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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`PHARMACYCLICS LLC,
`Patent Owner.
`
`__________________
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`__________________
`
`PATENT OWNER’S SUR-REPLY
`
`
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`
`III.
`
`B.
`
`C.
`
`I.
`II.
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`Claim Construction .......................................................................................... 2
`A.
`Petitioner Disregards the Intrinsic Record ............................................ 2
`B.
`Petitioner Is Wrong on the Law ............................................................ 4
`Petitioner Has Not Demonstrated that the Challenged Claims Are
`Anticipated ....................................................................................................... 6
`A.
`Claims 4, 13, and 15, and Claims Depending Therefrom, Are
`Not Anticipated (Steroid-Resistant/Refractory Claims) ....................... 7
`The ’085 Publication Does Not Anticipate the Recited Clinical
`Efficacies (Claims 6-8, 29-31, 44-46, and 51-53) ................................. 9
`Petitioner Has Not Rebutted the Non-Enablement of the ’085
`Publication (All Claims) ...................................................................... 12
`IV. Petitioner Has Not Demonstrated that the Challenged Claims Are
`Obvious .......................................................................................................... 15
`A. Ground 2: the ’085 Publication in view of a POSA’s knowledge ...... 16
`B.
`Ground 3: the ’085 Publication in view of Shimabukuro-
`Vornhagen and Herman ...................................................................... 19
`1.
`Petitioner fails to address numerous facts negating a
`reasonable expectation of success ............................................. 19
`Petitioner oversimplifies and mischaracterizes the state of
`the art ......................................................................................... 20
`Ground 4: the ’085 Publication in view of Shimabukuro-
`Vornhagen and Uckun ......................................................................... 22
`Petitioner Fails to Counter Objective Indicia of Nonobviousness ................ 25
`A.
`Petitioner Does Not Rebut the Nexus Between the Challenged
`Claims and the Objective Evidence .................................................... 25
`
`2.
`
`C.
`
`V.
`
`i
`
`

`

`
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`B.
`
`Petitioner Fails to Rebut Evidence Demonstrating
`Nonobviousness ................................................................................... 26
`
`ii
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`

`

`
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Allergan, Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ............................................................................ 4
`Allergan Sales LLC v. Sandoz, Inc.,
`935 F.3d 1370 (Fed. Cir. 2019) ................................................................ 3, 4, 5, 6
`Bristol-Meyers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ...................................................................... 5, 11
`In re Copaxone Consolidated Cases,
`906 F.3d 1013 (Fed. Cir. 2018) ............................................................................ 5
`
`Donghee Am., Inc. v. Plastic Omnium Advanced Innovation &
`Research,
`IPR2017-01605, Paper 43 (PTAB Dec. 11, 2018) ............................................. 13
`Ferrum Ferro Capital, LLC v. Allergan Sales, LLC,
`IPR2015-00858, Paper 10 (PTAB Sept. 21, 2015) ............................................... 5
`Forest Labs., LLC v. Sigmapharm Labs., LLC,
`918 F.3d 928 (Fed. Cir. 2019) ............................................................................ 26
`Fox Factory, Inc. v. SRAM, LLC,
`944 F.3d 1366 (Fed. Cir. 2019) .......................................................................... 25
`Galderma Labs., L.P. v. Teva Pharm. USA, Inc.,
`799 F. App’x 838 (Fed. Cir. 2020) ..................................................................... 10
`Hewlett-Packard Co. v. Mustek Sys., Inc.,
`340 F.3d 1314 (Fed. Cir. 2003) .......................................................................... 11
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) ............................................................................ 3
`Impax Labs., Inc. v. Aventis Pharms., Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) .......................................................................... 14
`
`iii
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`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`Impax Labs., Inc. v. Aventis Pharms. Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .......................................................................... 14
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) ............................................................................ 4
`King Pharm., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .................................................................... 10, 11
`LA Biomedical Research Inst. v. Eli Lilly & Co,
`849 F.3d 1049 (Fed. Cir. 2017) .................................................................... 4, 5, 6
`Minton v. Nat’l Assoc. of Sec. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) ............................................................................ 4
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .................................................................... 11, 12
`Mylan v. Aventis,
`IPR2016-00712, Paper 112 (PTAB Oct. 22, 2019) .............................................. 5
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) ............................................................................ 8
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd.,
`851 F.3d 1270 (Fed. Cir. 2017) ............................................................................ 8
`Novartis Pharms. Corp. v. West-Ward Pharms. Int’l,
`923 F.3d 1051 (Fed. Cir. 2019) .......................................................................... 20
`OSI Pharms., LLC v. Apotex Inc.,
`939 F.3d 1375 (Fed. Cir. 2019) .......................................................................... 24
`Packers Plus Energy Servs. Inc. v. Baker Hughes Oilfield Operations, LLC,
`IPR2016-01000, Paper 34 (PTAB Nov. 6, 2017) ............................................... 12
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 10
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ............................................................................ 8
`
`iv
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`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`Sanofi Mature IP v. Mylan Labs. Limited,
`757 F. App’x 988 (Fed. Cir. 2019) ....................................................................... 4
`
`
`
`
`
`
`v
`
`

