throbber

`
`
`
`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 IPR2018-01427
`Patent 8,597,649
`_____________________
`
`
`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 IPR2018-01427
`Patent No. 8,597,649
`
`
`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. .................................................... 10 
`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. 
`
`- i-
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`I.
`
`Introduction
`
`Teva’s Patent Owner Response (“POR”) exposed multiple infirmities that
`
`defeat Lilly’s obviousness case. Teva demonstrated that Lilly’s principal
`
`references—Tan 1995 and Wimalawansa—would not have motivated a POSA to
`
`develop an anti-CGRP antibody for human therapeutic use. Tan 1995, a basic
`
`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
`
`immunoblockade in a rat saphenous nerve assay. Wimalawansa—far from
`
`suggesting humanizing anti-CGRP antibodies, as Lilly argues—expressly conveys
`
`to a POSA that “[c]learly, more data from carefully designed studies are necessary
`
`before … humanized anti-CGRP monoclonal antibodies … can be evaluated as
`
`therapeutic agents.” And Lilly has not shown that such data existed prior to 2005.
`
`Unable to overcome these and other fatal defects, Lilly accuses Teva of
`
`“impermissibly reading safety and efficacy requirements into the claims.” But it
`
`was Lilly who premised its Petition on human therapeutic use. Teva rebutted
`
`Lilly’s arguments by, inter alia, showing that Lilly failed to consider safety, and
`
`fell short of demonstrating efficacy.
`
`Rather than considering the prior art as a whole, as it must, Lilly, through
`
`hindsight, selectively cherry-picks references Lilly believes support its arguments,
`
`while ignoring references that undermine them. Even worse, on cross-examination
`
`- 1 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`Dr. Charles and his replacement, Dr. Balthasar1, distanced themselves from
`
`unfavorable portions of Lilly’s own references upon which they themselves relied.
`
`Specifically, these experts refused to consider teachings that call into question the
`
`safety of long-term (as with an antibody) inhibition of CGRP, the body’s most
`
`potent vasodilator. Given that Lilly constructed its obviousness case on a
`
`
`
`therapeutic utility, the lack of safety and efficacy in its evidence cannot be ignored.
`
`On Reply, Lilly now pivots from its initial “human therapeutic use”
`
`arguments, focusing instead on the mere “potential” for therapeutic use. But Lilly
`
`cannot re-craft its challenge on Reply to attempt to rehabilitate its Petition. Henny
`
`Penny Corp. v. Frymaster LLC, No. 18-1596 (Fed. Cir. 2019).
`
`To support its new rationale, Lilly again cherry-picks isolated, out-of-
`
`context phrases to repaint the field as of 2005. For example, to support the alleged
`
`in vivo effectiveness of Tan’s C4.19 antibody, Lilly cites to Teva’s Dr. Ferrari. But
`
`Dr. Ferrari’s testimony referred to Tan’s Fab’ fragment, not full-length C4.19. And
`
`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
`
`
`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
`
`new expert Dr. Balthasar in an effort to repair Dr. Charles’ failed opinions.
`
`- 2 -
`
`

`

`
`
`Case IPR2018-01427
`Patent No. 8,597,649
`
`“assignment of a site … of antibody localization was not possible.” 2
`
`Similarly, Lilly’s speculation about “increased dose” goes squarely against
`
`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.
`
`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, 13-14, 26-30, 32, 34-35. Lilly
`
`specifically argued the reason for humanizing a murine antibody was to retain “the
`
`antibody’s therapeutic utility” “in humans.” Id., 34-35. By doing so, Lilly (not
`
`Teva) read “safety and efficacy requirements into the claims.” Under a similar
`
`challenge to composition of matter claims, as here, the Board held the petitioner to
`
`
`2 Emphasis added throughout unless otherwise noted.
`
`- 3 -
`
`

