person of ordinary skill in the art would have
`known that triptans inhibit the release of CGRP, correct?
`
`A:
`
`Anybody reading that article [published in 1999] would have.
`
`Ex. 1304, 90:10-15; Reply, 7;
`see also Ex. 2212, ¶21; POR, 45-46
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`
`
`Prior Art Clinical Studies Disclosed the Vascular Safety of
`CGRP Antagonism (Ex. 1025)
`
`Ex. 1025, 1108; Reply, 7-8
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`
`
`Prior Art Clinical Studies Disclosed the Vascular Safety of
`CGRP Antagonism (Ex. 1025)
`
`Ex. 1025, 1109; Ex. 1306, ¶33; Reply, 7
`
`Dr. Charles’s testimony:
`
`Q:
`
`So isn’t that the point is that the reader would say, “Well,
`I don’t know if this is safe or not based on the data
`sample that I have here in this Exhibit 1025”?
`
`A: No. I think the reader would . . . be reassured by the fact
`that – that there were no demonstrable changes in – in
`heart rate, blood pressure, and there were no vascular
`adverse effects reported
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 2272, 93:22-94:6
`
`24
`
`
`
`Researchers, Including Teva’s Experts, Praised
`“CGRP Antagonists” Before November 2005
`
`Dr. Ferrari’s statements in 2005:
`
`Ex. 1290, 657; Ex. 1306, ¶40; Reply, 8
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`
`
`Absolute Risk of Stroke in Migraine Patients Was Very Low
`
`Dr. Ferrari’s testimony:
`
`“Given the complex relationship between migraine and
`stroke, a POSA would have looked unfavorably on developing
`a new therapeutic that could worsen that troubling link.”
`
`Ex. 2212, ¶59
`
`Ex. 2157, 535; Ex. 1306, ¶59; Reply, 15
`
`Dr. Ferrari’s cross-examination:
`
`Q: Okay. 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.
`
`Ex. 1303, 193:3-10; Reply, 15; Ex. 2157, 536; Ex. 1306, ¶59
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`26
`
`
`
`Tan 1995 Did Not Raise Safety Concerns
`
`Ex. 1022, 568; Ex. 1305, ¶58; Ex. 1306, ¶42; Reply, 10-11
`
`Ex. 1022, 568; Ex. 1305, ¶58; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`27
`
`Ex. 1022, 569; Ex. 1305, ¶59; Reply, 11
`
`
`
`Tan 1995 Did Not Raise Safety Concerns
`
`Dr. Ferrari’s cross-examination:
`
`Q: And sumatriptan was observed to cause transient
`increases in blood pressure in some patients; is that
`correct?
`
`A:
`
`I don’t think that increase in blood pressure has ever
`been a major concern for sumatriptan.
`
`Dr. Charles’s testimony:
`
`Ex. 1303, 25:11-17; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1306, ¶44; Reply, 11
`
`28
`
`
`
`Anti-CGRP Antagonist Antibodies Were Reported to Be Safe
`
`Ex. 1033, 101; Ex. 1305, ¶62; Ex. 1306, ¶43; Reply, 12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`29
`
`
`
`Anti-CGRP Antagonist Antibodies Were Reported to Be Safe
`
`Ex. 1055, 93; Ex. 1305, ¶65; Ex. 1306, ¶49; Reply, 12
`
`Dr. Balthasar’s testimony:
`
`Q:
`
`A:
`
`So when Andrews says that there were no signs of
`physical or behavioral abnormality, what he is referring
`to is the animal did not die or pass out, right?
