`
`
`
`
`
`
`
`
`
`
`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. IPR2018-01426
`Patent No. 9,890,211 B2
`______________________
`
`PETITIONER’S SUPPLEMENTAL BRIEF
`(REGARDING FOX FACTORY , INC. v. SRAM, LLC)
`
`
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`
`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
`
`i
`
`
`
`
`
`
`
`
`
`
`ADCC
`
`CDC
`
`CDR
`
`FDA
`
`IPR
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`
`GLOSSARY
`
`Antibody-dependent cellular cytotoxicity
`
`Complement-dependent cytotoxicity
`
`Complementarity-determining region
`
`U.S. Food and Drug Administration
`
`Inter partes review
`
`Italicized text
`
`Emphasis added unless otherwise indicated
`
`Lilly or Petitioner Eli Lilly and Company
`
`pM
`
`picomolar
`
`Teva or Patent
`Owner
`
`’211 patent
`
`’614 patent
`
`’951 patent
`
`’881 patent
`
`’794 patent
`
`Teva Pharmaceuticals International GmbH
`
`U.S. Patent No. 9,890,211
`
`U.S. Patent No. 9,340,614 (Ex. 1001 in IPR2018-01422)
`
`U.S. Patent No. 9,266,951 (Ex. 1001 in IPR2018-01423)
`
`U.S. Patent No. 9,346,881 (Ex. 1001 in IPR2018-01424)
`
`U.S. Patent No. 8,007,794 (Ex. 2024)
`
`ii
`
`
`
`
`
`I.
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`
`Introduction
`In Fox Factory, Inc. v. SRAM, LLC, the Federal Circuit reaffirmed and
`
`clarified that a patentee bears the burden of establishing a presumption of nexus,
`
`which requires demonstrating that a product cited for secondary considerations is
`
`“coextensive” with the challenged claims. 944 F.3d 1366, 1373 (Fed. Cir. 2019). The
`
`court rejected the patentee’s attempt to broaden the coextensiveness requirement to
`
`an inquiry of whether the claims “cover” the cited products. Id. at 1377.
`
`For nexus in this case, Teva relied solely on the presumption. Sur-reply, 25.
`
`Like the patentee in Fox Factory, Teva advanced the legally deficient argument that
`
`its claims merely “cover[]” Ajovy® and Emgality®. Id., 25-26; POR, 51-52;
`
`Ex. 2226, ¶114; Paper 69, 63. Teva failed to satisfy the coextensiveness requirement
`
`because these products have numerous features that “materially impact” their
`
`functionality but are not recited as limitations. Fox Factory, 944 F.3d at 1375-76.
`
`Indeed, it is undisputed that the specific, optimized sequences of Ajovy® and
`
`Emgality® materially impact their function, but the challenged claims do not claim
`
`any of the optimized sequences and instead broadly recite antibodies without any
`
`requirement for amino acid sequence. Thus, Fox Factory further confirms that nexus
`
`is lacking for Teva’s purported secondary considerations.
`
`II. Legal Standard for Presumption of Nexus
`Fox Factory reaffirmed that a patentee bears the burden of establishing a
`
`1
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`presumption of nexus. Fox Factory, 944 F.3d at 1373, 1378 (citing WMS Gaming
`
`
`
`Inc. v. Int’l Game Tech., 184 F.3d 1339, 1359 (Fed. Cir. 1999)). If the patentee fails
`
`to establish the presumption, the petitioner has no burden of rebuttal. Id. at 1375.
`
`When a product is covered by more than one patent, the patentee has the burden to
`
`show that the secondary considerations are due to the challenged claims rather than
`
`the other patents. Id. (citing Therasense, Inc. v. Becton, Dickinson & Co., 593 F.3d
`
`1289, 1299 (Fed. Cir. 2010)).
`
`In Fox Factory, the nexus deficiency arose from overbroad genus claims, not
`
`the inclusion of a claimed part within a whole product. The patentee established that
`
`thirteen bicycle chainring products were “covered” by the claims, and the secondary
`
`considerations evidence pertained to those chainrings (not larger products like
`
`bicycles, cranksets, or drivetrains). Id. at 1371. Those chainring products, however,
`
`contained multiple features that “materially impact[ed]” their functionality but were
`
`not recited as limitations in the challenged claims. Id. at 1375-76. Nexus could not
`
`be presumed because the claims were not limited to those material features—and
`
`thus were not coextensive with the chainring products. Id.
`
`Fox Factory’s adherence to the coextensiveness requirement parallels other
`
`requirements for secondary considerations. For example, when a patentee fails to
`
`establish that other embodiments within the scope of the claims would perform “in
`
`the same manner” as a cited product, nexus is likewise lacking due to overbroad
`
`2
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`claiming. Allergan, Inc. v. Apotex Inc., 754 F.3d 952, 963 (Fed. Cir. 2014).