`

`
`
`Case IPR2018-01427
`Patent No. 8,597,649
`
`its “therapeutic utility” motivation arguments. Phigenix v. ImmunoGen, IPR2014-
`
`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
`
`the cited references”); see also id., 21 (“Petitioner does not persuade us … that a
`
`skilled artisan would have had a reasonable expectation of success … that [the
`
`claimed] immunoconjugate would be useful in the treatment of breast tumors in
`
`humans.”).
`
`As in Phigenix, having relied on therapeutic utility for motivation, Lilly was
`
`required to consider and demonstrate that the art evidenced efficacy and safety of
`
`the claimed antibodies for therapeutic use. Lilly recognized as much by arguing
`
`safety with respect to “immunogenicity” in humans in its reason to humanize.
`
`Petition, 35. But Lilly’s Petition stops there, saying nothing to address the myriad
`
`teachings in the art about cardiovascular and cerebrovascular safety concerns
`
`associated with long-term depletion of CGRP. Lilly also failed to prove reasonable
`
`expectation of efficacy.
`
`Recognizing gaps in its case that Teva highlighted, Lilly now seeks to retreat
`
`from its original therapeutic-based rationale. Lilly argues for the first time on
`
`Reply that a POSA would have been motivated to make “any … antibody having
`
`- 4 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`
`known functional properties.” Reply, 4 (emphasis in original). But Lilly’s rationale
`
`in the Petition controls; the Board should review the record through the lens of
`
`“therapeutic utility” of the claimed antibodies. Henny Penny, No. 18-1596, 9
`
`(“[A]n IPR petitioner 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
`
`Sanofi-Aventis U.S. LLC. v. Immunex Corp., IPR2017-01884, Paper 96, 17
`
`(P.T.A.B. Feb. 14, 2019). Sanofi-Aventis is inapposite because its mouse antibody
`
`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
`
`activity.” Id., 18. The field also identified targeting receptors—as the claimed
`
`antibody in that case did—as “more promising” than targeting their ligands
`
`(cytokines), and “several companies” were seeking to do just that. Id., 20. This
`
`utility led the Board to conclude that MAb230 was “a promising candidate from
`
`- 5 -
`
`

