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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. IPR2018-01425
`Patent No. 9,890,210 B2
`______________________
`
`PETITIONER’S SUPPLEMENTAL BRIEF
`(REGARDING FOX FACTORY , INC. v. SRAM, LLC)
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` IPR2018-01425
`Patent No. 9,890,210
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`Table of Contents
`I.
`Introduction ...................................................................................................... 1
`Legal Standard for Presumption of Nexus ...................................................... 1
`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
`V.
`The Alder License Further Demonstrates Lack of Nexus ............................... 7
`VI. Conclusion ....................................................................................................... 7
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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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` IPR2018-01425
`Patent No. 9,890,210
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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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`’210 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. 9,890,210
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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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` IPR2018-01425
`Patent No. 9,890,210
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`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, 25.
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`Like the patentee in Fox Factory, Teva advanced the legally deficient argument that
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`its claims merely “cover[]” Ajovy® and Emgality®. Id.; POR, 45; Ex. 2225, ¶102;
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`Paper 69, 63. Teva failed to satisfy the coextensiveness requirement because these
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`products have numerous features that “materially impact” their functionality but are
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`not recited as limitations. Fox Factory, 944 F.3d at 1375-76. Indeed, it is undisputed
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`that the specific, optimized sequences of Ajovy® and Emgality® materially impact
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`their function, but the challenged claims do not claim any of the optimized sequences
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`and instead broadly recite antibodies without any requirement for amino acid
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`sequence. Thus, Fox Factory further confirms that nexus is lacking for Teva’s
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`purported secondary considerations.
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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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`Patent No. 9,890,210
`presumption of nexus. Fox Factory, 944 F.3d at 1373, 1378 (citing WMS Gaming
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`Inc. v. Int’l Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999)). If the patentee fails
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`to establish the presumption, the petitioner has no burden of rebuttal. Id. at 1375.
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`When a product is covered by more than one patent, the patentee has the burden to
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`show that the secondary considerations are due to the challenged claims rather than
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`the other patents. Id. (citing Therasense, Inc. v. Becton, Dickinson & Co., 593 F.3d
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`1289, 1299 (Fed. Cir. 2010)).
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`In Fox Factory, the nexus deficiency arose from overbroad genus claims, not
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`the inclusion of a claimed part within a whole product. The patentee established that
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`thirteen bicycle chainring products were “covered” by the claims, and the secondary
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`considerations evidence pertained to those chainrings (not larger products like
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`bicycles, cranksets, or drivetrains). Id. at 1371. Those chainring products, however,
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`contained multiple features that “materially impact[ed]” their functionality but were
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`not recited as limitations in the challenged claims. Id. at 1375-76. Nexus could not
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`be presumed because the claims were not limited to those material features—and
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`thus were not coextensive with the chainring products. Id.
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`Fox Factory’s adherence to the coextensiveness requirement parallels other
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`requirements for secondary considerations. For example, when a patentee fails to
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`establish that other embodiments within the scope of the claims would perform “in
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`the same manner” as a cited product, nexus is likewise lacking due to overbroad
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`2
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`Patent No. 9,890,210
`claiming. Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 963 (Fed. Cir. 2014).
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`III. Teva Failed to Meet Its Burden of Establishing that Ajovy® and
`Emgality® Are Coextensive with the Challenged Claims
`A. Unclaimed Sequence and Mutations Materially Impact Function
`Even one unclaimed feature that materially impacts a product’s functionality
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`prevents application of a presumption of nexus. Fox Factory, 944 F.3d at 1375. Here,
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`the specific sequences of Ajovy® and Emgality®, represented to FDA as materially
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`impacting function, defeat Teva’s presumption of nexus argument.
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`The materiality of amino acid sequence to antibody function is universally
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`recognized. E.g., Ex. 1062, 41; Ex. 1063, 63 (“the amino acid sequences …
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`determine the shape and ionic properties of the antigen-binding site” and “define the
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`specificity of an antibody”); MorphoSys AG v. Janssen Biotech Inc., 358 F. Supp. 3d
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`354, 366 (D. Del. Jan. 25, 2019) (small sequence changes can dramatically affect
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`antibody function). Indeed, the parties’ experts agree that amino acid sequence
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`dictates antibody functionality. Ex. 1011, ¶¶19, 40 (Dr. Vasserot: CDRs have
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`hypervariable sequences and are “critical” for antigen binding); Ex. 1301, 81:11-22
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`(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 function. For example, Teva represented to the FDA that multiple mutations
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`were introduced into Ajovy® that materially impact properties including binding
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`affinity, e.g., to residues 99 and 100. Ex. 1320, 8-9 (“A99L” and “R100A”); Ex.
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`3
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`Patent No. 9,890,210
`1301, 115:9-116:9. Binding affinity materially impacts functionality. E.g., Ex. 1023,
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`2:12-27 (affinity is “critical[]” for an antibody’s 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. Ex.
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`1320, 8-9 (“A330S” and “P331S”); Ex. 1301, 116:11-21. Similarly, Emgality®
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`contains mutations at residues 233 and 234 eliminating ADCC and CDC. Ex. 2216,
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`17. Killing cells is undesired for antibodies used to antagonize CGRP in treating
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`migraine, and thus these disabling mutations also “materially impact” functionality.
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`Ex. 1011, ¶¶111, 121-122; Ex. 1010, ¶¶152, 163-164; Ex. 1062, 43; Ex. 2098, 646.
