`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ELI LILLY AND COMPANY,
`Petitioner,
`
`v.
`
`TEVA PHARMACEUTICALS INTERNATIONAL GMBH,
`Patent Owner.
`_____________________
`
`CASE IPR2018-01426
`Patent 9,890,211
`_____________________
`
`
`PATENT OWNER’S SURREPLY
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`Case IPR2018-01426
`Patent No. 9,890,211
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`
`B.
`
`2.
`
`3.
`
`I.
`II.
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`Lilly premised its case on the “therapeutic utility” of anti-CGRP
`antibodies; it should be held to this rationale. ................................................. 3
`III. Lilly’s new “potential therapeutic” rationale fails the obviousness
`inquiry. ............................................................................................................. 5
`A.
`The record does not demonstrate that a full-length anti-
`CGRP antibody would have been reasonably expected to be
`effective in vivo. .................................................................................... 6
`Lilly failed to demonstrate that humanized anti-CGRP
`antibodies would have been safe in humans. ...................................... 10
`1.
`Lilly improperly ignores myriad teachings showing
`CGRP’s vasoprotective role. .................................................... 11
`Risk concerns of antagonizing CGRP with long-acting
`antibodies were not “theoretical.” ............................................ 11
`Any alleged safety of blocking the CGRP pathway
`with small molecules,
`receptor antagonists, or
`aptamers is irrelevant to the safety of anti-CGRP
`antibodies. ................................................................................ 13
`Lilly improperly dismisses safety concerns with
`antagonizing CGRP in migraineurs. ........................................ 19
`IV. Lilly’s motivation arguments fail
`to consider pharmacological
`differences between receptor and ligand antagonism. ................................... 21
`Lilly failed to prove that a POSA would have arrived at the claimed
`affinity (KD). .................................................................................................. 24
`VI. Lilly never articulated which prior art antibody a POSA would have
`humanized in order to arrive at the claimed antibodies. ................................ 24
`VII. Lilly misreads Teva’s secondary indicia arguments and has not
`rebutted the presumption of nexus................................................................. 25
`VIII. Conclusion ..................................................................................................... 28
`
`4.
`
`V.
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`I.
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`Introduction
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`Teva’s Patent Owner Response (“POR”) exposed multiple infirmities that
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`defeat Lilly’s obviousness case. Teva demonstrated that Lilly’s principal
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`references—Tan 1995 and Wimalawansa—would not have motivated a POSA to
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`develop an anti-CGRP antibody for human therapeutic use. Tan 1995, a basic
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`research paper attempting to “prob[e] the role of CGRP as an endogenous
`
`vasodilator” in rats, reported that its full-length anti-CGRP antibody failed to show
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`immunoblockade in a rat saphenous nerve assay. Wimalawansa—far from
`
`suggesting humanizing anti-CGRP antibodies, as Lilly argues—expressly conveys
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`to a POSA that “[c]learly, more data from carefully designed studies are necessary
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`before … humanized anti-CGRP monoclonal antibodies … can be evaluated as
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`therapeutic agents.” And Lilly has not shown that such data existed prior to 2005.
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`Unable to overcome these and other fatal defects, Lilly accuses Teva of
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`“impermissibly reading safety and efficacy requirements into the claims.” But it
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`was Lilly who premised its Petition on human therapeutic use. Teva rebutted
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`Lilly’s arguments by, inter alia, showing that Lilly failed to consider safety, and
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`fell short of demonstrating efficacy.
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`Rather than considering the prior art as a whole, as it must, Lilly, through
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`hindsight, selectively cherry-picks references Lilly believes support its arguments,
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`while ignoring references that undermine them. Even worse, on cross-examination
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`Dr. Charles and his replacement, Dr. Balthasar1, distanced themselves from
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`unfavorable portions of Lilly’s own references upon which they themselves relied.
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`Specifically, these experts refused to consider teachings that call into question the
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`safety of long-term (as with an antibody) inhibition of CGRP, the body’s most
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`potent vasodilator. Given that Lilly constructed its obviousness case on a
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`
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`therapeutic utility, the lack of safety and efficacy in its evidence cannot be ignored.