`

`
`
`Case IPR2018-01427
`Patent No. 8,597,649
`
`which to derive an effective therapeutic.”3 Id., 18. The record here reveals no such
`
`known utility in the art for Teva’s antibodies, and Lilly has not provided sufficient
`
`evidence to show a mouse anti-CGRP antibody to be a more “promising
`
`candidate” than the receptor antagonists the art was focused on.
`
`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
`
`“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
`
`in vivo saphenous nerve assay. EX2054, ¶102; EX1022, 571, 565, Abstract; POR,
`
`42. Lilly’s own Dr. Vasserot agreed with Teva’s experts on this shortcoming and
`
`the unreliability of Tan’s results. EX2191, 118:12-119:1; POR, 3. Dr. Charles—a
`
`clear outlier among the experts—testified that C4.19 “showed a 16% reduction in
`
`
`3 Also, in Sanofi-Aventis, Patent Owner stated, in response to an enablement
`
`decision: “There is no reasonable basis for concluding that antibodies that bind to
`
`‘the perfect target’ and inhibit ‘an important regulator’ would be therapeutically
`
`ineffective.” Sanofi-Aventis U.S. LLC. v. Immunex Corp. at 24. Here, no such
`
`admission has been made.
`
`- 6 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`skin blood flow” in a saphenous nerve assay. EX1002, ¶121; POR, 3. But given
`
`Dr. Charles’ gross mischaracterization of prior art in these proceedings (EX2192,
`
`182:21-183:12; 154:18-20), his opinion must be given little weight. POR, 3-4.
`
`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
`
`resorts to mischaracterizing Teva’s experts’ testimonies. For example, Lilly cites to
`
`Dr. Ferrari for his alleged admission of C4.19’s in vivo activity. Reply, 3. But Dr.
`
`Ferrari was referring to Tan’s Fab’ fragment, not the full-length antibody. EX1303,
`
`160:2-9, 162:12-22. Lilly then points to Dr. Tomlinson’s acknowledgment that he
`
`“humanized antibodies all the time” as evidence of motivation in 2005. Reply, 5.
`
`But Dr. Tomlinson was discussing his humanization activities from 2007 to 2016,
`
`not prior to 2005. EX1301, 55:1-13. Similarly disingenuous is Lilly’s allegation
`
`that “Teva’s experts conceded that a POSA would have found it appropriate to use
`
`humanized antibodies throughout drug development, including binding assays, in
`
`vitro testing, and animal studies.” Reply, 5-6. The transcripts illuminate the truth:
`
`
`
`Dr. Tomlinson stated that a POSA would have humanized an antibody
`
`to be tested only when “[g]iven sufficient motivation to do so ….
`
`which at the time wasn’t the case,” for CGRP. EX1301, 204:4-15;
`
`
`
`Dr. Ferrari admitted that he is “not an expert in [the drug
`
`development] field.” EX1303, 54:25-55:6;
`
`- 7 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`
`
`Dr. Rapoport’s testimony related to clinical trials in humans; not in
`
`vitro or animal testing. EX1304, 145:15-146:3.
`
`
`
`Ultimately, Lilly failed to prove that a POSA would have viewed Tan’s
`
`C4.19 as engaging at the site of action in vivo. Instead, Lilly’s Petition speculated,
`
`without support, that “slow distribution to the site of immunoblockade could be
`
`overcome by (1) increasing the dose, (2) chronic administration, and/or (3) active
`
`immunization.” Petition, 45. Now that Teva has highlighted this speculation, Lilly
`
`belatedly relies on Dr. Balthasar’s assertion that “carcass” experiments show that
`
`“full-length antibodies were expected to distribute from general circulation into the
`
`interstitial space4, so long as they are given sufficient time.” Reply, 20; EX1329,
`
`¶¶24-29. But the art shows that in a carcass (a crude mix of leftover body parts),
`
`“assignment of a site, or sites, of antibody localization was not possible.” EX2270,
`
