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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`v.
`MERCK SERONO S.A.,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00480
`Patent 7,713,947
`____________________________________________________
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`PATENT OWNER’S SUR-REPLY
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`The Cited Portion Of Bodor Is Not “By Another” .......................................... 2
`
`A.
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`The Burden Did Not Shift To PO.......................................................... 3
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`B. Without Bodor’s 6-Line Regimen, Petitioner’s Sole Ground
`
`Fails ....................................................................................................... 3
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`C.
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`The Only Evidence Shows The Regimen In Bodor Was By
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`Serono .................................................................................................... 4
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`D. Drs. Bodor And Dandiker Did Not Co-Invent the Regimen In
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`Bodor ..................................................................................................... 6
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`III. The Challenged Claims Would Not Have Been Obvious ............................... 8
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`A.
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`Bodor And Stelmasiak Fail To Disclose Or Suggest All Claim
`
`Limitations ............................................................................................. 8
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`1.
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`No Disclosure Or Suggestion Of The Claimed Weight-
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`Based Induction Or Maintenance Dosing ................................... 8
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`2.
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`No Disclosure Or Suggestion Of The Claimed
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`Maintenance Period .................................................................. 10
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`B. No Motivation Or Reasonable Expectation Of Success ..................... 12
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`1.
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`2.
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`Petitioner’s Routine-Optimization Argument Fails .................. 12
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`No Motivation To Start With Bodor’s Dose ............................. 16
`i
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`Petitioner’s Revised Bioavailability Argument Is
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`a)
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`Improper ......................................................................... 16
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`b)
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`Petitioner’s New Bioavailability Argument Fails .......... 19
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`3.
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`No Motivation Or Reasonable Expectation Of Success
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`To Re-Treat After Bodor’s 10-Month Cladribine-Free
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`Period ........................................................................................ 21
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`IV. Objective Indicia Support Non-Obviousness ................................................ 23
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`A.
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`Skepticism ........................................................................................... 23
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`B. Unexpected Results ............................................................................. 25
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`C.
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`Long-Felt, Unmet Need ....................................................................... 26
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`D. Nexus ................................................................................................... 26
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`V.
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`Conclusion .................................................................................................... 28
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`TABLE OF AUTHORITIES
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`
`
`CASES
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ....................................................................... 25
`
`Page(s)
`
`Corephotonics, Ltd. v. Apple Inc.,
`84 F.4th 990 (Fed. Cir. 2023) ........................................................................ 16
`
`Duncan Parking Techs., Inc. v. IPS Grp., Inc.,
`914 F.3d 1347 (Fed. Cir. 2019) ....................................................................... 7
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ....................................................................... 3
`
`Ethicon LLC v. Intuitive Surgical, Inc.,
`847 F. App’x 901 (Fed. Cir. 2021) .................................................................. 3
`
`Ethicon, Inc. v. U.S. Surgical Corp.,
`135 F.3d 1456 (Fed. Cir. 1998) ....................................................................... 5
`
`Fleming v. Escort Inc.,
`774 F.3d 1371 (Fed. Cir. 2014) ....................................................................... 5
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) ..................................................................... 27
`
`Google LLC v. IPA Techs. Inc.,
`34 F.4th 1081 (Fed. Cir. 2022) ........................................................................ 3
`
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) ..................................................................... 16
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..................................................................... 27
`
`In re Matthews.,
`408 F.2d 1393 (C.C.P.A. 1969) ....................................................................... 6
`
`
`
`iii
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`Maxlinear, Inc. v. Cresta Tech. Corp.,
`No. IPR2015-00594, Paper 90 (P.T.A.B. Aug. 15, 2016) ............................... 3
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`Neptune Generics, LLC v. Eli Lilly & Co.,
`921 F.3d 1372 (Fed. Cir. 2019) ..................................................................... 24
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`Novartis AG v. Ezra Ventures LLC,
`909 F.3d 1367 (Fed. Cir. 2018) ....................................................................... 6
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`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) ....................................................... 8
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) ..................................................................... 26
`
`Volvo Penta of the Americas, LLC v. Brunswick Corp.,
`81 F.4th 1202 (Fed. Cir. 2023) ...................................................................... 27
`
`Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc.,
`853 F.3d 1272 (Fed. Cir. 2017) .............................................................. 16, 18
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) ..................................................................... 26
`
`OTHER AUTHORITIES
`
`Manual of Patent Examing Procedure (MPEP) (9th ed. 2022) ................................. 6
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`Patent Trial and Appeal Board Consolidated Trial Practice Guide
`(November 2019) ........................................................................................... 19
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`
`
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`iv
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`
`
`INTRODUCTION1
`Petitioner asks the Board first to find that a POSA would have overlooked
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`I.