`

`
`
`’604 patent
`
`aGVHD
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`BTK
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`cGVHD
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`CLL
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`FDA
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`IL-10
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`IL-6R
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`IPR
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`GLOSSARY
`
`U.S. Patent No. 9,795,604
`
`Acute graft versus host disease
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`Bruton’s tyrosine kinase
`
`Chronic graft versus host disease
`
`Chronic lymphocytic leukemia
`
`Food and Drug Administration
`
`Interleukin 10
`
`Interleukin 6 receptor
`
`Inter partes review
`
`Italicized text
`
`Emphasis added unless otherwise indicated
`
`ITK
`
`NIH
`
`Interleukin-2-inducible T cell kinase
`
`National Institutes of Health
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`Patent Owner
`
`Pharmacyclics LLC
`
`Petitioner
`
`Sandoz Inc.
`
`POSA
`
`SLL
`
`TNFα
`
`Person of ordinary skill in the art
`
`Small lymphocytic lymphoma
`
`Tumor necrosis factor alpha
`
`vi
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`

`

`
`I.
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`Introduction
`It would be unprecedented, on this trial record, to hold the challenged claims
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`unpatentable. Petitioner ignores or mischaracterizes swaths of evidence. And the
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`dispositive fact—undisputed by Petitioner—is that ibrutinib was completely
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`untested and unstudied for cGVHD, an exceedingly difficult disease to treat.
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`Petitioner’s attempt to disregard the claimed treatment limitations ignores the
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`specification and prosecution history. Contrary to Petitioner’s contention, these
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`limitations were added during prosecution and successfully argued to overcome
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`multiple rejections, including anticipation and obviousness. Under settled law, they
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`must be given patentable weight.
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`Ground 1, Petitioner’s anticipation theory, fails. Under the correct
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`construction, the ’085 Publication does not describe the claimed efficacy limitations,
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`expressly or inherently. Further, as the Board correctly determined at institution,
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`the ’085 Publication does not describe treating steroid-resistant/refractory cGVHD
`
`patients. Claims reciting these particularly difficult-to-treat patients therefore are
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`not anticipated (irrespective of claim construction).
`
`Separately, Ground 1 fails for all claims because Petitioner has not met its
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`burden of proving that the ’085 Publication enables treating cGVHD. Petitioner
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`presents no evidence on this point, while Dr. Koreth, a cGVHD specialist from Dana-
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`1
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`