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`On Reply, Lilly now pivots from its initial “human therapeutic use”
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`arguments, focusing instead on the mere “potential” for therapeutic use. But Lilly
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`cannot re-craft its challenge on Reply to attempt to rehabilitate its Petition. Henny
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`Penny Corp. v. Frymaster LLC, No. 18-1596 (Fed. Cir. 2019).
`
`To support its new rationale, Lilly again cherry-picks isolated, out-of-
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`context phrases to repaint the field as of 2005. For example, to support the alleged
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`in vivo effectiveness of Tan’s C4.19 antibody, Lilly cites to Teva’s Dr. Ferrari. But
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`Dr. Ferrari’s testimony referred to Tan’s Fab’ fragment, not full-length C4.19. And
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`Lilly’s new arguments that carcass studies support speculation that Tan’s antibody
`
`would eventually reach its site of action given more time also fail because
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`1 Teva discredited a number of Dr. Charles’ opinions, and showed him to be
`
`unqualified to offer them. POR, 3-4. On Reply, Lilly submitted the declaration of a
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`new expert Dr. Balthasar in an effort to repair Dr. Charles’ failed opinions.
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`“assignment of a site … of antibody localization was not possible.” 2
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`Similarly, Lilly’s speculation about “increased dose” goes squarely against
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`safety concerns regarding long-term CGRP ligand antagonism, which would
`
`remove CGRP’s protective role during ischemic events, where the risk of stroke
`
`and heart attacks are elevated. This is important because migraineurs were known
`
`to have increased risk of these life-threatening conditions.
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`Lilly also fails to rebut Teva’s strong showing of numerous indicia of non-
`
`obviousness, which support confirming the challenged claims. In short, Teva’s
`
`Response demonstrates that Lilly’s Petition fails to show that the claimed
`
`humanized antibodies would have been obvious. Lilly’s Reply does not salvage its
`
`Petition.
`
`II. Lilly premised its case on the “therapeutic utility” of anti-CGRP
`antibodies; it should be held to this rationale.
`
`Lilly provided only one reason for developing a humanized anti-CGRP
`
`antibody: human therapeutic use. Petition, 12-13, 25-28, 32-33. Lilly specifically
`
`argued the reason for humanizing a murine antibody was to retain “the antibody’s
`
`therapeutic utility” “in humans.” Id., 32-33. By doing so, Lilly (not Teva) read
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`“safety and efficacy requirements into the claims.” Under a similar challenge to
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`composition of matter claims, as here, the Board held the petitioner to its
`
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`2 Emphasis added throughout unless otherwise noted.
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`“therapeutic utility” motivation arguments. Phigenix v. ImmunoGen, IPR2014-
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`00676, Paper 39, 16 (P.T.A.B. Oct. 27, 2017) (“when asserting that an ordinary
`
`artisan would have had a reason to … prepare [the claimed] immunoconjugate,
`
`Petitioner relies on the position that an ordinary artisan would have expected such
`
`an immunoconjugate to work clinically to treat tumors in humans upon reading
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`the cited references”); see also id., 21 (“Petitioner does not persuade us … that a
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`skilled artisan would have had a reasonable expectation of success … that [the
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`claimed] immunoconjugate would be useful in the treatment of breast tumors in
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`humans.”).
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`As in Phigenix, having relied on therapeutic utility for motivation, Lilly was
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`required to consider and demonstrate that the art evidenced efficacy and safety of
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`the claimed antibodies for therapeutic use. Lilly recognized as much by arguing
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`safety with respect to “immunogenicity” in humans in its reason to humanize.
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`Petition, 29. But Lilly’s Petition stops there, saying nothing to address the myriad
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`teachings in the art about cardiovascular and cerebrovascular safety concerns
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`associated with long-term depletion of CGRP. Lilly also failed to prove reasonable
`
`expectation of efficacy.