`
`Yeah, I could only speculate on what they would be
`looking at and measuring to be able to make that
`statement, but I think that most institutional animal use
`committees would require assessment of a wide range
`of parameters to evaluate safety of treatments.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 2273, 138:15-139:3
`
`30
`
`
`
`Tan Did Not Raise Safety Concerns
`
`Ex. 1287, 247; Reply, 3, 11-12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`
`
`Purported Safety Concerns Did Not Deter Researchers
`
`Ex. 1309, Abstract; Ex. 1305, ¶51; Reply, 9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`
`
`Purported Safety Concerns Did Not Deter Researchers
`
`Ex. 1240, 923; Ex. 1305, ¶54; Ex. 1306, ¶¶17, 31; Reply, 9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`
`
`Teva’s Purported Safety Concerns Were Resolved by
`November 2005 (Exs. 1025, 1042, 2019)
`
`Dr. Charles’s testimony:
`
`Q:
`
`A:
`
`Q:
`
`A:
`
`… You would agree that the clinical safety of
`targeting CGRP for therapeutic use had not
`been established as of 2005, correct?
`
`I do not agree with that, no.
`
`And what part do you disagree with?
`
`There were multiple studies in humans that
`indicate that, in fact, it was safe to
`therapeutically target CGRP, and animals also.
`
`Ex. 2272, 40:11-20
`
`1990
`
`1995
`
`2000
`
`2005
`
`2004
`
`2004
`
`2005
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1306, ¶¶33-36, 38; Reply, 7-8
`34
`
`
`
`The Prior Art Contradicts Teva’s Hypothetical
`Application of the “Spare Receptor Theory”
`
`Teva’s arguments:
`
`“As Dr. Foord explains, in the CGRP receptor system, less
`than 1% of receptors needed to be bound by ligand to elicit
`a full response in the cell. EX2230, ¶¶38-42, 94; EX2062,
`74; EX2063, 15; EX2064, 537.”
`
`POR, 31
`
`Ex. 2065, 1071; Ex. 1305, ¶¶41-42; Ex. 1300, 69:4-8; Reply, 17
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`
`
`Prior Art Clinical Evidence Undermines Teva’s Hypothetical
`Application of the “Spare Receptor Theory”
`
`Ex. 1044, Abstract; Ex. 1306, ¶67; Reply, 17
`
`Dr. Charles’s testimony:
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1306, ¶67; Reply, 17
`
`36
`
`
`
`Ligand Cross-Binding Did Not Undermine Motivation
`
`Ex. 2059, 63 (annotation added); Ex. 1306, ¶72; Reply, 18
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`
`
`Tan 1995 (Ex. 1022): IgG “Clearly Diffuses” to the Site of Action
`
`Ex. 1022, 571; Ex. 1305, ¶20; Reply, 20
`Dr. Balthasar’s testimony:
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1305, ¶21; Reply, 20
`
`38
`
`
`
`Tan 1995 Provided Guidance to Improve Immunoblockade
`
`Ex. 1022, 571; Ex. 1008, ¶122; Ex. 1305, ¶¶24-29; Pet., 39-42; Reply, 20
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`
`
`Teva’s Secondary Considerations Are Not Commensurate with
`the Scope of the Challenged Claims
`
`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.”
`
`Reply, 21
`
`Antibody Format
`(e.g., fragments)
`
`Fab, Fab', F(ab’)2 , Fv,
`single chain (ScFv),
`fusion proteins
`
`Ex. 1301, 27:25-28:6; Ex. 1001,
`12:40-46; Pet., 22; Reply, 23
`
`Sequence Mutations
`
`20220
`
`Ex. 1301, 92:8-10; Reply, 22
`
`Antibody Class
`
`Binding Affinity
`
`IgA, IgD, IgE, IgG, IgM Ex. 1301, 37:16-39:11; Reply, 23
`
`2 pM-250 nM
`
`Ex. 1001, 5:54-65; Reply, 22
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`40
`
`
`
`Teva’s Secondary Considerations Lack Nexus to the Claims
`
`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, 24
`
`Dr. Rapoport’s cross-examination:
`
`Q:
`
`So let’s just – I think you said you didn’t consider whether it preferentially binds to
`CGRP as opposed to amylin, correct?