`

`
`Farber Cancer institute, cites numerous references and explains specifically why
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`the ’085 Publication does not enable the claimed methods.
`
`Grounds 2-4, Petitioner’s obviousness theories, fail because none of the other
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`references fills the deficiencies of the ’085 Publication. Nor does Petitioner prove a
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`reasonable expectation of success. Instead of engaging with the trial record,
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`Petitioner disregards the failures plaguing the field and the complexity and
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`unpredictability of the disease. No challenged claim should be held unpatentable.
`
`II. Claim Construction
`Petitioner Disregards the Intrinsic Record
`A.
`Petitioner’s construction rests on the false premise that “the applicant never
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`relied on the efficacy limitations for patentability.” Reply, 5.
`
`During prosecution, the applicant amended claim 1 to recite treating cGVHD,
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`both in the preamble (“method of treating chronic graft versus host disease
`
`(GVHD)”) and as a separately recited method step (“thereby treating the graft versus
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`host disease”). EX1009, 2-3; EX2055, ¶82. The applicant argued this amendment
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`conferred patentability because Izumi—a prior-art reference disclosing BTK
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`inhibitors (including ibrutinib) for hematopoietic stem cell transplantation—did not
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`“teach or suggest treating GVHD.” EX1009, 9; EX1021, 12-13; EX2027, Example
`
`1. The applicant further argued that a POSA “would not have reasonably expected”
`
`that these prior-art BTK inhibitors “would have been effective treatments of
`
`2
`
`

`

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`GVHD.” EX1009, 9. The Examiner thereafter withdrew anticipation, obviousness,
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`and enablement rejections in view of these amendments and arguments. EX2030,
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`4. Because cGVHD treatment was central to claim allowance, these limitations must
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`be given patentable weight. E.g., Allergan Sales LLC v. Sandoz, Inc., 935 F.3d 1370,
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`1376 (Fed. Cir. 2019) (efficacy limitations must be given weight when they “were
`
`expressly relied on to define the claimed methods and distinguish them from the
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`prior art”).
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`Petitioner also nowhere discusses the specification and its incontrovertible
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`focus on treating patients with cGVHD. POR, 10 (citing EX1001, 1:29-46; 28:48-
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`29:51; 38:38-45; 40:55-64; 42:29-33; 71:42-67; 72:2-73:28). Indeed, Petitioner’s
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`only mention of the intrinsic record is to argue that the specific efficacy limitations
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`of the dependent claims (e.g. partial or complete responses) were added “after the
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`Examiner allowed the claims.” Reply, 5. But Petitioner does not explain (and cites
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`no law in support) how this somehow erases the specification’s focus on treatment,
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`negates the prosecution exchange amending the claims and relying on actual
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`treatment, or eliminates the more specific and measurable efficacy limitations of
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`these dependent claims, which further define and narrow the treatment limitations
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`central to allowance. E.g., Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329-30 (Fed.
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`Cir. 2005) (“whereby” clause given weight because it was “an integral part of the
`
`invention” as shown by the specification and prosecution history); Allergan Sales,
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`3
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`

`

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`935 F.3d at 1376 (“[H]aving reviewed the intrinsic evidence, we are persuaded that
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`the ‘wherein’ clauses are material to patentability and thus limiting.”); cf. Minton v.
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`Nat’l Assoc. of Sec. Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003) (giving
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`limitation no weight when “nothing in the specification or the prosecution history
`
`suggests otherwise”).
`
`Petitioner also ignores entirely the preamble of claim 1, which recites a
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`“method of treating chronic graft versus host disease (GVHD).” Reply, 2. At a
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`minimum, this preamble requires Petitioner to show a reasonable expectation that
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`administering ibrutinib would effectively treat patients with cGVHD. See, e.g.,
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`Sanofi Mature IP v. Mylan Labs. Limited, 757 F. App’x 988, 992-993 (Fed. Cir.
`
`2019); Jansen v. Rexall Sundown, Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003).
`
`Petitioner Is Wrong on the Law
`B.
`Petitioner argues that the efficacy limitations should be ignored because
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`“[w]hat happens after administration is a result of the drug’s biological effect on the
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`disease.” Reply, 4. This is not the law. Numerous Federal Circuit and Board
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`decisions hold that efficacy limitations deserve patentable weight in precisely this
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`circumstance. E.g. Allergan Sales, 935 F.3d at 1373-76 (giving efficacy limitations
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`patentable weight where treatment results from the drug’s biological effect on the
`
`disease); LA Biomedical Research Inst. v. Eli Lilly & Co., 849 F.3d 1049, 1060-62
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`(Fed. Cir. 2017) (same); Allergan, Inc. v. Sandoz, Inc., 726 F.3d 1286, 1294 (Fed.
`
`4
`
`