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`Recognizing gaps in its case that Teva highlighted, Lilly now seeks to retreat
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`from its original therapeutic-based rationale. Lilly argues for the first time on
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`Reply that a POSA would have been motivated to make “any … antibody having
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`known functional properties.” Reply, 4 (emphasis in original). But Lilly’s rationale
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`in the Petition controls; the Board should review the record through the lens of
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`“therapeutic utility” of the claimed antibodies. Henny Penny, No. 18-1596, 9
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`(“[P]etitioner may not raise in reply ‘an entirely new rationale’ for why a claim
`
`would have been obvious.”). To the extent that Lilly is now trying to fill holes in
`
`its Petition with new art and testimony from a new expert, such belated arguments
`
`should be rejected. Id.
`
`III. Lilly’s new “potential therapeutic” rationale fails the obviousness
`inquiry.
`
`As with its original “therapeutic utility” rationale, Lilly’s new argument—
`
`motivation to humanize based on “the prospect of creating a ‘potential
`
`therapeutic’”—equally falls short of establishing obviousness. Reply, 5; citing
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`Sanofi-Aventis U.S. LLC. v. Immunex Corp., IPR2017-01884, Paper 96, 17
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`(P.T.A.B. Feb. 14, 2019). Sanofi-Aventis is inapposite because its mouse antibody
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`MAb230 had properties the literature identified as being desirable characteristics in
`
`a therapeutic: a high affinity and the ability “to block both IL-4 and IL-13
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`activity.” Id., 18. The field also identified targeting receptors—as the claimed
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`antibody in that case did—as “more promising” than targeting their ligands
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`(cytokines), and “several companies” were seeking to do just that. Id., 20. This
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`utility led the Board to conclude that MAb230 was “a promising candidate from
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`which to derive an effective therapeutic.”3 Id., 18. The record here reveals no such
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`known utility in the art for Teva’s antibodies, and Lilly has not provided sufficient
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`evidence to show a mouse anti-CGRP antibody to be a more “promising
`
`candidate” than the receptor antagonists the art was focused on.
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`A. The record does not demonstrate that a full-length anti-CGRP
`antibody would have been reasonably expected to be effective in
`vivo.
`
`Nothing in the record demonstrates that full-length anti-CGRP antibodies
`
`would be expected to successfully achieve immunoblockade in vivo to suggest a
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`“promising candidate” or an “effective therapeutic,” as in Sanofi-Aventis. As Dr.
`
`Foord explained, Tan’s C4.19 antibody failed to engage at the site of action in the
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`in vivo saphenous nerve assay. EX2232, ¶102; EX1022, 571, 565, Abstract; POR,
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`39-40. Lilly’s own Dr. Vasserot agreed with Teva’s experts on this shortcoming
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`and the unreliability of Tan’s results. EX2191, 118:12-119:1; POR, 3. Dr.
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`Charles—a clear outlier among the experts—testified that C4.19 “showed a 16%
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`3 Also, in Sanofi-Aventis, Patent Owner stated, in response to an enablement
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`decision: “There is no reasonable basis for concluding that antibodies that bind to
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`‘the perfect target’ and inhibit ‘an important regulator’ would be therapeutically
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`ineffective.” Sanofi-Aventis U.S. LLC. v. Immunex Corp. at 24. Here, no such
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`admission has been made.
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`reduction in skin blood flow” in a saphenous nerve assay. EX1012, ¶124; POR, 3.
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`But given Dr. Charles’ gross mischaracterization of prior art in these proceedings
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`(EX2192, 182:21-183:12; 154:18-20), his opinion must be given little weight.
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`POR, 3-4.
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`
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`In an attempt to find any support for in vivo effectiveness of Tan’s C4.19—
`
`and thus a reason to humanize it with a reasonable expectation of success—Lilly
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`resorts to mischaracterizing Teva’s experts’ testimonies. For example, Lilly cites to
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`Dr. Ferrari for his alleged admission of C4.19’s in vivo activity. Reply, 3. But Dr.
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`Ferrari was referring to Tan’s Fab’ fragment, not the full-length antibody. EX1303,
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`160:2-9, 162:12-22. And is it undisputed that the ’211 claims do not encompass
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`Fab’ fragments.
