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`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 No. IPR2018-01711
`Patent No. 9,884,907
`______________________
`
`PETITIONER’S SUPPLEMENTAL BRIEF
`(REGARDING FOX FACTORY, INC. v. SRAM, LLC)
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`
` IPR2018-01711
`Patent No. 9,884,907
`
`Table of Contents
`I.
`Introduction ...................................................................................................... 1
`Legal Standard for Presumption of Nexus ...................................................... 2
`II.
`III. Teva Failed to Meet Its Burden of Establishing that Ajovy® and
`Emgality® Are Coextensive with the Challenged Claims ............................... 3
`A. Unclaimed Sequence and Mutations Materially Impact
`Function ................................................................................................. 3
`Other Unclaimed Features Materially Impact Function ....................... 5
`B.
`IV. No Nexus Exists Outside of the Alleged Presumption .................................... 6
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`i
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`
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`ADCC
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`CDC
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`CDR
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`FDA
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`IPR
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` IPR2018-01711
`Patent No. 9,884,907
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`GLOSSARY
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`Antibody-dependent cellular cytotoxicity
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`Complement-dependent cytotoxicity
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`Complementarity-determining region
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`U.S. Food and Drug Administration
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`Inter partes review
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`Italicized text
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`Emphasis added unless otherwise indicated
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`Lilly or Petitioner Eli Lilly and Company
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`pM
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`picomolar
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`Teva or Patent
`Owner
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`’907 patent
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`’045 patent
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`’614 patent
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`’951 patent
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`’881 patent
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`’794 patent
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`Teva Pharmaceuticals International GmbH
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`U.S. Patent No. 9,884,907
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`U.S. Patent No. 8,586,045 (Ex. 1001 in IPR2018-01710)
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`U.S. Patent No. 9,340,614 (Ex. 1001 in IPR2018-01422)
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`U.S. Patent No. 9,266,951 (Ex. 1001 in IPR2018-01423)
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`U.S. Patent No. 9,346,881 (Ex. 1001 in IPR2018-01424)
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`U.S. Patent No. 8,007,794 (Ex. 2024)
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`ii
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`I.
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` IPR2018-01711
`Patent No. 9,884,907
`
`Introduction
`In Fox Factory, Inc. v. SRAM, LLC, the Federal Circuit reaffirmed and
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`clarified that a patentee bears the burden of establishing a presumption of nexus,
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`which requires demonstrating that a product cited for secondary considerations is
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`“coextensive” with the challenged claims. 944 F.3d 1366, 1373 (Fed. Cir. 2019). The
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`court rejected the patentee’s attempt to broaden the coextensiveness requirement to
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`an inquiry of whether the claims “cover” the cited products. Id. at 1377.
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`For nexus in this case, Teva relied solely on the presumption. Sur-reply, 26-
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`27. Like the patentee in Fox Factory, Teva advanced the legally deficient argument
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`that its claims merely “cover[]” Ajovy® and Emgality®. Id.; POR, 49; Ex. 2272,
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`¶110. Teva failed to satisfy the coextensiveness requirement because these products
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`have numerous features that “materially impact” their functionality but are not
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`recited as limitations in the challenged method-of-treatment claims. Fox Factory,
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`944 F.3d at 1375-76. Indeed, the amino acid sequences of Ajovy® and Emgality®
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`drive their therapeutic properties, i.e., efficacy and safety for treating migraine,
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`which are responsible for Teva’s alleged secondary considerations evidence. All
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`challenged claims, however, broadly recite using antibodies without any requirement
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`for sequence and without any requirement for particular levels of safety and efficacy,
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`let alone those observed for Ajovy® and Emgality®. Thus, Fox Factory confirms that
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`nexus is lacking.
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`1
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`Patent No. 9,884,907
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`II. Legal Standard for Presumption of Nexus
`Fox Factory reaffirmed that a patentee bears the burden of establishing a
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`presumption of nexus. Fox Factory, 944 F.3d at 1373, 1378. If the patentee fails to
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`establish the presumption, the petitioner has no burden of rebuttal. Id. at 1375. When
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`a product is covered by multiple patents, the patentee must also show that the
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`secondary considerations are due to the challenged claims, not other patents. Id.
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`Under Fox Factory, a patentee relying on the presumption must establish that
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`alleged praise or success is (1) “tied to a specific product” and (2) the product is
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`“coextensive” with the challenged claims. 944 F.3d at 1373. There, the patentee
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`relied on the success of thirteen bicycle chainring products “embody[ing]” the
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`challenged patent. Id. at 1370. The court, however, found a lack of coextensiveness
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`because the products’ performance (i.e., improved chain retention) was materially
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`impacted by features not recited as limitations, such as an 80% gap-filling feature
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`that had been specifically claimed in a different patent. Id. at 1375-76, 1378.
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`In holding the presumption inapplicable, the court did not require the
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`unclaimed features (e.g., 80% gap-filling) to be specifically identified in industry
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`praise or the sole basis for commercial success. Rather, the presumption did not
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`apply because patentee failed to meet its burden of establishing that those unclaimed
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`features were “insignificant” to the chainring products’ functionality. Id. at 1375-76.