`

`
`Cir. 2013) (same); Ferrum Ferro Capital, LLC v. Allergan Sales, LLC, IPR2015-
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`00858, Paper 10, at 5-8 (PTAB Sept. 21, 2015) (same); Mylan v. Aventis, IPR2016-
`
`00712, Paper 112, at 12-14 (PTAB Oct. 22, 2019) (same).
`
`Petitioner’s cited cases do not govern. Regarding BMS (Reply, 3), Petitioner
`
`ignores critical facts central to its conclusion not present here: (i) the limitations at
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`issue were irrelevant to allowance, (ii) the limitations were duplicative of other
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`claim elements, and (iii) the patentee argued the limitations were not limiting for
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`purposes of infringement. Bristol-Meyers Squibb Co. v. Ben Venue Labs., Inc., 246
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`F.3d 1368, 1374-76 (Fed. Cir. 2001); POR, 13-14. Indeed, the Federal Circuit has
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`repeatedly distinguished BMS for these same reasons. E.g. LA Biomedical, 849 F.3d
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`at 1060-62; Allergan Sales, 935 F.3d at 1380 (J. Prost, concurring) (“Sandoz’s
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`reliance on Bristol-Meyers Squibb is therefore misplaced.”).
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`Petitioner’s newly cited case, In re Copaxone Consolidated Cases (Reply, 3-
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`4), supports Patent Owner. Petitioner points only to the first part of the decision,
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`which addresses “superfluous” claim language dissimilar to the specific and
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`measurable efficacy limitations of the ’604 patent. 906 F.3d 1013, 1023 (Fed. Cir.
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`2018). Petitioner ignores the second part of the Copaxone decision, clarifying that
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`efficacy limitations akin to those in the ’604 patent must be considered in analyzing
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`obviousness. Id. at 1029 (giving patentable weight to “wherein” and “thereby” claim
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`5
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`

`

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`limitations requiring “improved tolerability,” “reduced frequency,” and “reduced
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`severity” in evaluating obviousness).
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`Finally, Petitioner fails to counter Patent Owner’s cited cases, addressing only
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`two of over ten cited. See POR, 5-16. Regarding Allegan Sales, Petitioner’s only
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`argument is based on the incorrect assertion, discussed above, that the efficacy
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`limitations were not relied on during prosecution. Reply, 4-5. Regarding LA
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`Biomedical, Petitioner crop-quotes the decision to imply that “wherein” clauses are
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`generally not given patentable weight (Reply, 5), though the quoted sentence says
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`no such thing (849 F.3d at 1061). Moreover, LA Biomedical makes clear that
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`limitations akin to those here should be given patentable weight: they are “drafted
`
`as part of a separate step of the method.” Id. Petitioner’s only other point—that LA
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`Biomedical was “different from cases in which the claims contain express dosage
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`amounts” (Reply, 5)—applies only to a subset of dependent claims. Like the claims
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`in LA Biomedical, the vast majority of challenged claims (e.g. claims 1, 4, 13, and
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`15) instead require administering a “therapeutically effective amount.” These
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`treatment limitations should similarly be given patentable weight.
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`III. Petitioner Has Not Demonstrated that the Challenged Claims Are
`Anticipated
`At institution, the Board correctly found that the steroid-resistant/refractory
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`claims are not anticipated. Further, as discussed below and in Patent Owner’s
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`6
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`