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`Lilly then points to Dr. Tomlinson’s acknowledgment that he “humanized
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`antibodies all the time” as evidence of motivation in 2005. Reply, 5. But Dr.
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`Tomlinson was discussing his humanization activities from 2007 to 2016, not prior
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`to 2005. EX1301, 55:1-13. Similarly disingenuous is Lilly’s allegation that “Teva’s
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`experts conceded that a POSA would have found it appropriate to use humanized
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`antibodies throughout drug development, including binding assays, in vitro testing,
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`and animal studies.” Reply, 5-6. The transcripts illuminate the truth:
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`
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`Dr. Tomlinson stated that a POSA would have humanized an antibody
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`to be tested only when “[g]iven sufficient motivation to do so ….
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`which at the time wasn’t the case,” for CGRP. EX1301, 204:4-15;
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`Dr. Ferrari admitted that he is “not an expert in [the drug
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`development] field.” EX1303, 54:25-55:6;
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`Dr. Rapoport’s testimony related to clinical trials in humans; not in
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`vitro or animal testing. EX1304, 145:15-146:3.
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`
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`Ultimately, Lilly failed to prove that a POSA would have viewed Tan’s
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`C4.19 as engaging at the site of action in vivo. Instead, Lilly’s Petition speculated,
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`without support, that “slow distribution to the site of immunoblockade could be
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`overcome by (1) increasing the dose, (2) chronic administration, and/or (3) active
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`immunization.” Petition, 44. Now that Teva has highlighted this speculation, Lilly
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`belatedly relies on Dr. Balthasar’s assertion that “carcass” experiments show that
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`“full-length antibodies were expected to distribute from general circulation into the
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`interstitial space4, so long as they are given sufficient time.” Reply, 20; EX1327,
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`¶¶24-29. But the art shows that in a carcass (a crude mix of leftover body parts),
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`“assignment of a site, or sites, of antibody localization was not possible.” EX2270,
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`3045; EX2273, 92:14-16. Thus, Lilly fails to show that a full-length antibody
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`would distribute into interstitial spaces with additional time.
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`4 The interstitial space is a space “between cells, within tissue.” EX2273,
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`84:2-3.
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`Lilly also provides no credible evidence that, even if the antibody reaches
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`the interstitial spaces, it would be able to access the synaptic cleft, especially in
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`sufficient concentration for immunoblockade. It is undisputed that the “carcass”
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`experiment presents no data relating to an antibody’s penetration of the synaptic
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`cleft or of an antibody’s binding to CGRP in the synaptic cleft. EX2273, 93:19-
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`95:6; 95:10-12; EX1022, 566. Other references Lilly advances to fill this gap are
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`equally uninformative.
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`For example, Lilly cites to Tan 1995’s statement that a full-length antibody
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`“clearly diffuses” to the site of action as evidence of its in vivo effectiveness.
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`Reply, 19-20. But Tan 1995 based this conclusion on another study: Tan 1994.
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`EX1022, 571. Tan 1994’s isolated vas deferens “tissue bath” is not an “equivalent”
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`to an in vivo study, and thus is not a representation of an antibody’s ability to
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`penetrate multiple biological compartments in a complex system, such as a human
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`body. EX2273, 77:20-78:3; EX1021, 705. Similarly, in the Louis/Dockray
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`experiments, the antibodies “leaked” into the interstitial space due to “plasma
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`extravasation.” EX1022, 571; EX1048, Abstract; EX1050, Abstract; EX1049, 259;
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`EX2273, 42:15-17; 57:12-15; 62:13-22. Such “leakage” does not occur in a
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`neuromuscular junction or during migraine. EX2273, 34:18-35:6, 73:1-8, 13-17;
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`EX2269, Abstract. And as Dr. Balthasar admitted, “antibodies can transport out of
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`leaky vasculature more efficiently than non-leaky vasculature.” EX2273, 26:17-22;
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`EX2268, 550-551. Thus, EX1021 and EX1048-1050 would have not been
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`informative as to a full-length antibody’s ability to enter synaptic clefts during
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`migraine. And, while Dr. Balthasar purports to disagree with Dr. Foord’s
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`conclusion that C4.19 did not reach the synaptic cleft, he admitted that he was
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`unqualified to provide such an opinion. EX2273, 82:12-83:1.