`3045; EX2273, 92:14-16. Thus, Lilly fails to show that a full-length antibody
`
`would distribute into interstitial spaces with additional time.
`
`Lilly also provides no credible evidence that, even if the antibody reaches
`
`the interstitial spaces, it would be able to access the synaptic cleft, especially in
`
`sufficient concentration for immunoblockade. It is undisputed that the “carcass”
`
`
`4 The interstitial space is a space “between cells, within tissue.” EX2273,
`
`84:2-3.
`
`- 8 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`experiment presents no data relating to an antibody’s penetration of the synaptic
`
`cleft or of an antibody’s binding to CGRP in the synaptic cleft. EX2273, 93:19-
`
`95:6; 95:10-12; EX1022, 566. Other references Lilly advances to fill this gap are
`
`equally uninformative.
`
`
`
`For example, Lilly cites to Tan 1995’s statement that a full-length antibody
`
`“clearly diffuses” to the site of action as evidence of its in vivo effectiveness.
`
`Reply, 20. But Tan 1995 based this conclusion on another study: Tan 1994.
`
`EX1022, 571. Tan 1994’s isolated vas deferens “tissue bath” is not an “equivalent”
`
`to an in vivo study, and thus is not a representation of an antibody’s ability to
`
`penetrate multiple biological compartments in a complex system, such as a human
`
`body. EX2273, 77:20-78:3; EX1021, 705. Similarly, in the Louis/Dockray
`
`experiments, the antibodies “leaked” into the interstitial space due to “plasma
`
`extravasation.” EX1022, 571; EX1048, Abstract; EX1050, Abstract; EX1049, 259;
`
`EX2273, 42:15-17; 57:12-15; 62:13-22. Such “leakage” does not occur in a
`
`neuromuscular junction or during migraine. EX2273, 34:18-35:6, 73:1-8, 13-17;
`
`EX2269, Abstract. And as Dr. Balthasar admitted, “antibodies can transport out of
`
`leaky vasculature more efficiently than non-leaky vasculature.” EX2273, 26:17-22;
`
`EX2268, 550-551. Thus, EX1021 and EX1048-1050 would have not been
`
`informative as to a full-length antibody’s ability to enter synaptic clefts during
`
`migraine. And, while Dr. Balthasar purports to disagree with Dr. Foord’s
`
`- 9 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`conclusion that C4.19 did not reach the synaptic cleft, he admitted that he was
`
`unqualified to provide such an opinion. EX2273, 82:12-83:1.
`
`None of Lilly’s cited art rehabilitates Tan 1995’s showing that the full-
`
`
`
`length antibody failed to immunoblockade, such that a POSA would have had a
`
`reasonable expectation of success. And Lilly has not explained why a POSA would
`
`have considered such an antibody as a “potential therapeutic.”
`
`B.
`
`Lilly failed to demonstrate that humanized anti-CGRP antibodies
`would have been safe in humans.
`
`Dr. Charles confirms: “[c]ertainly, we’re always concerned about safety
`
`issues, including stroke, in any circumstance where we’re administering therapy.”
`
`EX2272, 81:3-5. Yet neither the Petition nor the opening declarations (EX1002
`
`and EX1003) discussed the increased incidence of stroke in migraineurs or safety
`
`concerns with depleting CGRP’s vasoprotective role long-term, nor provided
`
`evidence of how a POSA would have overcome these safety concerns and
`
`proceeded to humanize an anti-CGRP antibody for human use. The Reply equally
`
`fails to fill this hole.
`
`1.
`
`Lilly improperly ignores myriad teachings showing CGRP’s
`vasoprotective role.
`
`Teva demonstrated the art-recognized importance of CGRP for vascular
`
`health. POR, 23-24. Lilly’s attempts to dismiss CGRP’s potent cerebro- and
`
`cardioprotective roles, as recognized by the field during the relevant time, is in
`
`- 10 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`error.
`
`
`
`As of 2005, the field believed that CGRP played a “pivotal role” in the