`

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`Response, when the efficacy limitations are given patentable weight, no claim is
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`anticipated. The ’085 Publication also does not enable the challenged claims.1
`
`A. Claims 4, 13, and 15, and Claims Depending Therefrom, Are
`Not Anticipated (Steroid-Resistant/Refractory Claims)
`Petitioner initially relied on the knowledge of the POSA to allege that the ’085
`
`Publication discloses the steroid-resistant/refractory subpopulations of claims 4, 13,
`
`and 15. Pet., 38-39. The Board correctly determined this was improper, finding
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`the ’085 Publication does not describe a method of
`
`treating steroid-
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`resistant/refractory patients. Paper 8, 20-21. Petitioner now changes its theory,
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`pointing to two newly-cited paragraphs to allege anticipation. Reply, 9-10.
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`These paragraphs similarly fail to describe steroid-resistant/refractory
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`patients. Indeed, neither paragraph uses the terms steroids or cGVHD. Nor do they
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`recite treating any disease resistant to a drug therapy—let alone the particularly
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`difficult to treat subpopulations of patients with steroid-resistant/refractory cGVHD.
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`EX1002, ¶¶[0121], [0124]. Newly cited ¶[0124] is directed to potential drug
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`combinations, disclosing an extensive laundry list of drugs and drug categories. Id.,
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`¶[0124]. Newly cited ¶[0121] is directed to unspecified combination therapies for
`
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`1 Petitioner incorrectly states the POR addresses Ground 1 only at pages 53-56.
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`Reply, 6. Ground 1 is also addressed at pages 16-17, 20-21, and 50-51.
`
`7
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`

`

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`unspecified diseases, and references sequential administration. Id., ¶[0121]. From
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`this, Petitioner makes the unsupported leap that this co-administration includes
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`administration of ibrutinib to cGVHD patients when steroids fail. Reply, 10. But
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`nowhere in the ’085 Publication is it articulated that ibrutinib is administered when
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`one of the multitude of drugs listed in ¶[0124] fails to treat cGVHD (or any other
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`disease). Nor does it describe the various claimed subcategories of steroid-resistant
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`patients. EX2055, ¶136.
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`Thus, Petitioner’s argument fails for multiple reasons.
`
` Petitioner
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`impermissibly (1) picks and chooses from multiple laundry lists of potential diseases
`
`and potential drug combinations;
`
`(2)
`
`interprets, based on an expert’s
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`“understanding” (not the reference’s description) that certain listed drugs are steroids
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`that could be used in combination with ibrutinib for GVHD (EX2056, 212:8-13);
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`and (3) concocts multiple “categories of patients” (i.e., steroid-dependent, steroid-
`
`resistant, or refractory patients) nowhere disclosed using the knowledge of the POSA
`
`(Pet., 38-39). Reply, 9-10; Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369,
`
`1371 (Fed. Cir. 2008); Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.
`
`Ltd., 851 F.3d 1270, 1274-75 (Fed. Cir. 2017). Indeed, a combination therapy is
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`incontrovertibly different than treating, as Petitioner described, a patient for whom
`
`steroids did not work. Pet. 38; Perricone v. Medicis Pharm. Corp., 432 F.3d 1368,
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`1378-79 (Fed. Cir. 2005) (claims reciting a specific patient type—one with skin
`
`8
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`