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`None of Lilly’s cited art rehabilitates Tan 1995’s showing that the full-
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`
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`length antibody failed to immunoblockade, such that a POSA would have had a
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`reasonable expectation of success. And Lilly has not explained why a POSA would
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`have considered such an antibody as a “potential therapeutic.”
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`B.
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`Lilly failed to demonstrate that humanized anti-CGRP antibodies
`would have been safe in humans.
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`Dr. Charles confirms: “[c]ertainly, we’re always concerned about safety
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`issues, including stroke, in any circumstance where we’re administering therapy.”
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`EX2272, 81:3-5. Yet neither the Petition nor the opening declarations (EX1012
`
`and EX1013) discussed the increased incidence of stroke in migraineurs or safety
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`concerns with depleting CGRP’s vasoprotective role long-term, nor provided
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`evidence of how a POSA would have overcome these safety concerns and
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`proceeded to humanize an anti-CGRP antibody for human use. The Reply equally
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`fails to fill this hole.
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`1.
`
`
`Lilly improperly ignores myriad teachings showing CGRP’s
`vasoprotective role.
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`Teva demonstrated the art-recognized importance of CGRP for vascular
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`health. POR, 23-24. Lilly’s attempts to dismiss CGRP’s potent cerebro- and
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`cardioprotective roles, as recognized by the field during the relevant time, is in
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`error.
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`As of 2005, the field believed that CGRP played a “pivotal role” in the
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`“physiology and pathophysiology of cardiovascular regulation.” EX2003, 923 ;
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`EX2214, ¶36; POR, 10. This role included protecting tissues during ischemia
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`through, e.g., ischemic preconditioning. EX2272, 25:8-26:17, 29:16-30:25, 35:1-
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`36:21; EX2263, 53-54; EX2264, 246.
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`Even Lilly’s EX1284 demonstrates CGRP’s cardioprotective role: CGRP
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`reduced infarct size in an ischemia rat model by up to 89%, while BIBN4096BS
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`blocked “[t]he cardioprotective effect of CGRP.” EX1284, 591-592, Figure 3.
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`Notably, Lilly omitted this unfavorable information, and its expert refused to even
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`acknowledge it as “germane” during cross-examination. EX2272, 20:1-21:3.
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`Importantly, the authors of EX1284 concluded that “CGRP is a very potent
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`myocardial protective substance.” EX1284, 593; EX2272, 21:17-22:4.
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`2.
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`Risk concerns of antagonizing CGRP with long-acting
`antibodies were not “theoretical.”
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`Concerns regarding CGRP ligand antagonism were not “theoretical,” as
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`Lilly and its experts assert. Reply, 9. By 2005, researchers observed negative
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`effects when administering anti-CGRP antibodies to animals. Tan 1995
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`
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`demonstrated that anti-CGRP antibodies increased baseline mean arterial pressure
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`(MAP).5 EX1022, 568, Figure 2; EX2214, ¶51; EX2232, ¶78; POR, 25. Similarly,
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`Tjen-A-Looi demonstrated that an anti-CGRP antibody increased pulmonary
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`arterial pressure in rats. POR, 23; EX2084, H687; EX231, ¶81. And Wong showed
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`that an anti-CGRP antibody6 blocked CGRP-induced decrease in blood pressure
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`and heart rate in rats. EX1033, 102, Table 2; EX2232, ¶81.
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`Lilly does not contest that anti-CGRP antibodies increase blood pressure in
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`5 Lilly introduced a new exhibit—the Tan Thesis (EX1287)—on Reply, even
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`though none of its experts rely upon it. Id., 11. Beyond untimeliness (see Paper
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`43), Lilly has not established that EX1287 was publicly available or qualifies as
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`prior art. In any event, it would not have prompted a POSA to ignore the greater
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`weight of the prior art and the expectation that a full length anti-CGRP antibody
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`would not be suitable for human therapeutic use.