`
`A:
`
`Right.
`
`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, 141:16-20, 142:1-8; Reply, 24
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`41
`
`
`
`Teva’s Secondary Considerations Lack Nexus to the Claims
`
`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.”
`Teva’s claims:
`
`Reply, 24
`
`Teva’s claims:
`
`Wimalawansa (Ex. 1096):
`
`Ex. 1096, 567, 570; Reply, 24
`
`Ex. 1001 (’614), claim 1;
`Ex. 1001 (’951), claim 1;
`Ex. 1001 (’881), claim 1;
`Ex. 1001 (’649), claim 1
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`
`
`Teva’s Secondary Considerations Lack Nexus to the Claims
`
`Teva’s claims:
`
`Wimalawansa (Ex. 1096):
`
`Ex. 1096, 567, 570; Reply, 24
`
`Ex. 1001 (’210), claim 1;
`Ex. 1001 (’211), claim 1
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`43
`
`
`
`Teva’s Evidence of Industry Acclaim Is Deficient
`
`Teva’s arguments:
`
`“Lilly’s expert, Dr. Charles, has himself praised the
`claimed humanized anti-CGRP antibodies–repeatedly.
`Dr. Charles has touted the claimed antibodies as:
`
`•
`
`‘very exciting and compelling, … . EX2182, 207”
`
`POR, 49
`
`Ex. 2182, 207; Reply, 25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`44
`
`
`
`Teva’s Purported Evidence of Licensing
`Does Not Support Patentability
`
`Dr. Stoner’s cross-examination:
`
`Q:
`
`A:
`
`Do you consider the settlement and license agreement to be a patent portfolio license, you,
`Dr. Stoner?
`
`I was aware that the license related to all of these patents which are necessary to practice
`the Alder product.
`
`Q: When you say “all of these patents,” you mean that at least 188 patents and applications
`listed in schedule 1.14 in 65 countries and eight families? When you say “all these patents,”
`is that what you meant?
`
`A:
`
`Yes, all these related patents.
`
`Q: … if just claims 1 through 7 and 15 through 20, which are the challenged claims of the 614
`patent, if just those claims were canceled, Alder Bio would still owe the same consideration
`under this agreement because Alder Bio admits that it infringes the remaining claims or the
`614 patent and all claims of the 187 additional licensed patents, correct?
`
`A:
`
`Q:
`
`That’s certainly a reasonable interpretation of this paragraph.
`
`And to that same effect, if 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?
`
`A:
`
`That appears to be a reasonable interpretation of this paragraph …
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`45
`
`Ex. 1302, 45:20-46:12, 179:14-180:19; Reply, 27
`
`
`
`Multiple Prior Art Studies Reported Anti-CGRP Antibodies
`with Nanomolar Affinities
`
`Ex. 1021, 707; Ex. 1012, ¶69; Pet. (IPR2018-01426), 18, 31; Reply, 18
`
`Dr. Vasserot’s testimony:
`
`Ex. 1013, ¶122; Pet. (IPR2018-01426), 37
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`46
`
`
`
`A POSA Would Have Been Motivated to Make Anti-CGRP
`Antibodies with the Claimed Affinities
`
`Dr. Tomlinson’s statements in 2004:
`
`Ex. 1266, 521; Ex. 1327, ¶78; Reply (IPR2018-01426), 18
`
`Dr. Tomlinson’s cross-examination:
`
`Q:
`
`For therapeutic antibodies that act by binding a target
`antigen, is strong binding affinity to that antigen a
`desirable characteristic?
`
`A:
`
`Yes.
`
`Ex. 1301, 211:16-21; Reply (IPR2018-01426), 18
`
`Q: And as of 2005, a person of ordinary skill could use
`affinity maturation techniques to improve binding
`affinity stronger than one nanomolar, correct?
`
`A:
`
`Yes.