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`No presumption of nexus applies because the challenged claims do not recite
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`any amino acid sequences, let alone sequences with the functionality-conferring
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`mutations of Ajovy® and Emgality®. See Fox Factory, 944 F.3d at 1375-76;
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`Celltrion, Inc. v. Genentech, Inc., IPR2017-01374, Paper 85 at 48 (PTAB Nov. 29,
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`2018) (an antibody drug with specific mutations lacks nexus to broader sub-genus
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`claims encompassing other mutations). Indeed, Dr. Tomlinson admitted that an
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`unfathomable number of individual mutations—20220—can be made to the amino
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`acid sequence in the variable region of an antibody, none of which are excluded by
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`the challenged claims. 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;
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`4
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`Patent No. 9,890,210
`Therasense, 593 F.3d at 1299. For example, Teva represented that the unchallenged
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`’794 patent, directed to specific sequences, “protect[s]” Ajovy®. Ex. 2225, 74-75
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`n.1; 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 discussed above. Ex.
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`2024, col. 73 (SEQ ID NO 1). Claim 7 is limited to a heavy chain produced from
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`Accession No. PTA-6867, which includes the mutations to residues 330 and 331 that
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`eliminate ADCC and CDC. Id., 58:3-17. Lilly also did not challenge the sequence-
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`specific claims of the ’614, ’951, and ’881 patents.
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`B. Other Unclaimed Features Materially Impact Function
`Like in Fox Factory, numerous other features encompassed by the claims but
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`not recited as limitations—pM-level binding affinity, antibody format, and antibody
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`class—also materially impact the functionality of Ajovy® and Emgality®, preventing
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`application of any presumption of nexus. 944 F.3d at 1375-76.
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`Binding affinity materially impacts an antibody’s functionality. Ex. 1011, ¶40;
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`Ex. 1023, 2:12-27; Ex. 1266, 521 (Dr. Tomlinson: “[a]n ideal drug would have …
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`very high affinity”). But while Ajovy® and Emgality® have pM-range binding
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`affinities, the claims contain no affinity limitation whatsoever. Dr. Tomlinson
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`admitted that the 2 pM and 31 pM affinities of these products “do not represent” the
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`range of affinities covered by the claims. Ex. 1301, 103:16-104:19.
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`Antibody subclass further materially impacts antibody performance. Ex.
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`5
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`Patent No. 9,890,210
`1010, ¶152; Ex. 2225, ¶25; Ex. 1058, 100; supra § III.A. Subclasses IgG1 and IgG3,
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`encompassed by the claims, have robust cytotoxicity (ADCC and CDC). Ex. 1301,
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`112:5-115:1; Ex. 1011, ¶¶26, 44; Ex. 1073, 121-122. Ajovy® and Emgality®, by
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`contrast, are IgG2 and IgG4 antibodies, respectively, which display modest
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`cytotoxicity. Ex. 1320, 8; Ex. 2216, 17; Ex. 1062, 43. Both antibodies were further
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`mutated to eliminate even this cytotoxicity, as cell-death is problematic and
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`undesired in a migraine treatment. Ex. 1320, 9; Ex. 2216, 17; Ex. 1010, ¶¶152, 163-
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`164. Notably, 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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`IV. No Nexus Exists Outside of the Alleged Presumption
`Teva made no attempt to meet its burden of proving that the above-described
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`antibody features are “insignificant” or that nexus applies outside of the
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`presumption. Fox Factory, 944 F.3d at 1374-75; Sur-reply, 25. Any such argument
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`is waived. Moreover, in briefing, Lilly specifically identified each of these features
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`as materially affecting antibody functionality. Reply, 21-22. Instead of substantively
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`responding, Teva relied solely on the presumption of nexus, arguing only that the
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`claims “cover” Ajovy® and Emgality®. Sur-reply, 25; Ex. 2225, ¶102. Fox Factory
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`confirms that Teva’s approach is legally insufficient.
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`Any belated attempt to contend that the properties of Ajovy® or Emgality® are
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`attributable to the ’210 patent claims—as opposed to the unclaimed material features
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`6
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`Patent No. 9,890,210
`detailed above—should be rejected. Teva’s own expert conceded that the only
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`property he considered was the ability to “block the CGRP pathway,” which was
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`already known in the art and thus cannot support nexus. Reply, 23; Ex. 1304, 142:1-
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`8. Moreover, Teva has not shown that other humanized antibodies (e.g., with worse
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`affinities and different sequences, types, subtypes, or fragments) would behave “in
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`the same manner” as Ajovy® or Emgality®, as required. Allergan, 754 F.3d at 963.
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`V. The Alder License Further Demonstrates Lack of Nexus
`Teva offered no technical analysis of whether Alder’s antibody is covered by
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`the claims. Instead, for nexus, Teva merely argues that a license agreement includes
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`the ’210 patent. POR, 45, 53-54. But that license broadly includes 188 patents spread
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`across 8 patent families, and Alder’s payments under the agreement will not change
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`even if all challenged claims are held unpatentable. Reply, 26; Ex. 2257, 20-28; Ex.
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`1302, 45:20-46:19, 179:14-180:19. Thus, Teva has not met its burden of establishing
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`that the Alder antibody is covered by the ’210 patent (much less coextensive), or that
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`the limitations of the other 187 licensed patents are immaterial.
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`VI. Conclusion
`The record shows that Teva has not met its burden of proving nexus, which
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`the Federal Circuit’s recent decision in Fox Factory further confirms.
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`Respectfully submitted,
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`Date: January 13, 2020
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`By: / William B. Raich /
`William B. Raich (Reg. No. 54,386)
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`7
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` IPR2018-01425
`Patent No. 9,890,210
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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 13, 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.
`
`
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`
`
`By: / William Esper /
`William Esper
`Litigation Legal Assistant
`
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER, LLP
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`Date: January 13, 2020
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