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`6 Lilly relies on Wong’s allusion to its antibody’s safety (Reply, 11-12), but
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`Dr. Balthasar admitted that he could not “draw direct reference from the sentence
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`[referring to MAP and heart rate] alone to which study it refers to.” EX2273,
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`158:17-20.
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`animals. Reply, 10. Instead, Lilly attempts to undermine these in vivo examples by
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`arguing that the blood pressure increases were “minor” and “transient” and would
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`not have been a safety concern. Reply, 10-11. Lilly is wrong; according to Dr.
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`Ferrari’s unrebutted testimony, “mortality from a myocardial infarction (MI) or
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`cerebrovascular accidents doubles for each 20-mm Hg increase in systolic blood
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`pressure (BP) above 115 mm Hg.” EX2127, S383; EX2214, ¶54. Further, none of
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`Lilly’s antibody-related references determine the consequences of obliterating
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`CGRP-mediated vasodilation during an ischemic attack—the real concern in the
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`field in 2005. EX2214, ¶46.
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`3.
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`Any alleged safety of blocking the CGRP pathway with
`small molecules, receptor antagonists, or aptamers is
`irrelevant to the safety of anti-CGRP antibodies.
`
`Lilly argues that “more recent” art than that cited by Teva shows that no
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`safety concern existed. Reply, 12. Lilly is incorrect. Lilly’s “more recent”
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`references involve either BIBN4096BS or CGRP8-37 (see graphic below), neither of
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`which is informative as to the safety of anti-CGRP antibodies, given their short
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`half-lives and different mechanism of action (both are receptor antagonists). Reply,
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`13-14; EX1283, Abstract; EX2152, 165; EX1284, Abstract; EX1285, Abstract;
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`EX1318, Abstract; EX1263, Abstract.
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`Ex. 2079
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`- CGRP “Improves myocardial contractility
`in patients with congestive heart failure"
`
`- Evaluated circadian variation in plasma
`concentrations of CGRP
`
`- CGRP “delays the onset of myocardial
`ischaemia during treadmill exercise"
`
`- mama-37)
`
`- mama-37)
`
`|:|= Teva Exhibit
`!= Lilly Exhibit
`|:|= Studies showing CGRP vasoprotecfive activity
`I:I= Short-term CGRP receptor antagonist studies
`- = Short-term aptamer study
`
`- CGRP “may be acting as a local mediat-
`in the pathophysiology of [acute myocardial
`infarction]”
`
`- CGRP levels were “reduced” after
`subarachnoid haemorrhage (SAH)
`
`
`
`
`
`cardiovascular episodes."
`
`- Age-related changes in CGRP levels “may
`contribute to the increased incidence of
`
`- CGRP“may reverse significantlythe W
`vasoconstriction seen after SAH"
`
`- CGRP(8-37)
`
`the myocardium during ischemia.”
`
`- CGRP is possibly involved in “protection of
`
`
`
`
`
`- CGRP(8-37)
`
`- BIBN4DQGBS
`
`CGRP protects against “hypertension-
`induced" organ damage and from
`"ischemiai’reperfusion injury"
`
`- BIBN4OQGBS
`
`
`
`- CGRP plays a “pivotal role" in the
`
`"physiology and pathophysiology of
`cardiovascular regulation."
`
`
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`Lilly argues that “blocking the CGRP pathway7 was [] safe … for treating
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`migraine.” Reply, 6. Devoid of any evidence of safety of anti-CGRP antibodies, all
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`Lilly offers are references relating to small molecules (with “significantly” shorter
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`half-lives than full length antibodies, as Dr. Charles admitted) and receptor
`
`antagonists. None of these molecules would have been probative of the safety of
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`anti-CGRP antibodies.