`
`Ex. 1301, 213:21-25; Reply (IPR2018-01426), 18
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`47
`
`
`
`A POSA Would Have Been Motivated to Make Anti-CGRP
`Antibodies with the Claimed Affinities
`
`Teva’s arguments:
`“[A] POSA would not have concluded that Tan 1994’s anti-CGRP antibodies had KDs of 10 nM or
`less, which defeats Lilly’s second alleged ‘reason’ to make the claimed antibodies. … But, as Dr.
`Tomlinson explains, Tan 1994 was not designed in a manner draw conclusions regarding affinity.
`EX2226, ¶¶104-109.”
`
`POR (IPR2018-01426), 42-43
`
`Dr. Balthasar’s testimony:
`
`Ex. 1327, ¶71; Reply (IPR2018-01426), 18
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`48
`
`
`
`Detailed Analysis
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`49
`
`
`
`Teaching Away Requires Criticizing, Discrediting, or
`Otherwise Discouraging Investigation
`
`Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013)
`
`“[N]or do these articles indicate in any way that the side effects would be serious enough to
`dissuade the development of a 0.3% adapalene product….A teaching that a composition may be
`optimal or standard does not criticize, discredit, or otherwise discourage investigation into other
`compositions. ”
`
`Reply, 16
`
`Sanofi-Aventis U.S. LLC v. Immunex Corp., IPR2017-01884, Paper 96 at
`20, 21 (PTAB Feb. 14, 2019)
`
`“We are not persuaded that the potential risk of side effects would have deterred a person of
`ordinary skill in the art from developing a way to block both IL-4 and IL-13 signaling. [] First, we
`note the literature cited by Patent Owner’s expert Dr. Finkelman characterizes the side effects as
`theoretical.”
`
`“The problem with Patent Owner’s argument is that the law does not require the prior art to
`explicitly suggest humanizing MAb230. … Petitioner need not show that MAb230 was the only
`option or even the best option for a person of ordinary skill in the art. On the contrary, Petitioner
`may show that MAb230 was a ‘suitable option from which the prior art did not teach away.”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 9-10
`
`50
`
`
`
`Lilly Need Not Identify a Specific Antibody to Humanize
`
`Teva’s argument:
`
`“Lilly never articulated which prior art antibody a POSA would have humanized in order to
`arrive at the claimed antibodies.”
`
`Sur-reply, 24
`
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171, 184 (D. Mass. 2013)
`A POSA would have “the motivation or attempt to combine the teachings of the prior art
`references to make a human, high-affinity, neutralizing antibody to IL-12” when the prior art
`disclosed neutralizing mouse and humanized antibodies to IL-12 and “methodology to achieve
`the functional result.”
`
`Pet., 31
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`51
`
`
`
`The Prospect of Creating a “Potential Therapeutic”
`Is Sufficient Motivation
`
`Sanofi-Aventis U.S. LLC v. Immunex Corp., IPR2017-01884, Paper 96,
`19-20 (PTAB Feb. 14, 2019)
`“We are also persuaded that Petitioner has shown that a person of ordinary skill in the art would
`have had a reason to humanize Hart’s MAb230 using Schering-Plough’s humanization technique
`to create a potential therapeutic for allergic diseases with a reasonable expectation of success.”
`
`Reply, 5
`
`Abbott GmbH & Co., KG v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171, 185 (D. Mass. 2013)
`
`“Based on the jury's implicit factual findings, the Court concludes that there was clear and
`convincing evidence of a need to create a human, neutralizing, high-affinity antibody to IL–12. A
`person of ordinary skill in the art at the time knew that the overproduction of IL–12 was causing
`diseases, and that an antibody that neutralized IL–12 could be therapeutic.”