`

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`sunburn—not anticipated because prior art merely described administering a cream
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`to skin surfaces).
`
`B.
`
`The ’085 Publication Does Not Anticipate the Recited
`Clinical Efficacies (Claims 6-8, 29-31, 44-46, and 51-53)
`Petitioner initially relied solely on inherency to assert that the ’085 Publication
`
`anticipates the efficacy limitations recited in claims 6-8, 29-31, 44-46, and 51-53.
`
`Pet., 40-41. Now, Petitioner newly argues that the ’085 Publication expressly
`
`describes them. Reply, 10-11. Neither argument is correct.
`
`The challenged claims recite disease-specific clinical efficacies defined in
`
`NIH Guidelines. EX1001, 71:42-49; EX2055, ¶85. For example, a “partial
`
`response” as claimed requires “an objective response in one involved organ with no
`
`evidence of progression elsewhere and no requirements for additional systemic
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`therapy.” EX1001, 71:46-49.
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`Because these efficacy limitations are not described, Petitioner strings
`
`together multiple disparate statements from the ’085 Publication. Reply, 10-11. For
`
`example, citing ¶¶[0004]-[0005], Petitioner states that doses of 420 mg/day were
`
`administered in clinical trials “to obtain the desired therapeutic effect.” Reply, 11,
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`16. But those trials were directed to “patients with CLL and SLL,” not cGVHD.
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`EX1002, ¶¶[0004]-[0005]. Moreover, even for those cancers, no therapeutic effects
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`are reported. Id.
`
`9
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`

`

`Petitioner also cites ¶¶[0117]-[0119] as purportedly describing “the outcomes
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`
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`recited in the dependent claims.” Reply, 11. But these paragraphs make no mention
`
`of any disease, and certainly not the recited patient outcomes.
`
`Petitioner’s inherency argument also fails. The “proper inquiry for inherent
`
`anticipation is whether the claimed efficacy limitations ‘necessarily result’ from
`
`practicing” the prior art. Galderma Labs., L.P. v. Teva Pharm. USA, Inc., 799 F.
`
`App’x 838, 845 (Fed. Cir. 2020); see also Par Pharm., Inc. v. TWi Pharm., Inc., 773
`
`F.3d 1186, 1195 (Fed. Cir. 2014) (“that a certain thing may result from a given set
`
`of circumstances is not sufficient” to establish inherency). Here, Petitioner admits
`
`that treating cGVHD with ibrutinib (in its immediate-release commercial form) leads
`
`to multiple, different possible outcomes. Reply, 12; EX2056, 26:7-27:19.
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`Moreover, Petitioner does not dispute that the prophetic stomach-bypassing
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`formulations of the ’085 Publication had not been made or tested, much less shown
`
`to necessarily treat cGVHD. POR, 13; Reply, 11-12. Because the claimed efficacy
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`limitations do not necessarily occur, they cannot be inherently anticipated.
`
`Petitioner’s cited cases do not support its arguments. In King, the claimed
`
`method, administering metaxalone with food, was widely practiced in the prior art.
`
`King Pharm., Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275-76 (Fed. Cir. 2010).
`
`Although previously unrecognized, the “natural result” flowing from that
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`administration was increased metaxalone bioavailability. Id. at 1276. The court
`
`10
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`