`
`“physiology and pathophysiology of cardiovascular regulation.” EX2003, 923;
`
`EX2141, ¶36; POR, 10. This role included protecting tissues during ischemia
`
`through, e.g., ischemic preconditioning. EX2272, 25:8-26:17, 29:16-30:25, 35:1-
`
`36:21; EX2263, 53-54; EX2264, 246.
`
`Even Lilly’s EX1284 demonstrates CGRP’s cardioprotective role: CGRP
`
`reduced infarct size in an ischemia rat model by up to 89%, while BIBN4096BS
`
`blocked “[t]he cardioprotective effect of CGRP.” EX1284, 591-592, Figure 3.
`
`Notably, Lilly omitted this unfavorable information, and its expert refused to even
`
`acknowledge it as “germane” during cross-examination. EX2272, 20:1-21:3.
`
`Importantly, the authors of EX1284 concluded that “CGRP is a very potent
`
`myocardial protective substance.” EX1284, 593; EX2272, 21:17-22:4.
`
`2.
`
`Risk concerns of antagonizing CGRP with long-acting
`antibodies were not “theoretical.”
`
`Concerns regarding CGRP ligand antagonism were not “theoretical,” as
`
`Lilly and its experts assert. Reply, 9-10. By 2005, researchers observed negative
`
`effects when administering anti-CGRP antibodies to animals. Tan 1995
`
`demonstrated that anti-CGRP antibodies increased baseline mean arterial pressure
`
`- 11 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`(MAP).5 EX1022, 568, Figure 2; EX2141, ¶51; EX2054, ¶78; POR, 25. Similarly,
`
`Tjen-A-Looi demonstrated that an anti-CGRP antibody increased pulmonary
`
`arterial pressure in rats. POR, 23; EX2084, H687; EX2054, ¶81. And Wong
`
`showed that an anti-CGRP antibody6 blocked CGRP-induced decrease in blood
`
`pressure and heart rate in rats. EX1033, 102, Table 2; EX2054, ¶81.
`
`
`
`Lilly does not contest that anti-CGRP antibodies increase blood pressure in
`
`animals. Reply, 11. Instead, Lilly attempts to undermine these in vivo examples by
`
`arguing that the blood pressure increases were “minor” and “transient” and would
`
`not have been a safety concern. Id. Lilly is wrong; according to Dr. Ferrari’s
`
`
`5 Lilly introduced a new exhibit—the Tan Thesis (EX1287)—on Reply, even
`
`though none of its experts rely upon it. Id., 11-12. Beyond untimeliness (see Paper
`
`43), Lilly has not established that EX1287 was publicly available or qualifies as
`
`prior art. In any event, it would not have prompted a POSA to ignore the greater
`
`weight of the prior art and the expectation that a full length anti-CGRP antibody
`
`would not be suitable for human therapeutic use.
`
`6 Lilly relies on Wong’s allusion to its antibody’s safety (Reply, 12), but Dr.
`
`Balthasar admitted that he could not “draw direct reference from the sentence
`
`[referring to MAP and heart rate] alone to which study it refers to.” EX2273,
`
`158:17-20.
`
`- 12 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`unrebutted testimony, “mortality from a myocardial infarction (MI) or
`
`cerebrovascular accidents doubles for each 20-mm Hg increase in systolic blood
`
`pressure (BP) above 115 mm Hg.” EX2127, S383; EX2141, ¶54. Further, none of
`
`Lilly’s antibody-related references determine the consequences of obliterating
`
`CGRP-mediated vasodilation during an ischemic attack—the real concern in the
`
`
`
`field in 2005. EX2141, ¶46.
`
`3.
`
`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
`
`safety concern existed. Reply, 13. Lilly is incorrect. Lilly’s “more recent”
`
`references involve either BIBN4096BS or CGRP8-37 (see graphic below), neither of
`
`which is informative as to the safety of anti-CGRP antibodies, given their short
`
`half-lives and different mechanism of action (both are receptor antagonists). Reply,
`
`13-14; EX1283, Abstract; EX2152, 165; EX1284, Abstract; EX1285, Abstract;
`
`EX1318, Abstract; EX1263, Abstract.
`
`- 13 -
`
`