`
`Reply, 5
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`52
`
`
`
`Sanofi-Aventis v. Immunex Is Highly Analogous
`
`Sanofi v. Immunex
`
`The instant case
`
`Prior art antibody blocked IL-4 and IL-
`13 activity. (Immunex, IPR2017-
`01884, Paper 96, 18; Sur- Reply, 5)
`
`Tan: MAb C4.19 IgG blocked “the hypotensive effects of
`exogenous rαCGRP in vivo.” (Ex. 1022, 570; Pet., 17.)
`Wong: antibody 4901 “is extremely effective in vivo as an
`immunoneutralizing agent.” (Ex. 1033, 104; Pet. 34.)
`
`The prior art disclosed that anti-IL-4R
`antibodies “could advantageously be
`humanized and thus used for long
`term treatment of allergic disorders.”
`(Immunex, Paper 96, 19.)
`
`Wimalawansa: disclosed humanized anti-CGRP antagonist
`antibodies for use in treating several diseases including
`migraine, inflammation, and cardiogenic shock.
`(Ex. 1096, 567, 570 (“humanized monoclonal antibodies
`should be explored … .”); Pet. 19, 26.)
`
`Potential risk of side effects not a
`deterring factor in the prior art.
`(Immunex, Paper 96, 20.)
`
`Wong: Antibody 4901 “had no significant effect on MAP and
`heart rate.” (Ex. 1033, 101; Reply, 12.)
`Teva’s experts contemporaneously praised CGRP antagonists
`as “promising, new antimigraine drugs without vascular side
`effects.” (Ex. 1290, 657; Ex. 1297, S119; Reply, 8)
`Doods: “we expect that CGRP antagonists will be effective
`anti-migraine drugs” (Ex. 1024, 422; Pet. 26.)
`
`Claims do not require therapeutic
`efficacy. (Immunex, Paper 96, 23-24.)
`
`Claims do not require therapeutic efficacy. (Ex. 1001; Pet.,
`38 n.2; Reply, 4-5.)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`53
`
`
`
`Phigenix Is Inapposite
`
`Teva’s argument:
`
`“Under a similar challenge to composition of matter claims, as here, the Board held the
`petitioner to its ‘therapeutic utility’ motivation arguments. Phigenix v. ImmunoGen,
`IPR2014-00676, Paper 39, 16 (P.T.A.B. Oct. 27, 2017)”
`
`Sur-reply, 3-4
`
`Phigenix
`
`The instant case
`
`Claims recite a specific antibody conjugated
`to a specific toxin (Herceptin-maytansinoid)
`
`Claims recite broad genera of humanized
`anti-CGRP antagonist antibodies
`
`Key prior art human clinical study showed
`toxicity with a relevant immunoconjugate
`
`Human clinical trial with relevant CGRP
`pathway inhibitor (BIBN) showed no toxicity
`
`Toxicity of Herceptin was identified in later
`prior-art human studies
`
`Later prior-art human studies resolved
`purported safety concerns
`
`Tight nexus between objective indicia
`evidence and narrow claims that required a
`“specific antibody, linker, and toxin”
`
`Objective indicia evidence lack nexus to
`extremely broad claims
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`54
`
`
`
`Teva’s REOS Arguments Are Irrelevant
`
`Senju Pharm. Co. v. Lupin Ltd., 780 F.3d 1337, 1346-47 (Fed. Cir. 2015)
`
`“In composition claims 12–16 of the '045 patent, there is no limitation denoting the function of the
`composition and we decline to import this limitation into the claims.”
`
`Pet., 38 (n. 2); Reply, 19
`
`Sanofi-Aventis U.S. LLC v. Immunex Corp., IPR2017-01884, Paper 96 at 23
`(PTAB Feb. 14, 2019)
`
`“We agree with Petitioner that the pertinent question is not whether there is a reasonable
`expectation that the antibodies will actually be therapeutically effective. Rather, the question is
`whether a person of ordinary skill in the art would have reasonably expected to arrive at the
`claimed invention.”