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`Accordingly, Fox Factory demonstrates that no presumption of nexus applies
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`2
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`Patent No. 9,884,907
`to overbroad genus claims that fail to recite, as limitations, features materially
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`impacting the properties of a product cited for secondary considerations. See
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`Celltrion, Inc. v. Genentech, Inc., IPR2017-01374, Paper 85 at 48 (PTAB Nov. 29,
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`2018) (holding that an FDA-approved antibody drug having specific mutations
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`lacked nexus to broader sub-genus claims encompassing other mutations).
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`III. Teva Failed to Meet Its Burden of Establishing that Ajovy® and
`Emgality® Are Coextensive with the Challenged Claims
`The challenged method-of-treatment claims do not reference safety and do not
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`require clinical efficacy, much less the levels of efficacy that supported FDA
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`approval for Ajovy® and Emgality®. Pet., 20-22; Reply, 2-3. Multiple unclaimed
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`features materially impact the therapeutic properties of these antibody drugs,
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`demonstrating that they are not coextensive with Teva’s overbroad genus claims.
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`A. Unclaimed Sequence and Mutations Materially Impact Function
`Even one unclaimed feature that materially impacts a product’s functionality
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`prevents any presumption of nexus. Fox Factory, 944 F.3d at 1375. Here, the
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`sequences of Ajovy® and Emgality®, not recited in any challenged claim, drive their
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`therapeutic properties (i.e., efficacy and safety). Teva cannot meet its burden of
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`proving that sequence is insignificant to Ajovy® and Emgality® and their ability to
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`safely and effectively treat migraine by antagonizing CGRP.
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`The materiality of amino acid sequence to an antibody’s function and its
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`therapeutic properties is universally recognized. E.g., Ex. 1062, 41; Ex. 1063, 63
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`Patent No. 9,884,907
`(“the amino acid sequences … determine the shape and ionic properties of the
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`
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`antigen-binding site” and “define the specificity of an antibody”); MorphoSys AG v.
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`Janssen Biotech Inc., 358 F. Supp. 3d 354, 366 (D. Del. Jan. 25, 2019) (small
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`sequence changes can dramatically affect antibody properties). Indeed, the parties’
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`experts agree that sequence dictates function. Ex. 1017, ¶¶19, 40 (Dr. Vasserot:
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`CDRs have hypervariable sequences and are “critical” for antigen binding);
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`Ex. 1301, 81:11-22 (Dr. Tomlinson: CDRs “are responsible” for binding properties).
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`Ajovy® and Emgality® have specific amino acid sequences that are critical for
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`their therapeutic function. For example, Teva represented to the FDA that multiple
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`mutations were introduced into Ajovy® that materially impact properties including
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`binding affinity, e.g., to residues 99 and 100. Ex. 1320, 8-9 (“A99L” and “R100A”);
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`Ex. 1301, 115:9-116:9. Binding affinity materially impacts efficacy and safety.
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`Ex. 1017, ¶¶40, 55; Ex. 1023, 2:12-27 (affinity is “critical[]” to biological function).
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`Teva also represented to the FDA that specific mutations were introduced into
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`Ajovy®’s sequence to eliminate ADCC and CDC, i.e., its ability to kill cells.
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`Ex. 1320, 8-9 (“A330S” and “P331S”); Ex. 1301, 116:11-21. Killing cells is an
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`undesired side effect for antibodies used to antagonize CGRP in treating migraine,
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`and thus these disabling mutations also “materially impact” safety and efficacy.
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`Ex. 1017, ¶¶117, 127-128; Ex. 1016, ¶¶178, 190-191; Ex. 1062, 43; Ex. 2098, 646.
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`Emgality® similarly contains mutations eliminating ADCC and CDC. Ex. 2216, 17.
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`4
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`Patent No. 9,884,907
`No presumption applies because none of the challenged claims are limited to
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`
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`using antibodies having any particular sequences, let alone sequences with the
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`functionality-conferring mutations of Ajovy® and Emgality®. Fox Factory, 944 F.3d
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`at 1375-76; Celltrion, IPR2017-01374, Paper 85 at 48. A huge number of individual
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`mutations—20220—can be made to the amino acid sequence in an antibody’s variable
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`region, and the challenged claims exclude none of them. Ex. 1301, 91:25-92:22.
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`The materiality of sequence is further illustrated by Teva claiming specific
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`sequences in a separate, unchallenged patent. Fox Factory, 944 F.3d at 1377-78.
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`Teva represented that the unchallenged ’794 patent “protect[s]” Ajovy®. Ex. 2272,
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`81 n.5; Ex. 2168, 4. Claims 3 and 5 of the ’794 patent recite SEQ ID NO: 1, which
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`includes the affinity-conferring A99L and R100A mutations. Ex. 2024, col. 73 (SEQ
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`ID NO 1). Claim 7 is limited to a heavy chain produced from Accession No. PTA-
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`6867, which includes the mutations to residues 330 and 331 that eliminate ADCC
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`and CDC. Id., 58:3-17. Lilly also did not challenge the sequence-specific treatment
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`claims of the ’045 patent, or similar claims of the ’614, ’951, and ’881 patents.