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`concluded increased bioavailability was inherent because “hold[ing] otherwise
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`would remove from the public a method [] that has been performed for decades.”
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`Id. Here, in contrast, ibrutinib had never been administered to treat cGVHD (much
`
`less in the prophetic stomach-bypassing formulations of the ’085 Publication), and
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`the claimed outcomes do not necessarily occur.2
`
`BMS and Montgomery are similarly distinguishable. Both involved patents
`
`claiming newly discovered results achieved from actual prior-art clinical trials.
`
`BMS, 246 F.3d 1368; In re Montgomery, 677 F.3d 1375 (Fed. Cir. 2012). In BMS,
`
`the asserted prior-art reference reported on an actual clinical trial, in cancer patients,
`
`where taxol was administered using the same dosing regimen for the same purpose
`
`as was later-claimed. 246 F.3d at 1372, 1378. In Montgomery, the prior art
`
`described an actual clinical trial involving over 9,500 patients evaluating ramipril in
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`patients at high risk for stroke, the claimed indication. 677 F.3d at 1378. As the
`
`court explained, the prior art was “far from an abstract theory,” instead representing
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`
`2 Petitioner quotes Hewlett-Packard Co. v. Mustek Sys., Inc., 340 F.3d 1314, 1326
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`(Fed. Cir. 2003) for the proposition that the “prior art method need not actually
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`achieve the result every time.” Reply, 11. The cited quote was discussing
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`obviousness, not inherency.
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`11
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`an “advanced stage of testing designed to secure regulatory approval” for the very
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`same indication that was later claimed. Id. at 1382, 1383, n.14.
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`Not so here. The ’085 Publication’s scattershot disclosure of more than 150
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`potential uses is merely aspirational. EX2055, ¶94. It is precisely the type of
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`disclosure that Montgomery distinguished: “a document that recited administration
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`of all known compounds for treatment of all known diseases, with no evidence that
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`any of these treatments would be effective, would not inherently anticipate all
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`method-of-treatment claims involving those compounds and diseases.” 677 F.3d at
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`1382, n.13. Indeed, Petitioner identifies no case finding that a purely aspirational
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`disclosure—let alone a laundry list of potential uses like that in the ’085
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`Publication—inherently anticipates efficacy limitations, and Patent Owner is aware
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`of none.
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`C.
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`Petitioner Has Not Rebutted the Non-Enablement of the ’085
`Publication (All Claims)
`Petitioner relied solely on a presumption that the ’085 Publication was
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`enabled. Pet., 33. In response, Patent Owner presented significant evidence
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`rebutting that presumption (POR, 53-56; EX2055, ¶¶118-132), shifting the burden
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`of production to Petitioner. Packers Plus Energy Servs. Inc. v. Baker Hughes
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`Oilfield Operations, LLC, IPR2016-01000, Paper 34, at 12-13, 22-23, 30 (PTAB
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`Nov. 6, 2017). Petitioner has not met that burden.
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`12
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`Petitioner first argues Patent Owner’s “only” argument is that the ’085
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`Publication is “directed ‘only’ to formulations.” Reply, 7. While the ’085
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`Publication is plainly directed to formulations (EX1002, title), Patent Owner
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`additionally established, with expert testimony and prior art, that: cGVHD was
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`exceedingly difficult to treat; numerous drugs had failed clinically; and the ’085
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`Publication included no disclosure from which a POSA would understand how to
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`treat cGVHD with ibrutinib. POR, 53-56; EX2055, ¶¶118-132. Patent Owner
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`further showed that the ’085 Publication does not teach orally administering 420
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`mg/day for cGVHD (claims 24, 28, 35, 39, 43, 50 and 55). POR, 50-52.
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`Instead of responding to this evidence, Petitioner intones the ’085 Publication
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`“describes formulations and their use in treating disease,” such as by “explicitly
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`disclos[ing] methods of treating diseases—including GVHD—using ibrutinib.”
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`Reply, 7-8. But as Dr. Koreth explained, the sparse disclosure of the ’085
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`Publication would not enable a POSA to treat cGVHD patients with ibrutinib without
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`undue experimentation. EX2055, ¶¶118-132.
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`On that dispositive point, Petitioner provides no evidence whatsoever. Cf.
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`Donghee Am., Inc. v. Plastic Omnium Advanced Innovation & Research, IPR2017-
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`01605, Paper 43, at 33-39 (PTAB Dec. 11, 2018). The most Petitioner contends is
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`that the ’085 Publication discloses “both preclinical and clinical data about