`
`Reply, 19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`55
`
`
`
`Teva’s Evidence of Industry Acclaim Is Deficient
`
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369,
`1376 (Fed. Cir. 2013)
`
`“[I]ndustry praise of what was clearly rendered obvious by published
`references is not a persuasive secondary consideration.”
`
`Reply, 24-25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`56
`
`
`
`Anti-CGRP Antagonist Antibodies Had Already Been Generated
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1362 (Fed.
`Cir. 2007)
`“Admissions in the specification regarding the prior art are binding on
`patentee for the purpose of a later inquiry into obviousness.”
`
`Pet., 6, 33
`
`Teva’s specification:
`
`Ex. 1001, 26:13-17; Pet., 6
`
`Ex. 1001, 27:61-67; Pet., 6-7
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`57
`
`
`
`Tan’s Anti-CGRP Antagonist MAb C4.19
`
`Ex. 1021, 706; Ex. 1012, ¶69; Pet. (IPR2018-01426), 18
`
`Ex. 1021, 709; Ex. 1012, ¶69; Pet. (IPR2018-01426), 18
`
`Ex. 1021, 707; Ex. 1012, ¶69; Pet. (IPR2018-01426), 18, 31; Reply, 18
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`58
`
`
`
`Tan 1995 Discloses the Benefits of
`Anti-CGRP Antagonist Antibodies
`
`Ex. 1022, 572; Ex. 1008, ¶60; Pet., 18; Reply, 3
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`59
`
`
`
`Queen (Ex. 1023): Humanization Techniques Were Routine
`
`Ex. 1023, 1:44-47; Ex. 1008, ¶¶128-129; Pet., 29
`
`Ex. 1023, 2:30-33; Pet., 35
`
`Ex. 1023, 10:57-60; 1013, ¶54; Pet. (IPR2018-01426), 21-22, 37
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`60
`
`
`
`The Prospect of Creating a “Potential Therapeutic” Is
`Sufficient Motivation
`
`Dr. Vasserot’s testimony:
`
`“A POSA would have been particularly motivated to make a humanized antibody when its murine
`counterpart antibody had been shown to exhibit functional properties that could be useful in treating a
`disease. [ ] Routine humanization techniques known in the art would have provided a reasonable
`expectation for a POSA to obtain a humanized antibody with similar desirable properties. All of these
`were present for CGRP.”
`
`Ex. 1009, ¶¶70-71; Pet., 29; Reply, 5
`
`Q:
`
`So AME is the type of company that would take Tan 1994, humanize Tan’s antibody, and take it to
`clinic?
`
`A: We have done worse than that.
`
`Q:
`
`You have done worse than that. What have you done that’s worse than that?
`
`A: We have started projects with less data than that.
`
`Ex. 2191, 99:8-100:1; Reply, 5
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`61
`
`
`
`Prior Art Clinical Studies Disclosed the Vascular Safety of
`CGRP Antagonism (Ex. 2019)
`
`Ex. 2019, Abstract; Ex. 1306, ¶36; Reply, 8
`
`Dr. Ferrari’s cross-examination:
`
`Q:
`
`So in healthy volunteers, blocking the CGRP pathway
`had no clinically meaningful effect on blood pressure,
`correct?
`
`A: …in healthy volunteers under physiological
`circumstances, there is admittedly no effect on the
`parameters you just mentioned.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1303, 91:19-92:20; Reply, 8
`
`62
`
`
`
`Prior Art Clinical Studies Disclosed the Vascular Safety of
`CGRP Antagonism (Ex. 1042)
`
`Ex. 1042, Abstract; Ex. 1306, ¶35; Reply, 8
`
`Dr. Charles’s testimony:
`
`Q:
`
`A:
`
`Any – a study showing that there were no adverse events in
`healthy volunteers would be reassuring for you with respect to
`patients who have a history of ischemia?