`
`
`
`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
`
`prevents application of a presumption of nexus. Fox Factory, 944 F.3d at 1375. Here,
`
`the specific sequences of Ajovy® and Emgality®, represented to FDA as materially
`
`impacting function, defeat Teva’s presumption of nexus argument.
`
`The materiality of amino acid sequence to antibody function is universally
`
`recognized. E.g., Ex. 1062, 41; Ex. 1063, 63 (“the amino acid sequences …
`
`determine the shape and ionic properties of the antigen-binding site” and “define the
`
`specificity of an antibody”); MorphoSys AG v. Janssen Biotech Inc., 358 F. Supp. 3d
`
`354, 366 (D. Del. Jan. 25, 2019) (small sequence changes can dramatically affect
`
`antibody function). Indeed, the parties’ experts agree that amino acid sequence
`
`dictates antibody functionality. Ex. 1013, ¶¶20, 41 (Dr. Vasserot: CDRs have
`
`hypervariable sequences and are “critical” for antigen binding); Ex. 1301, 81:11-22
`
`(Dr. Tomlinson: CDRs “are responsible” for binding properties).
`
`Ajovy® and Emgality® have specific amino acid sequences that are critical for
`
`their function. For example, Teva represented to the FDA that multiple mutations
`
`were introduced into Ajovy® that materially impact properties including binding
`
`affinity, e.g., to residues 99 and 100. Ex. 1320, 8-9 (“A99L” and “R100A”); Ex.
`
`3
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`1301, 115:9-116:9. Binding affinity materially impacts functionality. E.g., Ex. 1013,
`
`
`
`¶69; Ex. 1023, 2:12-27 (affinity is “critical[]” for an antibody’s biological function).
`
`Teva also represented to the FDA that specific mutations were introduced into
`
`Ajovy®’s sequence to eliminate ADCC and CDC, i.e., its ability to kill cells. Ex.
`
`1320, 8-9 (“A330S” and “P331S”); Ex. 1301, 116:11-21. Similarly, Emgality®
`
`contains mutations at residues 233 and 234 eliminating ADCC and CDC. Ex. 2216,
`
`17. Killing cells is undesired for antibodies used to antagonize CGRP in treating
`
`migraine, and thus these disabling mutations also “materially impact” functionality.
`
`Ex. 1013, ¶¶139, 149-150; Ex. 1012, ¶¶167, 178-179; Ex. 1062, 43; Ex. 2098, 646.
`
`No presumption of nexus applies because the challenged claims do not recite
`
`any amino acid sequences, let alone sequences with the functionality-conferring
`
`mutations of Ajovy® and Emgality®. See Fox Factory, 944 F.3d at 1375-76;
`
`Celltrion, Inc. v. Genentech, Inc., IPR2017-01374, Paper 85 at 48 (PTAB Nov. 29,
`
`2018) (an antibody drug with specific mutations lacks nexus to broader sub-genus
`
`claims encompassing other mutations). Indeed, Dr. Tomlinson admitted that an
`
`unfathomable number of individual mutations—20220—can be made to the amino
`
`acid sequence in the variable region of an antibody, none of which are excluded by
`
`the challenged claims. Ex. 1301, 91:25-92:22.
`
`The materiality of sequence is further illustrated by Teva claiming specific
`
`sequences in a separate, unchallenged patent. Fox Factory, 944 F.3d at 1377;
`
`4
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`Therasense, 593 F.3d at 1299. For example, Teva represented that the unchallenged
`
`
`
`’794 patent, directed to specific sequences, “protect[s]” Ajovy®. Ex. 2226, 84 n.2;
`
`Ex. 2168, 4. Claims 3 and 5 of the ’794 patent recite SEQ ID NO: 1, which includes
`
`the affinity-conferring A99L and R100A mutations discussed above. Ex. 2024, col.
`
`73 (SEQ ID NO 1). Claim 7 is limited to a heavy chain produced from Accession
`
`No. PTA-6867, which includes the mutations to residues 330 and 331 that eliminate
`
`ADCC and CDC. Id., 58:3-17. Lilly also did not challenge the sequence-specific
`
`claims of the ’614, ’951, and ’881 patents.
`
`B. Other Unclaimed Features Materially Impact Function
`Like in Fox Factory, numerous other features encompassed by the claims but
`
`not recited as limitations—pM-level binding affinity, antibody format, and antibody
`
`class—also materially impact the functionality of Ajovy® and Emgality®, preventing
`
`application of any presumption of nexus. 944 F.3d at 1375-76.
`
`Binding affinity materially impacts functionality. Ex. 1013, ¶¶41, 69; Ex.
`
`1023, 2:12-27; Ex. 1266, 521 (Dr. Tomlinson: “[a]n ideal drug would have … very
`
`high affinity”). But while Ajovy® and Emgality® have pM-range binding affinities,
`
`the challenged claims encompass affinities up to 10 nM. Dr. Tomlinson admitted
`
`that the 2 pM and 31 pM affinities of these products “do not represent” the affinities
`
`(i.e., 5,000-fold range) covered by the claims. Ex. 1301, 103:16-104:19.
`
`Antibody subclass further materially impacts antibody performance. Ex.
`
`5
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`1012, ¶167; Ex. 2226, ¶25; Ex. 1058, 100; supra § III.A. Subclasses IgG1 and IgG3,
`
`
`
`encompassed by the claims, have robust cytotoxicity (ADCC and CDC). Ex. 1301,
`
`112:5-115:1; Ex. 1013, ¶¶27, 45; Ex. 1073, 121-122. Ajovy® and Emgality®, by
`
`contrast, are IgG2 and IgG4 antibodies, respectively, which display modest
`
`cytotoxicity. Ex. 1320, 8; Ex. 2216, 17; Ex. 1062, 43. Both antibodies were further
`
`mutated to eliminate even this cytotoxicity, as cell-death is problematic and
`
`undesired in a migraine treatment. Ex. 1320, 9; Ex. 2216, 17; Ex. 1012, ¶¶167, 178-
`
`179. Notably, Dr. Tomlinson admitted that he is unaware of anyone ever successfully
`
`making an FDA-approved antibody using IgG3. Ex. 1301, 34:9-35:1, 114:19-115:1.
`
`IV. No Nexus Exists Outside of the Alleged Presumption
`Teva made no attempt to meet its burden of proving that the above-described
`
`antibody features are “insignificant” or that nexus applies outside of the
`
`presumption. Fox Factory, 944 F.3d at 1374-75; Sur-reply, 25. Any such argument
`
`is waived. Moreover, in briefing, Lilly specifically identified each of these features
`
`as materially affecting antibody functionality. Reply, 21-23. Instead of substantively
`
`responding, Teva relied solely on the presumption of nexus, arguing only that the
`
`claims “cover” Ajovy® and Emgality®. Sur-reply, 25-26; Ex. 2226, ¶114. Fox
`
`Factory confirms that Teva’s approach is legally insufficient.
`
`Any belated attempt to contend that the properties of Ajovy® or Emgality® are
`
`attributable to the ’211 patent claims—as opposed to the unclaimed material features
`
`6
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`detailed above—should be rejected. Teva’s expert conceded that the only property
`
`
`
`he considered was the ability to “block the CGRP pathway,” which was already
`
`known in the art and thus cannot support nexus. Reply, 23-24; Ex. 1304, 142:1-8.
`
`Moreover, Teva has not shown that other humanized antibodies (e.g., with worse
`
`affinities and different sequences, types, subtypes, or fragments) would behave “in
`
`the same manner” as Ajovy® or Emgality®, as required. Allergan, 754 F.3d at 963.
`
`V. The Alder License Further Demonstrates Lack of Nexus
`Teva offered no technical analysis of whether Alder’s antibody is covered by
`
`the claims. Instead, for nexus, Teva merely argues that a license agreement includes
`
`the ’211 patent. POR, 52, 60-61. But that license broadly includes 188 patents spread
`
`across 8 patent families, and Alder’s payments under the agreement will not change
`
`even if all challenged claims are held unpatentable. Reply, 26-27; Ex. 2257, 20-28;
`
`Ex. 1302, 45:20-46:19, 179:14-180:19. Thus, Teva has not met its burden of
`
`establishing that the Alder antibody is covered by the ’211 patent (much less
`
`coextensive), or that the limitations of the other 187 licensed patents are immaterial.
`
`VI. Conclusion
`The record shows that Teva has not met its burden of proving nexus, which
`
`the Federal Circuit’s recent decision in Fox Factory further confirms.
`
`Respectfully submitted,
`
`Date: January 13, 2020
`
`By: / William B. Raich /
`William B. Raich (Reg. No. 54,386)
`
`
`
`7
`
`
`
`
`
`
`
` IPR2018-01426
`Patent No. 9,890,211
`
`CERTIFICATE OF SERVICE
`The undersigned certifies that a copy of the foregoing Petitioner’s
`
`Supplemental Brief was served electronically via email on January 13, 2020, in
`
`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 13, 2020
`
`
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
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.
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.
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