`

`Case IPR2018-01427
`
`Case IPR2018-01427
`Patent No. 8,597,649
`Patent No. 8,597,649
`
`Ex. 2079
`
`- 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."
`
`
`
`
`
`
`- 14 -
`
`-14-
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`Lilly argues that “blocking the CGRP pathway7 was [] safe … for treating
`
`migraine.” Reply, 6. Devoid of any evidence of safety of anti-CGRP antibodies, all
`
`Lilly offers are references relating to small molecules (with “significantly” shorter
`
`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
`
`anti-CGRP antibodies.
`
`
`
`References discussing BIBN4096BS are not probative of the safety of an
`
`anti-CGRP antibody for multiple undisputed reasons. BIBN4096BS is a small-
`
`molecule receptor antagonist with a “significantly” shorter half-life than a full-
`
`length antibody. As such, any of its adverse effects would be cleared from the body
`
`within 24 hours after administration, in stark contrast to an antibody’s effects,
`
`which will linger for weeks. POR, 6, 22, 28-30; EX2272, 86:13-87:9.; EX2054,
`
`¶¶76, 84; EX2137, ¶¶50-55, 60-71, 74-76; EX2141, ¶22, 62, 68; EX1042, 645;
`
`Petition, 34; EX1059, 143, Figure 4.16; EX2272, 85:15-86:12. Moreover, each of
`
`Lilly’s BIBN4096BS references were short-term studies, assessing effects for 24
`
`hours or shorter, and would not have informed a POSA of the risks of an antibody
`
`
`7 Lilly artfully uses the phrase “CGRP pathway” or “CGRP antagonist” to
`
`disguise its reliance on art directed to receptor antagonists (Reply, 6, 9, 14, 24-25),
`
`whereas the challenged claims recite ligand antagonists. EX1001, 101-102.
`
`- 15 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`that circulates in the body for weeks, even after only a single administration. POR,
`
`30; EX2141, ¶22; EX2054, ¶84; EX1025, 1104; EX1042, 647; EX1290, 657;
`
`EX1297, S119; EX2272, 83:22-88:12.
`
`
`
`Further, to the extent any of Lilly’s cited studies tested cerebrovascular or
`
`cardiovascular safety of BIBN4096BS, they were all done in “healthy volunteers,”
`
`which, according to Dr. Ferrari, “are the wrong experiments to assess
`
`cardiovascular safety of any drug interacting with CGRP” because they do not
`
`study whether the antagonist would “block rescue mechanisms in the times of
`
`ischemia.” POR, 26-27; EX1303, 87:5-17, 89:21-90:3; EX2141, ¶¶48-59; EX2193,
`
`222; EX2157, 533; EX1025, 1108; EX1042, 647; EX2272, 83:22-84:13. What is
`
`more, Olesen specifically warned against relying on its study for cardiovascular
`
`safety: “our data base was too small for us to assess cardiovascular safety.”
`
`EX1025, 1109; POR, 29; EX2141, ¶22. Dr. Charles blatantly ignored this warning
`
`(EX1330, ¶34), but Dr. Balthasar confirmed that Olesen’s statement is consistent
`
`with “what I would expect from a clinical investigation” because one “can’t make
`
`extrapolations off of -- beyond the sample size that’s present.” EX2273, 119:5-
`
`120:4. Finally, it is of no consequence that an increase in MAP observed with
`
`CGRP8-37 “did not deter development of BIBN4096BS or other receptor
`
`antagonists.” Reply, 11. As described, a POSA would not have equated short-term
`
`receptor antagonism with long-term ligand antagonism. POR, 28-34.
`
`- 16 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`Lilly’s reliance on the reported safety of triptans is even less probative of
`
`
`
`anti-CGRP antibody’s safety. As with BIBN4096BS, triptans are small-molecule
`
`therapeutics with a half-life of only “about two hours.” EX1282, 7; EX2272, 99:1-
`
`4. Thus, any adverse effects of triptans are similarly eliminated from the body
`
`within hours. Triptans also operate by a mechanism that is very different from anti-
`
`CGRP antibodies: triptans agonize 5-HT receptors. EX1040, 180-181; EX2141,
`
`¶21; EX2272, 99:20-100:1. And researchers were aware of three different potential
`
`actions of triptans downstream of the 5-HT receptors, none of which were linked
`
`directly to CGRP. EX1040, 180. While researchers had observed that triptans
`
`could inhibit the release of CGRP, researchers were not discussing CGRP as being
`
`the source of the triptans’ anti-migraine activity before 2005. EX1303, 23:22-24:18
`
`EX1040, 180. Further, researchers were seeking to generate improved triptans that
`
`targeted 5-HT receptor subtypes so that they would lack vasoconstrictive
`
`activity—a goal that would not be compatible with inhibiting the activity of CGRP,
`
`a highly potent vasodilator. EX2267, ¶19; EX2272, 102:15-104:9.
`
`Dr. Charles analogizes antibody-induced BP increases to similar increases
`
`observed with triptans, arguing that such transient changes were not of concern.
`
`EX1330, ¶44. But triptans’ mechanism of action and pharmacokinetics differ from
`
`that of antibodies and Dr. Charles has not explained the basis for equating the two
`
`classes of molecules. Moreover, because triptans were used as a treatment for
`
`- 17 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`
`acute migraine, physicians would not have been concerned with triptans’ long-term
`
`effects. EX2141, ¶21; EX1031, 322; EX1040, 176. Even then, the
`
`“vasoconstrictive risk factors” and “the overall associated cardiovascular risks
`
`continue to limit their use.” EX2141, ¶21; EX2162, 443-444; EX1304, 55:1-57:25.
`
`Lilly has not explained why a POSA would have looked to triptans in making any
`
`conclusion as to the safety of anti-CGRP antibodies.
`
`Finally, Lilly’s Reply advances an entirely new theory based on “aptamers.”
`
`The Board should reject this argument as untimely. Henny Penny, No. 18-1596, 9;
`
`Paper 43, 4-5. Moreover, Lilly’s aptamer art does not suggest safety of the claimed
`
`anti-CGRP antibodies. First, as with BIBN4096BS and triptans, aptamers have a
`
`short half-life—“hours to days,” not “weeks”—and would not have been
`
`informative on the safety of long-acting antibodies. EX1309, Abstract; EX2272,
`
`114:6-115:5. Second, aptamers are not “analogs to antibodies,” as Lilly
`
`simplistically argues. Reply, 9. Aptamers “bridge the gap between small molecules
`
`and biologics” and have many characteristics that are similar to small-molecules.
`
`EX1309, Abstract. Further, there is no evidence on the record that aptamers would
`
`have been safe in humans. And the only in vivo study in the record with aptamers,
`
`Messlinger, is an abstract that lacks specifics such as controls used or experimental
`
`details for its mouse model. EX1240; EX2272, 115:19-117:7, 118:9-120:24. Dr.
`
`Charles’ blind reliance on Messlinger’s scarce disclosure merely because
`
`- 18 -
`
`