`
`Yes . . . information about the vascular consequences of a
`Ex. 1042, Abstract; Reply, 8
`compound in healthy volunteers is reassuring about the use of
`these compounds in the setting of ischemia.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 2272, 96:22-97:7
`
`63
`
`
`
`Tan 1995 Did Not Raise Safety Concerns
`
`Teva’s arguments:
`
`“Moreover, at 3 mg/rat, MAb C4.19 raised [mean arterial
`pressure] nearly 13-fold, while having minimal, if any, effect
`in the saphenous nerve assay. EX1022, 568, Figure 2, 569;
`EX2230, ¶¶52, 78.”
`
`POR, 24
`
`Dr. Foord’s cross-examination:
`
`Q:
`
`Is it fair to state that at the one-minute mark, the
`monoclonal antibodies C14, c4.19 at 3 milligrams per
`kilogram, raised mean arterial pressure around 1.1-fold
`versus baseline, as reported in Tan 1995?
`
`A:
`
`Yes.
`
`Ex. 1300, 129:21-130:4; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`64
`
`
`
`Tan 1995 Did Not Raise Safety Concerns
`
`Dr. Balthasar’s testimony:
`
`Ex. 1305, ¶57; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`65
`
`
`
`Tjen-A-Looi (Ex. 2084) Is Not Relevant
`
`Dr. Balthasar’s testimony:
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1305, ¶67; Reply, 11
`
`66
`
`
`
`Tjen-A-Looi (Ex. 2084) Observed a Stronger Pulmonary Arterial
`Pressure Increase with CGRP8-37
`
`Ex. 2084, H687; Ex. 1305, ¶68; Ex. 1306, ¶45; Reply, 11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`67
`
`
`
`CGRP Deletion Did Not Produce Safety Concerns
`
`Ex. 1027, ¶[0069]; Ex. 1306, ¶47; Reply, 12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1027, claims 8 & 9; Reply, 12
`
`68
`
`
`
`CGRP Deletion Did Not Produce Safety Concerns
`
`Ex. 1288, Abstract; Ex. 1306, ¶48; Reply, 12
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`69
`
`
`
`Purported Safety Concerns Did Not Deter Researchers
`
`Ex. 1082, Abstract, 2 (citing Wimalawansa as ref. 19);
`Ex. 1306, ¶17; Reply, 9
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`70
`
`
`
`Teva’s Purported Safety Concerns Were Resolved by
`November 2005 (Ex. 2151)
`
`Dr. Ferrari’s cross-examination:
`
`Q:
`
`Exhibit 2151 does not study the effects of CGRP
`antagonism in healthy humans, correct?
`
`A:
`
`Correct.
`
`Q: And it doesn’t study the effects of CGRP antagonism in
`migraine patients?
`
`A:
`
`Correct.
`
`Q: And, in fact, it doesn’t study the effects of CGRP
`antagonism at all, correct?
`
`A: Correct.
`
`Ex. 1303, 111:11-20; Ex. 2151; Reply, 13
`
`1990
`
`1990
`
`1995
`
`2000
`
`2005
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Ex. 1306, ¶¶22, 38; Reply, 8, 13
`71
`
`
`
`Teva’s Purported Safety Concerns Were Resolved by
`November 2005 (Ex. 2058)
`
`Dr. Ferrari’s cross-examination:
`
`Exhibit 2058 explores the administration of exogenous CGRP to patients
`with angina, correct?
`
`Correct.
`
`Exhibit 2058 did not study the effects of CGRP in healthy humans,
`correct?
`
`Correct.
`
`Exhibit 2058 did not study the effects of CGRP in migraine patients,
`correct?
`
`Correct.
`
`Exhibit 2058 did not study the effects of a CGRP antagonist, correct?
`
`Correct.
`
`And this study does not evaluate whether inhibiting endogenous CGRP
`would result in a worsening of cardiac ischemic events, correct?
`
`Q:
`
`A:
`
`Q:
`
`A:
`
`Q:
`
`A:
`
`Q:
`
`A:
`
`Q:
`
`
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