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`References discussing BIBN4096BS are not probative of the safety of an
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`anti-CGRP antibody for multiple undisputed reasons. BIBN4096BS is a small-
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`molecule receptor antagonist with a “significantly” shorter half-life than a full-
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`length antibody. As such, any of its adverse effects would be cleared from the body
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`within 24 hours after administration, in stark contrast to an antibody’s effects,
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`which will linger for weeks. POR, 6, 22, 28-30; EX2272, 86:13-87:9.; EX2232,
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`¶¶76, 84; EX2226, ¶¶50-55, 60-71, 74-76; EX2214, ¶22, 62, 68; EX1042, 645;
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`Petition, 32; EX1059, 143, Figure 4.16; EX2272, 85:15-86:12. Moreover, each of
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`Lilly’s BIBN4096BS references were short-term studies, assessing effects for 24
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`hours or shorter, and would not have informed a POSA of the risks of an antibody
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`7 Lilly artfully uses the phrase “CGRP pathway” or “CGRP antagonist” to
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`disguise its reliance on art directed to receptor antagonists (Reply, 6, 7, 8, 9, 14,
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`23), whereas the challenged claims recite ligand antagonists. EX1001, 103-104.
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`that circulates in the body for weeks, even after only a single administration. POR,
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`29-30; EX2214, ¶22; EX2232, ¶84; EX1025, 1104; EX1042, 647; EX1290, 657;
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`EX1297, S119; EX2272, 83:22-88:12.
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`Further, to the extent any of Lilly’s cited studies tested cerebrovascular or
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`cardiovascular safety of BIBN4096BS, they were all done in “healthy volunteers,”
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`which, according to Dr. Ferrari, “are the wrong experiments to assess
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`cardiovascular safety of any drug interacting with CGRP” because they do not
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`study whether the antagonist would “block rescue mechanisms in the times of
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`ischemia.” POR, 27-28; EX1303, 87:5-17, 89:21-90:3; EX2214, ¶¶48-59; EX2193,
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`222; EX2157, 533; EX1025, 1108; EX1042, 647; EX2272, 83:22-84:13. What is
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`more, Olesen specifically warned against relying on its study for cardiovascular
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`safety: “our data base was too small for us to assess cardiovascular safety.”
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`EX1025, 1109; POR, 29; EX2214, ¶22. Dr. Charles blatantly ignored this warning
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`(EX1328, ¶34), but Dr. Balthasar confirmed that Olesen’s statement is consistent
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`with “what I would expect from a clinical investigation” because one “can’t make
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`extrapolations off of -- beyond the sample size that’s present.” EX2273, 119:5-
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`120:4. Finally, it is of no consequence that an increase in MAP observed with
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`CGRP8-37 “did not deter development of BIBN4096BS or other receptor
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`antagonists.” Reply, 11. As described, a POSA would not have equated short-term
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`receptor antagonism with long-term ligand antagonism. POR, 28-34.
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`Lilly’s reliance on the reported safety of triptans is even less probative of
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`anti-CGRP antibody’s safety. As with BIBN4096BS, triptans are small-molecule
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`therapeutics with a half-life of only “about two hours.” EX1282, 7; EX2272, 99:1-
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`4. Thus, any adverse effects of triptans are similarly eliminated from the body
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`within hours. Triptans also operate by a mechanism that is very different from anti-
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`CGRP antibodies: triptans agonize 5-HT receptors. EX1040, 180-181; EX2214,
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`¶21; EX2272, 99:20-100:1. And researchers were aware of three different potential
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`actions of triptans downstream of the 5-HT receptors, none of which were linked
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`directly to CGRP. EX1040, 180. While researchers had observed that triptans
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`could inhibit the release of CGRP, researchers were not discussing CGRP as being
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`the source of the triptans’ anti-migraine activity before 2005. EX1303, 23:22-24:18
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`EX1040, 180. Further, researchers were seeking to generate improved triptans that
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`targeted 5-HT receptor subtypes so that they would lack vasoconstrictive
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`activity—a goal that would not be compatible with inhibiting the activity of CGRP,
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`a highly potent vasodilator. EX2267, ¶19; EX2272, 102:15-104:9.
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`Dr. Charles analogizes antibody-induced BP increases to similar increases
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`observed with triptans, arguing that such transient changes were not of concern.
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`EX1328, ¶44. But triptans’ mechanism of action and pharmacokinetics differ from
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`that of antibodies, and Dr. Charles has not explained the basis for equating the two
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`classes of molecules. Moreover, because triptans were used as a treatment for
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`acute migraine, physicians would not have been concerned with triptans’ long-term
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`effects. EX2214, ¶21; EX1031, 322; EX1040, 176. Even then, the
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`“vasoconstrictive risk factors” and “the overall associated cardiovascular risks
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`continue to limit their use.” EX2214, ¶21; EX2162, 443-444; EX1304, 55:1-57:25.
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`Lilly has not explained why a POSA would have looked to triptans in making any
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`conclusion as to the safety of anti-CGRP antibodies.
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`Finally, Lilly’s Reply advances an entirely new theory based on “aptamers.”
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`The Board should reject this argument as untimely. Henny Penny, No. 18-1596, 9;
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`Paper 43, 4-5. Moreover, Lilly’s aptamer art does not suggest safety of the claimed
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`anti-CGRP antibodies. First, as with BIBN4096BS and triptans, aptamers have a
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`short half-life—“hours to days,” not “weeks”—and would not have been
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`informative on the safety of long-acting antibodies. EX1309, Abstract; EX2272,
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`114:6-115:5. Second, aptamers are not “analogs to antibodies,” as Lilly
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`simplistically argues. Reply, 9. Aptamers “bridge the gap between small molecules
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`and biologics” and have many characteristics that are similar to small-molecules.
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`EX1309, Abstract. Further, there is no evidence on the record that aptamers would
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`have been safe in humans. And the only in vivo study in the record with aptamers,
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`Messlinger, is an abstract that lacks specifics such as controls used or experimental
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`details for its mouse model. EX1240; EX2272, 115:19-117:7, 118:9-120:24. Dr.
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`Charles’ blind reliance on Messlinger’s scarce disclosure merely because
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`Messlinger was “widely known as an extremely careful scientist” once again
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`demonstrates Dr. Charles’ bias in these proceedings. EX2272, 117:8-16, 121:12-
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`122:6. For example, Dr. Charles “disagreed” with Susan Brain’s conclusion that
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`CGRP played a cardioprotective role even though the Brain review provided
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`substantially more evidence than the Messlinger abstract despite Dr. Charles’
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`admission that Dr. Brain was “a respected person in the field.” EX2272 41:9-12,
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`43:16-24; EX2003, 915.
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`In sum, the record lacks any evidence that anti-CGRP antibodies would have
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`been safe in humans. Lilly has not shown that a POSA would have found such
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`antibodies “potentially therapeutic” in 2005.
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`4.
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`Lilly improperly dismisses safety concerns with
`antagonizing CGRP in migraineurs.
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`Having failed in its Petition to consider migraine’s comorbidity with stroke
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`and hypertension, Lilly now attempts to dismiss these concerns by arguing that
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`they are “legally irrelevant” because “claims at issue do not distinguish between
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`target patient populations.” Reply, 14. But it was Lilly—not Teva—who
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`specifically focused on migraine in its Petition as part of its motivation analysis, as
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`Dr. Charles admitted. Petition, 28-30; EX2192, 73:6-74:11. Thus, safety
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`considerations of anti-CGRP antibodies in migraine patients are “legally relevant.”
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`Lilly next argues that such considerations are irrelevant for most migraine
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`patients, because “the absolute risk” of stroke and myocardial ischemia in young
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`women is “low.” Reply, 15. But this argument is nothing more than an attempt to
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`detract from Lilly’s original failure to consider safety of the claimed antibodies in
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`migraineurs, despite the known link between stroke and migraine. EX2272, 80:1-
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`82:20; EX2266, 1123. In any event, Dr. Charles’ analysis on the risk to
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`migraineurs is wrong.
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`As Dr. Ferrari explains, it was known that CGRP played a key role in
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`preventing escalation of mild ischemic events into full-blown infarctions, such as
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`stroke and heart attacks. EX2214, ¶¶37-47; POR, 10. Dr. Charles attempts to
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`minimize the importance o