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`the field’s overwhelming skepticism of cladribine, including that of its own
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`declarant, Dr. Miller, so that the Board may find the challenged claims obvious
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`over Bodor and Stelmasiak. But Bodor’s regimen was attributable to the ʼ947
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`patent inventors, not “by another”; thus, it is not prior art against the ʼ947 patent.
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`Even if Bodor were prior art, Petitioner’s challenge fails.
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`Petitioner contends the challenged claims encompass flat and weight-based
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`regimens. Reply 11-13. But Petitioner misconstrues the claims. The claims must
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`be read in view of the ’947 specification, which teaches administering cladribine
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`based on patient weight. Ex. 1001, 14:41-44, 14:63-66. While the challenged
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`claims do not expressly recite determining patient weight before drug
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`administration, a POSA would have understood the claims require this when read
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`in view of the specification. Ex. 1061, 144:20-145:3.
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`Further, despite basing its initial obviousness theory on Bodor’s “improved”
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`bioavailability and ignoring Bodor’s bioavailability data (Pet. 23, 33), Petitioner
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`now changes course to argue that “Bodor’s bioavailability was at least comparable
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`to Stelmasiak’s.” Reply 23. Petitioner’s new bioavailability theory and related
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`1 All emphases added.
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`arguments not only contradict its original obviousness theory, but also go beyond
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`the proper scope of reply and should be disregarded.
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`Petitioner also attempts to revise the basis for its flawed routine-optimization
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`argument—from evaluating efficacy (Pet. 41-42) to evaluating “cladribine’s
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`effect” as measured by lymphocyte counts. Reply 26-27. But Petitioner fails to
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`show how lymphocyte count would be linked to any efficacy parameter, or what
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`lymphocyte level a POSA would look to for optimization. Petitioner’s revised
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`routine-optimization argument thus fares no better.
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`Petitioner disregards coherence in outcome measures, and instead cherry-
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`picks outcomes for support. Reply 14. For example, Petitioner focuses on Rice’s
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`MRI outcomes, but ignores that Rice’s study failed to meet its primary and
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`secondary clinical outcome measures such that Rice reported “clinical efficacy was
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`not shown.” Ex. 1018, 1153.
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`Finally, Petitioner disparages objective indicia for allegedly lacking nexus.
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`Reply 31-32. But Petitioner misunderstands the law—objective indicia evidence
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`need only be reasonably commensurate with the claim scope.
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`For at least the foregoing reasons, patentability should be affirmed.
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`II. THE CITED PORTION OF BODOR IS NOT “BY ANOTHER”
`Rather than address the evidence that the ’947 patent inventors developed
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`Bodor’s regimen, Petitioner speculates about others and incorrectly suggests
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`Drs. Bodor and Dandiker co-invented the regimen just because they invented a
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`formulation. Patent Owner’s (“PO’s”) unrebutted evidence shows Bodor’s
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`regimen came from the ’947 patent inventors. The Board should not allow their
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`own work to be used against them.
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`A. The Burden Did Not Shift To PO
`The Board held that “[t]he shifting burden of production is not applicable to
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`[“by another”] analysis under § 102(e).” Maxlinear, Inc. v. Cresta Tech. Corp.,
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`No. IPR2015-00594, Paper 90, at 14 (P.T.A.B. Aug. 15, 2016). Regardless, “the
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`burden of persuasion is on the petitioner to prove” references qualify as prior art,
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`“and that burden never shifts to the patentee.” Dynamic Drinkware, LLC v. Nat’l
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`Graphics, Inc., 800 F.3d 1375, 1378-81 (Fed. Cir. 2015).