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`B. Other Unclaimed Features Materially Impact Function
`As in Fox Factory, more unclaimed features materially impact the therapeutic
`
`properties of Ajovy® and Emgality®, further rendering the presumption inapplicable.
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`Binding affinity materially impacts an antibody’s efficacy and safety.
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`Ex. 1017, ¶¶40, 55; Ex. 1023, 2:12-27; Ex. 1266, 521 (Dr. Tomlinson: “[a]n ideal
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`5
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`Patent No. 9,884,907
`drug would have … very high affinity”). But while Ajovy® and Emgality® have pM-
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`range affinities, all challenged claims contain no affinity limitation whatsoever. Dr.
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`Tomlinson admitted that the 2 pM and 31 pM affinities of these products “do not
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`represent” the range of affinities covered by the claims. Ex. 1301, 101:15-104:19.
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`Antibody subclass also materially impacts function. Ex. 1016, ¶178;
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`Ex. 2272, ¶29; Ex. 1058, 100. IgG1 and IgG3, encompassed by the claims, have
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`robust cytotoxicity (ADCC and CDC). Ex. 1301, 112:5-115:1; Ex. 1017, ¶¶26, 44;
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`Ex. 1073, 121-122. The subclasses of Ajovy® and Emgality® (IgG2 and IgG4), by
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`contrast, display only modest cytotoxicity. Ex. 1062, 43. Both antibodies were
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`further mutated to eliminate even this cytotoxicity, as cell-death is problematic and
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`undesired in a migraine treatment. Ex. 1320, 8-9; Ex. 2216, 17; Ex. 1016, ¶¶178,
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`190-191. Dr. Tomlinson admitted that he is unaware of anyone ever successfully
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`making an FDA-approved antibody using IgG3. Ex. 1301, 34:9-35:1, 114:19-115:1.
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`Accordingly, differences in sequence, affinity, and antibody subclass would
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`lead to materially different therapeutic properties as compared to Ajovy® and
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`Emgality®. Reply, 21-24. Notably, even these antibodies have fundamental
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`differences in treating headache: Emgality® is FDA-approved to treat cluster
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`headache while Ajovy® failed in that indication. Ex. 2153, 1; Ex. 1304, 74:17-75:12.
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`IV. No Nexus Exists Outside of the Alleged Presumption
`Any belated attempt to contend that the beneficial properties of using Ajovy®
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`Patent No. 9,884,907
`or Emgality® are attributable to the ’907 patent claims is waived and should be
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`rejected. Sur-reply, 26-27 (relying solely on the presumption). Indeed, Teva’s expert
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`conceded that the only property he considered was the ability to “block the CGRP
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`pathway,” which was a mechanism already known in the art to treat migraine and
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`thus cannot support nexus. Reply, 23-24; Ex. 1304, 142:1-8. Teva also has not shown
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`that treatments with other antibodies (e.g., with different sequences and worse
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`properties) would perform “in the same manner” as Ajovy® or Emgality®, as
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`required. Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 963 (Fed. Cir. 2014).
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`Furthermore, any reliance on the cited products as representative “species”
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`fails. Even 300 antibodies are not representative of a functionally defined genus like
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`Teva’s challenged claims here. AbbVie Deutschland GmbH v. Janssen Biotech, Inc.,
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`759 F.3d 1285, 1291-92, 1301 (Fed. Cir. 2014); Celltrion, IPR2017-01374, Paper 85
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`at 45, 48 (a small number of species is “inadequate proof” for nexus). Moreover, in
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`contrast to the claims in Fox Factory and Celltrion, which recited structural features
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`relevant to functionality (and also involved up to thirteen cited products), Teva’s vast
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`challenged claims lack any function-conferring structure and encompass an
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`unfathomable number of amino acid sequences. Fox Factory, 944 F.3d at 1369-70;
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`Celltrion, IPR2017-01374, Paper 85 at 48. Thus, Teva failed to prove nexus.
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`Respectfully submitted,
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`Date: January 24, 2020
`
`By: / William B. Raich /
`William B. Raich (Reg. No. 54,386)
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`7
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` IPR2018-01711
`Patent No. 9,884,907
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`CERTIFICATE OF SERVICE
`The undersigned certifies that a copy of the foregoing Petitioner’s
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`Supplemental Brief was served electronically via email on January 24, 2020, in
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`its entirety on the following:
`
`Deborah A. Sterling
`Robert C. Millonig
`Gaby L. Longsworth
`Jeremiah B. Frueauf
`Olga A. Partington
`Dennies Varughese
`STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`dsterling-PTAB@sternekessler.com
`bobm-PTAB@sternekessler.com
`glongs-PTAB@sternekessler.com
`jfrueauf-PTAB@sternekessler.com
`opartington-PTAB@sternekessler.com
`dvarughe-PTAB@sternekessler.com
`
`
`Patent Owner has consented to service by email.
`
`
`
`
`
`
`
`By: / William Esper /
`William Esper
`Litigation Legal Assistant
`
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER, LLP
`
`
`
`
`Date: January 24, 2020
`
`
`
`
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