`

`
`
`Case IPR2018-01427
`Patent No. 8,597,649
`
`Messlinger was “widely known as an extremely careful scientist” once again
`
`demonstrates Dr. Charles’ bias in these proceedings. EX2272, 117:8-16, 121:12-
`
`122:6. For example, Dr. Charles “disagreed” with Susan Brain’s conclusion that
`
`CGRP played a cardioprotective role even though the Brain review provided
`
`substantially more evidence than the Messlinger abstract despite Dr. Charles’
`
`admission that Dr. Brain was “a respected person in the field.” EX2272 41:9-12,
`
`43:16-24; EX2003, 915.
`
`In sum, the record lacks any evidence that anti-CGRP antibodies would have
`
`been safe in humans. Lilly has not shown that a POSA would have found such
`
`antibodies “potentially therapeutic” in 2005.
`
`4.
`
`Lilly improperly dismisses safety concerns with
`antagonizing CGRP in migraineurs.
`
`Having failed in its Petition to consider migraine’s comorbidity with stroke
`
`and hypertension, Lilly now attempts to dismiss these concerns by arguing that
`
`they are “legally irrelevant” because “claims at issue do not distinguish between
`
`target patient populations.” Reply, 15. But it was Lilly—not Teva—who
`
`specifically focused on migraine in its Petition as part of its motivation analysis, as
`
`Dr. Charles admitted. Petition, 30-31; EX2192, 73:6-74:11. Thus, safety
`
`considerations of anti-CGRP antibodies in migraine patients are “legally relevant.”
`
`Lilly next argues that such considerations are irrelevant for most migraine
`
`- 19 -
`
`

`

`Case IPR2018-01427
`Patent No. 8,597,649
`
`patients because “the absolute risk” of stroke and myocardial ischemia in young
`
`women is “low.” Reply, 15. But this argument is nothing more than an attempt to
`
`detract from Lilly’s original failure to consider safety of the claimed antibodies in
`
`migraineurs, despite the known link between stroke and migraine. EX2272, 80:1-
`
`82:20; EX2266, 1123. In any event, Dr. Charles’ analysis on the risk to
`
`migraineurs is wrong.
`
`
`
`As Dr. Ferrari explains, it was known that CGRP played a key role in
`
`preventing escalation of mild ischemic events into full-blown infarctions, such as
`
`stroke and heart attacks. EX2141, ¶¶37-47; POR, 10. Dr. Charles attempts to
`
`minimize the importance of CGRP by pointing to the overall rate of stroke or
`
`myocardial infarction in young women w

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket