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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 PRELIMINARY RESPONSE
`
`
`
`

`

`2.
`
`3.
`
`B.
`
`
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`I.
`II.
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`Background and State of the Art ..................................................................... 4
`A.
`Chronic Graft Versus Host Disease Was Poorly Understood and
`Difficult to Treat .................................................................................... 4
`1.
`Treating cGVHD Was Unpredictable and Difficult at the
`Time of Invention........................................................................ 5
`The Role of B Cells and Inflammatory Cytokines in the
`Pathogenesis of cGVHD Was Poorly Understood ..................... 7
`Attempts to Develop Second-Line Treatments for
`cGVHD Failed ............................................................................ 9
`Imbruvica® Is the First and Only FDA-Approved Treatment for
`cGVHD ................................................................................................ 11
`III. The ’604 Patent and Its Prosecution History ................................................. 12
`A.
`The Specification and Claims ............................................................. 12
`B.
`Prosecution History ............................................................................. 14
`IV. Petitioner’s Asserted References ................................................................... 15
`A.
`’085 Publication (Ex. 1002) ................................................................ 15
`B.
`Shimabukuro-Vornhagen (Ex. 1003) .................................................. 17
`C.
`Herman (Ex. 1004) .............................................................................. 18
`D. Uckun (Ex. 1005) ................................................................................ 19
`Person of Ordinary Skill in the Art ................................................................ 19
`V.
`VI. Claim Construction ........................................................................................ 20
`
`i
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`A.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`B.
`C.
`
`“A Method of Treating Chronic Graft Versus Host Disease
`(GVHD)” and “Thereby Treating the Chronic GVHD in the
`Patient” ................................................................................................ 20
`“Therapeutically Effective Amount” .................................................. 24
`“Partial Response,” “Complete Response,” and “Severity of the
`GVHD is Reduced” ............................................................................. 26
`VII. Petitioner Has Not Established a Reasonable Likelihood of Prevailing
`as to Any Challenged Claim .......................................................................... 26
`A. Ground 1: Petitioner Has Not Demonstrated that the ’085
`Publication Anticipates the Challenged Claims .................................. 26
`1.
`The ’085 Publication Is Non-Enabling ..................................... 27
`a.
`The nature of the invention / relative level of skill ........ 28
`b.
`The state and unpredictability of the prior art ................ 28
`c.
`The quantity of experimentation / the lack of
`direction or guidance / the absence of working
`examples ......................................................................... 30
`Petitioner’s cited cases are inapposite ............................ 33
`d.
`The ’085 Publication Does Not Expressly or Inherently
`Disclose Multiple Claim Elements ........................................... 34
`Petitioner’s Anticipation Challenge Resorts to
`Impermissible Picking and Choosing ....................................... 39
`Ground 2: The Challenged Claims Are Not Obvious Over
`the ’085 Publication in View of a POSA’s Knowledge in the
`Art ........................................................................................................ 41
`1.
`Claim 1 Would Not Have Been Obvious.................................. 42
`2.
`The Additional Challenged Claims Would Not Have
`Been Obvious ............................................................................ 45
`a.
`Claims 4, 13, and 15 ....................................................... 45
`
`2.
`
`3.
`
`B.
`
`ii
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`
`
`b.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`C.
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`Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, and
`53 .................................................................................... 46
`Claims 9 and 10 .............................................................. 47
`c.
`Claims 24, 28, 35, 39, 43, 50, and 55 ............................. 48
`d.
`Ground 3: The Challenged Claims Are Not Obvious Over
`the ’085 Publication, Shimabukuro-Vornhagen, and Herman ............ 49
`1.
`Claim 1 Would Not Have Been Obvious.................................. 50
`2.
`The Additional Challenged Claims Would Not Have
`Been Obvious ............................................................................ 55
`a.
`Claims 4, 13, and 15 ....................................................... 55
`b.
`Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, and
`53 .................................................................................... 56
`Claims 9 and 10 .............................................................. 56
`c.
`Claims 24, 28, 35, 39, 43, 50, and 55 ............................. 57
`d.
`D. Ground 4: The Challenged Claims Are Not Obvious Over
`the ’085 Publication, Shimabukuro-Vornhagen, and Uckun .............. 57
`Objective Indicia of Nonobviousness ................................................. 60
`1.
`Long-felt, Unmet Need ............................................................. 61
`2.
`Industry Praise ........................................................................... 62
`3.
`Failures of Others ...................................................................... 63
`VIII. The Board Should Deny the Petition Based on its Discretion Under
`§ 314(a) .......................................................................................................... 63
`IX. Conclusion ..................................................................................................... 66
`
`E.
`
`iii
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`

`
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`TABLE OF AUTHORITIES
`
`Cases
`Aqua Prods., Inc. v. Matal,
`872 F.3d 1290 (Fed. Cir. 2017) (en banc) .......................................................... 33
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .................................................................... 41, 44
`Bicon, Inc. v. Straumann Co.,
`441 F.3d 945 (Fed. Cir. 2006) ............................................................................ 20
`Biodelivery Scis. Int’l, Inc. v. Aquestive Therapeutics, Inc.,
`IPR2015-00165, Paper 91 (PTAB Feb. 7, 2019) ................................................ 65
`Biofrontera Inc. v. DUSA Pharms, Inc.,
`IPR2018-01585, Paper 10 (PTAB Feb. 26, 2019) .............................................. 65
`Bristol-Meyers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .......................................................................... 24
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .................................................................... 38-39
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) .................................................... 63
`In re Depomed Patent Litig.,
`No. 13-4507, 2016 WL 7163647 (D.N.J. Sep. 30, 2016) ................................... 27
`
`Donghee Am., Inc. v. Plastic Omnium Advanced Innovation and
`Research, IPR2017-01605, Paper 43 (PTAB Dec. 11, 2018) ............................ 27
`E-One, Inc., v. Oshkosh Corp.,
`IPR2019-00161, Paper 16 (PTAB May 15, 2019) ............................................. 64
`Edwards Lifesci. Corp. v. Boston Scientific Scimed, Inc.,
`IPR2017-01298, Paper 8 (PTAB Oct. 25, 2017) ................................................ 36
`Endo Pharms. Inc. v. Watson Labs. Inc.,
`No. 2:13-cv-192, 2014 WL 2859349 (E.D. Tex. June 23, 2014) ....................... 23
`
`iv
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 48
`Gen. Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sep. 6, 2017) ................................................ 65
`GlaxoSmithKline LLC, v. Fibrogen, Inc.,
`IPR2016-01315, Paper 11 (PTAB Jan. 11, 2017) .............................................. 38
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) .......................................................................... 26
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) ......................................................... 20-21, 23-24
`Impax Labs., Inc. v. Aventis Pharm., Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .................................................................... 27, 32
`InTouch Techs., Inc. v. VGO Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) .......................................................................... 50
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) ........................................................ 20, 21, 22-23
`K/S Himpp v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) .................................................................... 35-36
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) .......................................................................... 38
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 41
`Luye Pharma Grp. Ltd. v. Alkermes Pharma Ireland Ltd.,
`IPR2016-01095, Paper 13 (PTAB Nov. 30, 2016) ............................................. 40
`MEHL/Biophile Int’l. Corp. v. Milgraum,
`192 F.3d 1362 (Fed. Cir. 1999) .......................................................................... 35
`Minton v. Nat’l. Ass’n. Sec. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 23
`
`v
`
`

`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .................................................................... 36-37
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 39
`NHK Spring Co., Ltd. v. Intri-plex Technologies, Inc.,
`IPR2018-00752, Paper 8 (PTAB Sep. 12, 2018) .......................................... 63-64
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd.,
`851 F.3d 1270 (Fed. Cir. 2017) .......................................................................... 38
`Novartis Pharm. Corp. v. W.-Ward Pharm. Int’l Ltd.,
`923 F.3d 1051 (Fed. Cir. 2019) .............................................................. 43-44, 52
`
`Nuvo Pharm. (Ireland) Designated Activity Co. v. Dr. Reddy’s
`Labs. Inc., 923 F.3d 1368 (Fed. Cir. 2019) ........................................................ 24
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ............................................................................ 37
`Panasonic Corp. v. Optical Devices, LLC,
`IPR2014-00302, Paper 9 (PTAB July 11, 2014) ................................................ 39
`PAR Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 37
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) .......................................................................... 33
`Robert Bosch Tool Corp. v. SD3, LLC,
`IPR2016-01751, Paper 15 (PTAB Mar. 22, 2017) ............................................. 60
`Sanofi v. Lupin Atlantis Holdings S.A.,
`No. 15-415, 2016 WL 5842327 (D. Del. Oct. 10, 2016) .............................. 24-25
`Star Sci., Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .................................................................... 46, 52
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................... 48
`
`vi
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`

`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`UCB, Inc. v. Accord Healthcare, Inc.,
`890 F.3d 1313 (Fed. Cir. 2018) .................................................................... 47-48
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) ............................................................................ 27
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .................................................................... 60-61
`Statutes
`21 U.S.C. § 356(a)(1) ............................................................................................... 11
`35 U.S.C. § 102 ........................................................................................................ 14
`35 U.S.C. § 103 ........................................................................................................ 14
`35 U.S.C. § 103(a) ................................................................................................... 44
`35 U.S.C. § 314(a) ....................................................................................... 28, 33, 63
`
`
`
`vii
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`

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`
`
`GLOSSARY
`
`’604 patent
`
`U.S. Patent No. 9,795,604
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`aGVHD
`
`ANDA
`
`BTK
`
`cGVHD
`
`CLL
`
`FDA
`
`HCT
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`IPR
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`Acute graft versus host disease
`
`Abbreviated New Drug Application
`
`Bruton’s tyrosine kinase
`
`Chronic graft versus host disease
`
`Chronic lymphocytic leukemia
`
`Food and Drug Administration
`
`Hematopoietic cell transplantation
`
`Inter partes review
`
`Italicized text
`
`Emphasis added unless otherwise indicated
`
`ITK
`
`MMF
`
`Office
`
`Interleukin-2-inducible T cell kinase
`
`Mycophenolate mofetil
`
`United States Patent and Trademark Office
`
`Patent Owner
`
`Pharmacyclics LLC
`
`Petitioner
`
`POSA
`
`Sandoz Inc.
`
`Person of ordinary skill in the art
`
`
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`viii
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`
`I.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`Introduction
`U.S. Patent No. 9,795,604 (“the ’604 patent”) discloses and claims methods
`
`of treating chronic graft versus host disease (“cGVHD”) with ibrutinib, an inhibitor
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`of Bruton’s tyrosine kinase (“BTK”), and the active ingredient in Imbruvica®.
`
`Imbruvica® is the first and only drug approved to treat cGVHD, a disease resulting
`
`in a 30–50% risk of mortality within five years of diagnosis. Numerous drugs had
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`been tested for cGVHD but failed in the clinic: prior to the claimed invention, there
`
`was an urgent need for new therapies.
`
`Petitioner nevertheless alleges that the claims are anticipated or rendered
`
`obvious, raising four grounds: (1) anticipation over the ’085 Publication (Ex. 1002);
`
`(2) obviousness over the ’085 Publication and the knowledge of a POSA; (3)
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`obviousness over the ’085 Publication, Shimabukuro-Vornhagen (Ex. 1003), and
`
`Herman (Ex. 1004); and (4) obviousness over the ’085 Publication, Shimabukuro-
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`Vornhagen, and Uckun (Ex. 1005). Petitioner asserts that these references are
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`meaningfully different from those considered during prosecution, as Petitioner
`
`alleges the references cited or discussed by the Office did not relate to ibrutinib or
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`GVHD. See, e.g., Pet., 1, 10. This is incorrect: the Office considered references
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`directed to both, allowing the claims because the prior art (like the art asserted here)
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`does not teach or suggest the claimed methods of treating cGVHD.
`
`1
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`

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`The abandoned ’085 Publication does not anticipate the challenged claims
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`because it would not enable a POSA to practice the claimed invention. The ’085
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`Publication discloses and claims formulations of ibrutinib, not methods of treatment.
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`It contains no in vitro, preclinical, or clinical data relevant to treating cGVHD, or
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`any other disease. It does not even mention cGVHD, instead referring generically
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`to “graft versus host disease” among a laundry list of over 150 diseases. Despite
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`this paucity of disclosure, and despite numerous statements from its expert (and
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`others) acknowledging the challenge and unpredictability of treating cGVHD,
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`Petitioner fails to even argue that the ’085 Publication is enabling.
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`The ’085 Publication also does not anticipate the challenged claims because
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`it fails to disclose multiple claim elements, expressly or inherently, and because it
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`requires one to choose without guidance a disease and dosing regimen from among
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`extensive lists of options.
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`The ’085 Publication does not render obvious the challenged claims, alone or
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`in combination. Fundamentally, Petitioner fails to establish motivation to combine
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`and reasonable expectation of success. Petitioner fails to identify any prior-art
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`publication describing the preclinical or clinical evaluation of ibrutinib (or any other
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`BTK inhibitor) in treating cGVHD. Further, the pathophysiology of cGVHD was
`
`poorly understood, there was a dearth of appropriate animal models, and the art was
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`replete with failed attempts to develop new therapies. Petitioner’s expert admitted
`
`2
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`

`

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`much of this in his publications, writing that treatment of cGVHD is “unpredictable,”
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`that new approaches are “urgently needed,” that cGVHD is poorly understood due
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`to the “absence of appropriate animal models,” and (prior to the invention) that
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`therapies for cGVHD were “of limited efficacy and there is no long-term satisfactory
`
`regimen for patients who fail front-line steroid-based therapy.”
`
`Petitioner’s obviousness grounds rely on the oversimplified and incorrect
`
`premise that any drug targeting B cells or inflammatory cytokines—irrespective of
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`the drug’s particular mechanism of action, and despite the absence of data showing
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`promise in treating cGVHD—would have been reasonably expected to succeed as a
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`cGVHD treatment. Petitioner’s theory trivializes the inherent complexity and
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`uncertainty
`
`in
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`therapeutic drug development—especially here, given
`
`the
`
`longstanding difficulty in developing therapies for cGVHD. And it is directly
`
`contradicted by the prior art teachings that (1) the role of B cells and cytokines were
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`poorly understood at the time of invention, and (2) the poor track record of drugs
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`targeting B cells and cytokines.
`
`Patent Owner provided substantial objective evidence of nonobviousness to
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`Petitioner before the filing of the Petition, in an interrogatory response in concurrent
`
`litigation over the ’604 patent. Yet Petitioner ignores that evidence, failing to
`
`address it in the Petition.
`
`3
`
`

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`For the reasons detailed below, Petitioner fails to show a reasonable likelihood
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`of prevailing as to any challenged claim. The Board should therefore deny
`
`institution.
`
`II. Background and State of the Art
`A. Chronic Graft Versus Host Disease Was Poorly Understood
`and Difficult to Treat
`GVHD occurs when a donor’s immune cells (the “graft”) attack a patient’s
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`healthy tissues and organs (the “host”). It is a major cause of morbidity and mortality
`
`following hematopoietic cell transplant (“HCT”). Ex. 1001, 1:29–45; Ex. 2001, 2;
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`Ex. 2002, 1, 17. Traditionally, GVHD was classified based on the time of onset; by
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`2013, however, this temporal classification was largely replaced by criteria that
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`distinguished acute GVHD (“aGVHD”) and chronic GVHD based on distinct
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`clinical manifestations. Ex. 2001, 2; see also Ex. 2005, 31.
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`Pathologically, the hallmark of aGVHD is selective epithelial damage of
`
`target organs; for example, the epidermis and hair follicles are damaged and
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`sometimes destroyed. Ex. 2005, 9. Small bile ducts are also profoundly
`
`affected. Id.
`
`cGVHD is a serious disease that significantly harms tissue and organ function
`
`and may lead to infection, skin erythema, chronic ulcers, gastrointestinal lesions, and
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`destruction of glands in the eyes, mouth, skin, and digestive tract. Ex. 2003, 2;
`
`4
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`

`

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`Ex. 2006, 2. The risk of developing cGVHD after HCT ranges from 30–70%.
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`Ex. 1001, 1:29–32; Ex. 2002, 12. The risk of death is high: up to a 50% risk of
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`mortality during the first five years after diagnosis. Ex. 2006, 2.
`
`1.
`
`Treating cGVHD Was Unpredictable and Difficult at
`the Time of Invention
`cGVHD was difficult to treat for several reasons. It manifests in multiple
`
`areas of the body in a variable and unpredictable pattern, often delaying diagnosis.
`
`Ex. 2005, 29. There was also little insight into its pathogenesis. Ex. 2006, abstract.
`
`As Petitioner’s expert explained in 2009:
`
`By contrast with acute GVHD, the pathophysiology of chronic GVHD
`remains poorly understood . . . . The response of chronic GVHD to
`treatment is unpredictable, and mixed responses in different organs can
`take place in the same patient.
`
`Ex. 2007, 7.
`
`In 2012, he expanded on these concerns:
`
`It is important to understand that, given the myriad clinical presentation
`of chronic GVHD that tend to occur at variable time after HCT
`[transplant], it is possible that separate pathogenic mechanisms might
`be involved in causing distinct manifestations and that no single
`putative mechanism might be sufficient to cause chronic GVHD.
`
`Ex. 2005, 33.
`
`5
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`

`

`An absence of appropriate animal models complicated drug development
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`U.S. Patent No. 9,795,604
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`
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`efforts for cGVHD. Ex. 2003, abstract; Ex. 2006, 2. Although several models had
`
`been used to study cGVHD pathogenesis, it was unclear that they accurately
`
`reflected disease pathogenesis in humans. Ex. 2008, 7 (“Because models of
`
`CGVHD do not replicate human disease . . . it is difficult to determine whether these
`
`results can be applicable to clinical GVHD prevention and treatment”).
`
`Further, drugs used for aGVHD often failed to successfully translate to
`
`cGVHD. Ex. 2010, 1; Ex. 2008, 2 (“[I]mportantly from the experimental view, it is
`
`not obvious whether findings based on the AGVHD models apply to CGVHD
`
`syndrome.”). For example, although infliximab, etanercept, and alemtuzumab
`
`showed some success in treating aGVHD, none were recommended for treating
`
`cGVHD. Ex. 2011, 3; Ex. 2012, abstract; Ex. 2001, 9–11. Consequently, the prior
`
`art recognized that cGVHD is not simply a continuation of aGVHD. Ex. 2010, 1.
`
`Instead, separate approaches were required for its treatment due to the distinct nature
`
`of the disease. Id.
`
`Petitioner’s expert, in his prior art publications, admits these challenges. For
`
`example, he explained in 2012 that “[t]he pathophysiology of chronic GVHD is
`
`generally much less well understood than that of acute GVHD and has undergone
`
`less intensive experimental modeling.” Ex. 2005, 31. He conceded that the
`
`difficulties in developing therapies for cGVHD were “due in part to the absence of
`
`6
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`

`

`
`appropriate animal models that can capture the kinetics and the protean
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`U.S. Patent No. 9,795,604
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`manifestation of chronic GVHD,” id., 32, and the “lack of standardized response
`
`criteria to measure therapeutic efficacy[, which] poses a major obstacle to pursuing
`
`therapeutic trials in chronic GVHD,” id., 33. He acknowledged that although the
`
`occurrence of aGVHD increases the probability of cGVHD, “no singular pathologic
`
`feature of the former predicts the development of the latter.” Id., 27–28.
`
`Thus, by October 2013, the difficulties in developing therapies and treating
`
`cGVHD were widely recognized. There was no FDA-approved therapy and no
`
`standard long-term solution. Ex. 2004, 9–10. The most widely used first-line
`
`therapy was a combination of systemic corticosteroids and a calcineurin inhibitor.
`
`Ex. 2002, 13. But these and other existing therapies were inadequate: cGVHD
`
`remained an enigma with little change over decades in its incidence, morbidity, and
`
`mortality. Ex. 2010, abstract.
`
`2.
`
`The Role of B Cells and Inflammatory Cytokines in
`the Pathogenesis of cGVHD Was Poorly Understood
`Several of Petitioner’s challenges focus on the role of B cells in cGVHD and
`
`ibrutinib’s B-cell effects. E.g., Pet., 55–59. Historically, however, the art identified
`
`donor-derived T cells as mediating GVHD pathogenesis. Ex. 1003, 7. Thus,
`
`preventive and treatment strategies had focused primarily on T-cell inhibition. Id.
`
`7
`
`

`

`By 2013, B cells were also believed to play a role in cGVHD, but this was
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`
`
`
`poorly understood. For example, Shimabukuro-Vornhagen explained that “[t]he
`
`mechanisms by which B cells contribute to acute and chronic GVHD currently are
`
`only incompletely understood” and that additional research was needed to elucidate
`
`the respective roles of pathogenic versus protective subsets of B cells. Ex. 1003, 7,
`
`12.
`
`Consequently, by 2013, there were few cGVHD clinical trial candidates
`
`targeting B cells, and none had progressed beyond early clinical studies. Ex. 1003,
`
`12. Rituximab, a chimeric monoclonal antibody that depletes B cells, had been
`
`studied for cGVHD. Id., 9, 11. But the literature expressed concern that rituximab’s
`
`non-selective depletion of B cells triggered, or even worsened, GVHD. Ex. 2013,
`
`1–2. Rituximab treatment was also associated with prolonged, life-threatening
`
`cytopenias. Id.; Ex. 2014, abstract.
`
`Other B-cell targeted therapies lacked sufficient efficacy and/or showed
`
`significant toxicity. Alemtuzumab, an antibody targeting the CD-52 antigen
`
`expressed on both B and T cells, was deemed “likely to significantly exacerbate the
`
`immunodeficiency associated with cGvHD.” Ex. 2001, 9; see id., 4. Clinical trials
`
`of ABX-CBL, an antibody targeting the CD-147 antigen expressed on both B and T
`
`cells, showed no benefit over existing therapies. Ex. 2015, 3.
`
`8
`
`