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`PO produced substantial, detailed evidence showing the ’947 patent
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`inventors developed Bodor’s regimen and communicated it to at least Dr. Dandiker
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`before February 4, 2004. After that, “the burden of production returned to
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`[Petitioner] to prove that” the cited regimen is “by another.” Id., 1380. Petitioner
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`has not met its burdens of production or persuasion.
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`B. Without Bodor’s 6-Line Regimen, Petitioner’s Sole Ground Fails
`According to the Federal Circuit, at Duncan step 1, the Board must hold a
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`petitioner to the specific disclosures it mapped to each limitation. Ethicon LLC v.
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`Intuitive Surgical, Inc., 847 F. App’x 901, 908-09 (Fed. Cir. 2021); Google LLC v.
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`3
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`IPA Techs. Inc., 34 F.4th 1081, 1086 n.3 (Fed. Cir. 2022) (excluding merely
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`“relevant” citations from Duncan analysis). The 6-line regimen is the only portion
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`of Bodor that Petitioner maps to several limitations, including the induction and
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`maintenance periods—and is the only disclosure from any source mapped to the
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`total doses and cladribine-free period. Pet. 45-52. Petitioner should be held to its
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`exclusive reliance on these 6 lines.
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`Even if the Board considered Petitioner’s immaterial additional citations to
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`Bodor, which Petitioner cited regarding “fine tuning,” motivation to combine, and
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`expectation of success, those portions do not disclose any regimen. Pet. 3, 33, 41-
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`45. Even if “relevance” were enough, those portions do not teach any
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`induction/maintenance period, cladribine-free period, or total doses. Without the
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`6-line regimen, Petitioner has identified nothing teaching these claim limitations.
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`Petitioner’s sole ground fails.
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`C. The Only Evidence Shows The Regimen In Bodor Was By Serono
`Petitioner vaguely speculates that IVAX had approximately 10,000
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`employees who could have developed Bodor’s regimen yet identifies no evidence.
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`Reply 8. The record shows Drs. Bodor and Dandiker did not work on any
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`regimen, let alone one with 6-7 days of dosing. Ex. 2054, ¶26; Ex. 2055, ¶23; see
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`also Ex. 2054, ¶¶11-18; Ex. 2055 ¶¶12-18. Instead, the ’947 patent inventors
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`developed and communicated a regimen to IVAX, including at least Dr. Dandiker.
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`4
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`Ex. 2049; Ex. 2053, ¶¶17-53; Ex. 2048, 17-19; Ex. 2055, ¶¶18, 24-27. The 6-line
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`flat-dosing regimen in Bodor is an (incomplete) excerpt of their disclosure. Ex.
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`1063, 100:2-16; 168:15-169:1; Ex. 2053, ¶48; Ex. 2055, ¶26.
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`Similarly, Petitioner questions Dr. De Luca’s contribution (Reply 6), yet
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`fails to rebut testimony showing Dr. De Luca was part of the Serono team that
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`developed the regimen. Ex. 2053, ¶¶18-22, 34, 40.
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`Dr. Munafo’s testimony is extensively corroborated—by detailed
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`contemporaneous documents (Ex. 2048; 2049; 2050), Drs. Bodor and Dandiker’s
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`testimony (Ex. 2054; Ex. 2055), and the ’947 patent (Ex. 1001). Contrary to
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`Petitioner’s argument, corroboration is judged under the “rule of reason,” so “there
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`need not be corroboration for every factual issue contested by the parties.”
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`Ethicon, Inc. v. U.S. Surgical Corp., 135 F.3d 1456, 1464 (Fed. Cir. 1998);
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`Fleming v. Escort Inc., 774 F.3d 1371, 1377 (Fed. Cir. 2014) (corroboration only
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`requires “evidence that, as a whole, makes credible the testimony of
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`the…inventor”). PO’s corroborating evidence far exceeds Ethicon’s. Ethicon,
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`Inc., 135 F.3d at 1464.
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`In contrast, Petitioner’s theory that unidentified IVAX personnel
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`independently invented the regimen is uncorroborated, unsupported, and
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`contradictory to Petitioner’s only ground. That is, if the flat-dosing regimen in
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`5
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`Bodor is materially different from Serono’s regimen, as Petitioner alleges, then it
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`cannot render the challenged claims’ weight-based doses obvious. Reply 7.
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`D. Drs. Bodor And Dandiker Did Not Co-Invent The Regimen In
`Bodor
`Petitioners do not explain how Drs. Bodor and Dandiker’s involvement in a
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`formulation renders them co-inventors of the dosing regimen. Petitioner’s
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`argument cites no law and is inconsistent with In re Matthews. 408 F.2d 1393,
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`1394-95 (C.C.P.A. 1969) (holding inventors of separate, but related inventions not
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`co-inventors).
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`Serono’s regimen (in Bodor) is distinct from Drs. Bodor and Dandiker’s
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`formulation. A product and process of use are distinct if either can be used
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`without the other. MPEP §806.05(h); see Novartis AG v. Ezra Ventures LLC, 909
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`F.3d 1367, 1372 (Fed. Cir. 2018). Here, Bodor teaches that its formulation can be
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`used to treat different diseases. Ex. 1022, 22:8-26. Further, Bodor (and its issued
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`patents) do not claim the regimen. Id., 40-53; Ex. 2029, 22:16-27:15; Ex. 2069,
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`22:20-26:32; see also Ex. 2054, ¶¶19-25; Ex. 2055, ¶¶19-22.
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`Indeed, the evidence shows that the regimen and formulation were distinct
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`projects developed “in parallel,” (Ex. 1063, 78:9-80:2), and that IVAX’s
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`formulation development was ongoing when the ’947 patent inventors disclosed
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`6
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`their regimen to IVAX. Ex. 2049, 9, 27-34. Serono—not Drs. Bodor and
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`Dandiker—worked on the regimen. Ex. 2054, ¶26; Ex. 2055, ¶23.
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`Even acknowledging Drs. Bodor and Dandiker’s formulation work, any
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`incidental relation to the regimen was not “significant enough…to render [them]
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`joint inventor[s] of the applied portions” of Bodor. Duncan Parking Techs., Inc. v.
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`IPS Grp., Inc., 914 F.3d 1347, 1358 (Fed. Cir. 2019). Petitioner has not shown the
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`formulation work significantly contributed to key aspects of the regimen like the
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`alleged induction period and cladribine-free period. Instead, both testified that
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`they did not “develop[], research[], or invent[] the [cited] dosing regimen...[or] any
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`cladribine dosing regimen for treating MS.” Ex. 2054, ¶26; Ex. 2055, ¶23.
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`Contrary to the excerpt Petitioner quotes out-of-context (Reply 5) Dr. Munafo
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`testified that he knew IVAX’s formulation could have a “hypothetical…effect
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`on…a dosing regimen.” Ex. 1063, 78:5-80:4, 164:11-18. But Serono disclosed its
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`regimen to IVAX before Bodor’s formulation was complete. Ex. 2049, 27-34, 47-
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`51; Ex. 1063, 165:6-14; Ex. 2055, ¶25-27. Petitioner has not shown the
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`formulation changed Serono’s dosing regimen.
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`***
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`The portion of Bodor relied on by Petitioner is not “by another” and
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`Petitioner’s sole ground fails.
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`7
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`III. THE CHALLENGED CLAIMS WOULD NOT HAVE BEEN
`OBVIOUS
`A. Bodor And Stelmasiak Fail To Disclose Or Suggest All Claim
`Limitations
`1.
`No Disclosure Or Suggestion Of The Claimed Weight-Based
`Induction Or Maintenance Dosing
`Petitioner contends the challenged claims encompass both flat and weight-
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`based regimens because “the claims do not require ‘any active, a priori, steps of
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`determining an individual patient’s weight and performing calculations to arrive at
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`a mg/kg dosing before any drug is administered.’” Reply 12 (quoting Paper 10
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`(“DI”), n.17). Petitioner misconstrues the claims. “The claims…do not stand
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`alone” and “must be read in view of the specification.” Phillips v. AWH Corp.,
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`415 F.3d 1303, 1315 (Fed. Cir. 2005) (en banc).
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`The specification explicates the claim term “the total dose of cladribine
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`reached at the end of the [induction/maintenance] period is [from about 1.7 mg/kg
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`to about 3.5 mg/kg/about 1.7 mg/kg].” Ex. 1001, 19:13-30. It states “patients in
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`Groups 2 and 3 receives 3 mg or 10 mg 2-CdA (…depending on the patient’s
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`weight)” and “[e]xamples of administration schemes for the induction period
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`depending on the patient’s weight are given below in Tables 3 and 4[.]” Id.,
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`14:41-44, 14:63-66. Tables 3 and 4 specifically teach using patient-weight ranges
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`to determine the number of cladribine pills to administer. Id., 15:1-45. Further,
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`the specification explains that “[t]he dosage administered…will vary” including
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`based on “body weight.” Id., 5:30-35. The specification thus teaches weight-based
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`dosing.
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`The MAVENCLAD® label, like the challenged claims, does not explicitly
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`instruct determining a patient’s weight to arrive at a mg/kg dose before
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`administration. Ex. 2001, 5 (“[t]he recommended cumulative dosage of
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`MAVENCLAD is 3.5 mg per kg body weight administered orally)…(see Table
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`1).” But it includes a table expressly using patient-weight ranges to determine the
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`number of cladribine pills to give to the patient in accordance with the cumulative
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`mg/kg dosage instruction, similar to the specification. Compare id., with Ex. 1001,
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`Tables 3-4.
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`Even without explicit instructions to determine patient weight, Petitioner’s
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`declarant Dr. Miller testified that the label’s “instructions clearly imply that…
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`somebody had to weigh the patient” and that “[o]f course it’s required that
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`someone weigh the patient. How can you make a dosage by patient weight if
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`somebody doesn’t weigh the patient?” Ex. 2079, 75:20-76:16. Like
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`MAVENCLAD®’s label, the claims are no different. Indeed, Dr. Lublin testified
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`that one must “know a patient’s weight before administering cladribine according
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`to the methods claimed in the ’947 patent.” Ex. 1061, 144:20-145:3. Thus, in
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`view of the specification, a POSA would have understood the challenged claims
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`require determining patient weight to arrive at the claimed mg/kg dosing.
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`In contrast to the challenged claims’ weight-based dosing, Bodor and
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`Stelmasiak only disclose flat dosing. POR 18-24; Ex. 2051, ¶¶18-19, 24, 85-97;
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`Ex. 2052, ¶¶66-77. And Stelmasiak, where patients with different weights
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`received the same dose, cladribine’s effect was not linked to dose in mg/kg—
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`Stelmasiak reported that “[t]here was no indication that a ‘good response’ is related
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`to the actual cladribine dose per body weight.” Ex. 1013, 7.
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`Even Dr. Miller considered MAVENCLAD®’s weight-based dosing
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`“unique” (Ex. 2007, 3:53-4:18; Ex. 2008, 4:17-5:1). Despite Petitioner’s argument
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`that this was limited to “approved MS drugs,” (Reply 13), Petitioner ignores that
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`like Bodor, FDA-approved COPAXONE® had a fixed daily dose (20 mg/day),
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`which Dr. Miller acknowledged did “not vary depending upon the patient’s
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`weight.” Ex. 2009, 124:11-125:1.
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`2.
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`No Disclosure Or Suggestion Of The Claimed Maintenance
`Period
`Petitioner argues a POSA would have re-treated to maintain lymphocyte
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`suppression achieved during an induction period. Reply 20. However, Petitioner
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`fails to show lymphocytes would remain suppressed for the claimed 8-10 months
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`between the induction/maintenance periods or explain why a POSA would have
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`waited 8-10 months to re-treat to maintain lymphocyte suppression.
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`10
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`Only by improperly shifting its obviousness theory to now rely on Rice does
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`Petitioner argue lymphocyte levels would remain suppressed. Reply 26; infra
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`Sections III.B.2, III.B.3. Even then Petitioner’s argument fails: Rice does not
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`show maintaining lymphocyte suppression (<1000 cell/µL) for more than 6 months
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`after the 0.7 mg/kg dosing phase. Ex. 1018, 1152.
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`The art did not suggest the claimed maintenance period 8-10 months after
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`the claimed induction period.
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`First, the prior art demonstrates concerns about cladribine’s safety and
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`retreatment. POR 5-6, 25-27, 30-33; Ex. 2051, ¶¶72-73, 98-101, 113-115.
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`Romine and Rice each set forth hematologic criteria before cladribine could be
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`administered and require disease progression for re-treatment. Ex. 1031, 36, 43;
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`Ex. 1018, 1146-1147. Rice also did not permit re-treatment until at least 12
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`months after the last cladribine dose. Ex. 1018, 1147.
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`Petitioner and Dr. Miller wrongly argue Romine’s “long-term toxicity”
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`discussion is “unrelated to cladribine.” Reply 15; Ex. 1084, ¶57; Ex. 1031, 43-44.
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`But even so, cladribine was not considered safe. As Beutler explained, “the
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`possibility of malignancies occurring long after administration of [cladribine]
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`cannot be dismissed.” Ex. 1014, 1720. Dr. Miller admitted cladribine “raised
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`safety concerns, particularly related to malignancies.” Ex. 2078, 1402; Ex. 2079,
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`143:4-144:9.
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`Second, a POSA would have understood that in 2004, FDA-approved MS
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`treatments were disease-modifying drugs dosed continuously to maintain the
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`drug’s pharmacological effects, efficacy, and safety. POR 27-30; Ex. 2051, ¶¶54-
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`58, 103. Even for natalizumab (dosed 300mg once every four weeks), Dr. Miller
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`admitted “you would not discontinue the medication at any particular point.” Ex.
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`2079, 182:21-183:7. Such continuous administration does not inform whether or
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`when to retreat with cladribine. Ex. 2051, ¶¶102-110. Even accepting Petitioner’s
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`characterization of natalizumab and other drugs (e.g., Ex. 2061) as being dosed
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`“cyclically,” Petitioner fails to explain how cladribine’s pharmacological effects,
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`efficacy, and risks, would have led to re-treatment as claimed. POR 27-30; Ex.
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`2051, ¶20; Reply 20.
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`Third, none of Romine, Rice, or Stelmasiak suggests the claimed
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`maintenance period. POR 30-35. Petitioner’s re-treatment argument ignores the
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`re-treatment criteria of Romine and Rice (including Rice’s timing requirement) and
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`Stelmasiak’s two-month cladribine-free period after its initial 6-month dosing
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`phase.
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`B. No Motivation Or Reasonable Expectation Of Success
`1.
`Petitioner’s Routine-Optimization Argument Fails
`Petitioner previously argued routine-optimization of cladribine dose/dosing
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`length by “evaluating the efficacy” based on “change[s] in a patient’s lymphocyte
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`12
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`count.” Pet. 41-42. But following Dr. Miller’s admission that “[l]ymphocyte
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`suppression is not a measure of efficacy” (Ex. 2009, 121:14-18), Petitioner revised
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`its flawed routine-optimization theory to argue a POSA would have optimized
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`based on “cladribine’s effect”—not efficacy—as measured by lymphocyte counts.
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`Reply 27. To distract from its revised theory, Petitioner alleges that “Merck
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`wrongly posits routine-optimization must correlate with therapeutic efficacy[.]”
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`Id., 2. PO merely responded to Petitioner’s arguments. Nonetheless, the Board
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`understood Petitioner’s argument as based on efficacy: “Petitioner argues[] it was
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`known that cladribine’s dose and length of administration are result-effective
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`variables that could be modified to achieve immunosuppression and therapeutic
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`efficacy, which can be measured, for example, by changes in a patient’s
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`lymphocyte counts.” DI 29; see also id., 30, 40-41, 49.
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`Petitioner’s revised routine-optimization argument remains flawed.
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`First, neither Dr. Miller nor Dr. Lublin considers the “therapeutic” effect of
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`lymphocyte suppression to include efficacy. Ex. 2079, 42:5-14; Ex. 2051, ¶¶21,
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`126, 136-144; see also POR 37-41.
`
`Petitioner argues that “[p]rior studies routinely used lymphocyte counts to
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`measure cladribine’s effect.” Reply 27. Stelmasiak explains, however, and Dr.
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`Miller agrees, that lymphocyte levels are a “hematological side effect” of
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`cladribine. Ex. 1013, 5; Ex. 2009, 37:19-38:9. Dr. Miller admits Rice measured
`13
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`lymphocyte levels for safety and never connected them to clinical or MRI
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`outcomes. Ex. 2009, 34:3-19, 36:5-15.
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`Second, Petitioner fails to show how a change in lymphocyte count would
`
`be linked to any parameter associated with efficacy. Reply 26-27. Dr. Miller
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`admitted that the magnitude of lymphocyte suppression does not necessarily
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`correlate with changes in EDSS, relapse rate, disease progression, or even MRI
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`outcomes. Ex. 2079, 40:10-41:16. Petitioner does not identify any efficacy
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`parameter linked to lymphocyte reduction that would allow for “fine-tuning”
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`dose/dosing length based on lymphocyte count.
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`Third, Petitioner fails to identify what lymphocyte level a POSA would
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`target in “fine-tuning” dose/dosing length or how to do so. Petitioner argues both
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`that suppression to 1000 cells/µL is simply “exemplary,” (Ex. 1084, ¶90), with no
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`“bright-line threshold” (Reply 22, 26) because “any percent [reduction] could be
`
`considered suppression” (Ex. 2079, 44:19-45:15), while simultaneously arguing
`
`the prior art provides guidance on threshold lymphocyte counts. Reply 27.
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`Regardless, absent a clear threshold—which Petitioner has not identified—against
`
`which a POSA could measure a change in lymphocyte count correlating to
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`“cladribine’s effect,” Petitioner cannot explain how a POSA would fine-tune
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`dose/dosing length.
`
`
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`14
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`Fourth, Petitioner fails to show a reasonable expectation of success in
`
`achieving the claimed method via routine-optimization. Ex. 2051, ¶22-23.
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`Petitioner argues “MRI scans can assess a positive treatment response in as little as
`
`6 months” and relapse rates can be “measured over one year.” Ex. 1084, ¶83.
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`Even accepting Petitioner’s 6 months-to-one year argument, this is an extended
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`period of observation for each patient that does not allow for quick and easy “fine-
`
`tuning.” Ex. 2051, ¶127. Petitioner fails to account for sufficient sample size
`
`(including placebo/control) and duration to enable proper assessment of any
`
`outcome. Ex. 1061, 40:8-41:6, 63:6-16. As Dr. Miller admitted, the “trial must be
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`of sufficient duration and numbers.” Ex. 2079, 97:8-98:4; see also Ex. 2051,
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`¶127 (relapses “require long follow-up of large patient numbers”).
`
`Further, Dr. Miller testified that MRI outcomes do not necessarily
`
`demonstrate a treatment effect. Ex. 2009, 19:4-17 (“decrease in T2-lesion volume”
`
`may or may not be “a treatment response to cladribine”); Ex. 2079, 112:1-21 (more
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`gadolinium-enhancing lesions could indicate “the patient is getting better, staying
`
`the same, or getting worse”). As an example, Dr. Miller testified he could not
`
`“draw a firm conclusion” about COPAXONE®’s efficacy from nine months of
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`clinical trial MRI data, as one does not “know for sure” whether “any observed
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`effect is actually the effect of Copaxone, as opposed to just normal progression of
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`the disease.” Ex. 2079, 113:15-116:16, 120:2-5.
`15
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`While Dr. Miller argues that relapse rate can be assessed in a year, he
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`testified that relapse rate is a “flawed” outcome measure with “confounding
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`issues,” including varying definitions of “relapse” subject to investigators’
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`interpretation. Ex. 2079, 91:10-22, 95:4-13, 103:2-20.
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`2.
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`No Motivation To Start With Bodor’s Dose
`a)
`Petitioner’s Revised Bioavailability Argument Is
`Improper
`Petitioner now argues that “Bodor’s bioavailability was at least comparable
`
`to Stelmasiak’s” (Reply 23), having abandoned claims of Bodor’s “improved” or
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`“enhanced” bioavailability. Pet. 3, 13, 23, 33, 43; Ex. 1002, ¶110. But “an IPR
`
`petitioner may not raise in reply ‘an entirely new rationale’ for why a claim would
`
`have been obvious.” Henny Penny Corp. v. Frymaster LLC, 938 F.3d 1324, 1330-
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`31 (Fed. Cir. 2019). To avoid “unfair surprise” to the PO, Petitioner is prohibited
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`from raising a new obviousness theory not preserved in the petition even if the new
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`theory is responsive to the PO’s response or the Board’s institution decision.
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`Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc., 853 F.3d 1272, 1286 (Fed. Cir.
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`2017); Corephotonics, Ltd. v. Apple Inc., 84 F.4th 990, 1002 (Fed. Cir. 2023).
`
`Petitioner’s new bioavailability arguments contradict its original
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`obviousness theory. Dr. Miller initially ignored Bodor’s bioavailability data (Ex.
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`1002, ¶79 (citing the Examples without identifying results)), but nevertheless
`
`
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`16
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`testified a POSA would have understood Bodor’s tablet to have “better
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`bioavailability.” Ex. 2009, 143:15-144:4. According to his first declaration:
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`[A] POSA would have understood Bodor’s oral cladribine tablet to
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`have an increased or enhanced bioavailability compared to earlier oral
`
`solutions…, such as Stelmasiak…a POSA would have understood the
`
`need to administer a lower dose of Bodor’s oral cladribine tablets to
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`achieve the same effect as compared to Stelmasiak’s (and Grieb’s) oral
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`solution.
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`Ex. 1002, ¶110. Confronted with Bodor’s data,2 Petitioner completely changes its
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`interpretation of Bodor’s bioavailability. Reply 23; Ex. 1084, ¶¶15, 60, 91, 94.
`
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`2 Petitioner argues PO misrepresented Bodor’s bioavailability by stating Bodor’s
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`tablets have lower bioavailability than Stelmasiak’s formulation. Reply 16-17; Ex.
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`1080, ¶¶17-18, 68-73; Ex. 1084, ¶¶15, 60. Dr. Miller, however, testified (1) “the
`
`bioavailability that Bodor reports for its 10 milligram tablets is 39.1 or 39.4
`
`percent;” (2) “Liliemark’s oral cladribine saline solution has about 50 percent
`
`bioavailability;” and (3) “Stelmasiak’s oral cladribine…was the same dosage form
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`disclosed by Liliemark.” Ex. 2009, 61:13-18, 58:3-59:4; Ex. 1002, ¶110.
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`According to Dr. Miller then, Bodor’s 10mg tablets have a lower bioavailability
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`than Stelmasiak’s oral formulation.
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`
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`17
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`IPR2023-00480
`U.S. Patent No. 7,713,947
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`Additionally, Dr. Miller now argues that “a POSA would have reasonably
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`
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`expected Bodor’s dose to sufficiently suppress lymphocyte counts, in light of
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`Stelmasiak’s and Rice’s data,” (Ex. 1084, ¶¶91, 94-96; Ex. 2079, 65:13-66:7),
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`altering his opinion that a POSA would not have expected “the same” lymphocyte
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`effects from Bodor’s dose based on Stelmasiak’s data. Ex. 1002, ¶110 (“A POSA
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`would not have expected Bodor’s cladribine tablets to provide the same in vivo
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`lymphocyte profile as Stelmasiak and Grieb report because of Bodor’s ‘improved
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`cladribine absorption’ and ‘higher bioavailability.’”). Petitioner attempts to
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`salvage its obviousness theory by belatedly arguing, for the
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