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`ibrutinib.” Reply, 9. But the referenced clinical trials and dosages are for different
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`diseases, not cGVHD, and the referenced preclinical bioavailability data merely
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`reflects blood levels in rats, not treatment of any disease. EX2055, ¶127. Petitioner
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`never attempts to show how these limited disclosures would enable a POSA to
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`administer ibrutinib to treat cGVHD patients. Dr. Ferrara’s declaration is entirely
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`silent on this point.
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`Petitioner also attempts to distinguish the Impax decisions, but those support
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`Patent Owner. Reply, 8-9. In Impax I, the Federal Circuit remanded to the district
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`court to determine whether the prior art enabled treating a specific disease with a
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`specific compound. Impax Labs., Inc. v. Aventis Pharms., Inc., 468 F.3d 1366, 1383
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`(Fed. Cir. 2006). On remand, the court concluded that the prior art was not enabled,
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`and in Impax II the Federal Circuit affirmed. Impax Labs., Inc. v. Aventis Pharms.
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`Inc., 545 F.3d 1312, 1315 (Fed. Cir. 2008). Petitioner’s attempt to distinguish
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`Impax II ignores that the court faulted the prior art for multiple reasons. Like
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`the ’085 Publication, the prior art merely provided a long list of potential diseases
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`for treatment, lacked working examples, and included broad and non-specific dosing
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`guidelines not correlated with any disease. 545 F.3d at 1315-16.3
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`3 Patent Owner does not, as Petitioner contends, require working examples or
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`proof of efficacy. Reply, 8; POR, 54-55. An anticipatory reference, however,
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`IV. Petitioner Has Not Demonstrated that the Challenged Claims Are
`Obvious
`Petitioner fails to dispute, or outright admits, dispositive facts: (1) cGVHD
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`pathogenesis was poorly understood, involving a “complex milieu” of different cell
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`types and signaling pathways; (2) steroid-resistant/refractory cGVHD patients were
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`especially difficult to treat given their immunocompromised and heterogenous
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`status; (3) there was a litany of prior-art failures; and (4) despite the unpredictable
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`state of the art, none of ibrutinib, any structurally related molecule, or any BTK
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`inhibitor had been studied in cGVHD, much less steroid-resistant/refractory
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`cGVHD. Reply, 14-23; see POR, 23-24, 26-27; EX2055, ¶¶147-150. Given these
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`uncontroverted facts, and the additional reasons below, Petitioner fails to show that
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`the challenged claims are obvious.
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`Notably, Petitioner states that Patent Owner addressed Grounds 2-4 only for
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`claims 1, 4, 13, and 15. Reply, 14, 18, 21. Not so—Patent Owner addressed
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`Grounds 2-4 for all challenged claims, including “clinical efficacy” claims 6-8, 29-
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`31, 44-46, and 51-53 (POR, 16-20) and “420 mg daily dose” claims 24, 28, 35, 39,
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`must provide some disclosure demonstrating that ibrutinib—untested and
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`unstudied in cGVHD—is enabled for treating cGVHD patients.
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`15
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`43, 50, and 55 (POR, 50-52). But because Petitioner limited its reply to claims 1, 4,
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`13, and 15 (Reply, 14-23), Patent Owner focuses on those claims below.
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`A. Ground 2: the ’085 Publication in view of a POSA’s
`knowledge
`Because the ’085 Publication fails to describe both chronic GVHD (claim 1)
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`and steroid-resistant/refractory cGVHD (claims 4, 13, and 15), Petitioner relies on
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`the Board’s preliminary determinations that those limitations would have been
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`obvious. Reply, 14, 16. But those determinations were made without the benefit of
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`Dr. Koreth’s testimony, the cross-examination of Dr. Ferrara, and Patent Owner’s
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`response and supporting evidence—which Petitioner ignores or distorts.
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`Petitioner argues that “[a] POSA with that (very high) level of education . . .
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`unquestionably would have been motivated to select GVHD” from among the
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`multitude of diseases identified in the ’085 Publication. Reply, 17. But regardless
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`of the level of skill, the ’085 Publication would not have motivated a POSA to pursue
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`ibrutinib for cGVHD given the lack of relevant data, the multitude of potential
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`alternative targets, and the complexity of the disease. POR, 22-24. Further, to prove
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`obviousness, Petitioner must show that a POSA would have reasonably expected
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`success in using ibrutinib to t