`

`Petitioner also relies on the purported role of inflammatory cytokines in
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`Case IPR2019-00865
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`cGVHD pathogenesis to support its challenges (Pet., 6, 9–10, 56–59), but their role
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`(if any) was likewise poorly understood. While one publication reported increased
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`levels of inflammatory cytokines in patients with cGVHD, it acknowledged that
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`other studies found no correlation between cytokine levels and disease severity.
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`Ex. 1010, 4. Further, drugs targeting the inflammatory cytokines TNFα (infliximab
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`and etanercept) and IL-6 (tocilizumab) were not recommended for cGVHD.
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`Ex. 2017, 3; Ex. 2001, 11. Even as of 2015, “no cytokine-inhibition strategy or
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`cytokine administration ha[d] proved efficacious in randomized studies” for treating
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`cGVHD. Ex. 2018, 5.
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`3.
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`Attempts to Develop Second-Line Treatments for
`cGVHD Failed
`Before 2013, steroids, the generally recommended first-line treatment
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`approach for cGVHD, failed to achieve control in half of patients experiencing
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`cGVHD. Ex. 2004, 9. Steroid use was also limited by treatment resistance and side
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`effects. Id., 8–10. Indeed, chronic steroid use was “toxic and often result[ed] in life-
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`threatening infectious complications,” thwarting use as a long-term treatment option.
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`Ex. 2002, 13; Ex. 2004, 9. By 2013, despite multiple attempts to develop better
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`second-line treatments for cGVHD, none succeeded. Ex. 2003, 1; Ex. 2004, 9.
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`9
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`Some drugs initially showed promise but failed in larger trials. Ex. 2006, 2–
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`3. For example, various case reports and phase II studies had suggested that
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`mycophenolate mofetil (“MMF”), a lymphocyte-inhibitor, could be used to treat
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`cGVHD. Ex. 2019, 1. But a subsequent phase III trial established that MMF did
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`not improve patient outcomes. Id., abstract. Similarly, thalidomide, a drug believed
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`to act on TNFα and other targets, showed encouraging results in early studies, but
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`subsequent trials showed no benefit and unacceptable side effects. Ex. 2001, 10;
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`Ex. 2006, 3.
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`Other therapies were used clinically because of a dearth of viable options.
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`Examples
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`included sirolimus, pentostatin, mesenchymal stem cells, and
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`extracorporeal photopheresis. Ex. 2001, 1, 4. But these also failed to provide long-
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`term efficacy beyond traditional steroid treatment. Id.; see also Ex. 2003, 1. As
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`described above, drug candidates that targeted B cells or particular cytokines were
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`likewise deemed unsuccessful.
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`Indeed, notwithstanding assertions made by Petitioner (e.g., Pet., 8),
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`Petitioner’s expert summarized the state of the art in 2012 as follows:
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`Current therapies for chronic GVHD are of limited efficacy and there
`is no long-term satisfactory regimen for patients who fail front-line
`therapy. Indeed,
`there
`is no Food and Drug
`steroid-based
`Administration-approved medication for use in chronic GVHD.
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`Ex. 2005, 33. In 2014, he wrote further:
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`10
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`Despite multiple clinical trials investigating innovative treatments for
`chronic graft-versus-host disease (cGVHD), standard treatment has
`not changed in the past 30 years and cGVHD remains the leading cause
`of morbidity and mortality for long-term transplant survivors.
`
`Ex. 2021, 1.
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`B.
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`Imbruvica® Is the First and Only FDA-Approved
`Treatment for cGVHD
`On August 2, 2017, Imbruvica® was approved by the FDA for the treatment
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`of patients with cGVHD after failure of one or more lines of systemic therapy.
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`Ex. 2022. Imbruvica® was approved after results from a multi-center trial showed a
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`high frequency of sustained responses: a best overall response rate of 67%, with
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`71% of responders showing sustained response for more than 20 weeks. Ex. 2023,
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`abstract. Imbruvica® was the first, and remains the only, FDA-approved treatment
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`for cGVHD.
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`The FDA designated ibrutinib as a “Breakthrough Therapy.” Ex. 2022. This
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`reflected FDA’s determination that preliminary clinical evidence indicated
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`“substantial improvement” over existing therapies on one or more clinically
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`significant endpoints. 21 U.S.C. § 356(a)(1). The CEO of the Lymphoma Research
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`Foundation explained the significance of ibrutinib’s approval as follows:
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`Today’s approval of ibrutinib is an important advancement for patients
`suffering from cGVHD . . . . This serious condition previously had
`limited treatment options, and today’s indication not only represents the
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`11
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`first approval for graft versus host disease, but represents hope for
`patients who undergo an allogeneic transplant for better outcomes in
`managing this disease.
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`Ex. 2026.
`
`Imbruvica®’s active ingredient is ibrutinib. Ex. 2036, 27. Ibrutinib inhibits
`
`BTK, expressed in B cells, as well as interleukin-2-inducible T-cell kinase (“ITK”),
`
`expressed in T cells. Ex. 2024, 2. Unlike rituximab, ibrutinib was reported not to
`
`deplete B cells. Ex. 2025, 7.
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`III. The ’604 Patent and Its Prosecution History
`A. The Specification and Claims
`The ’604 patent describes and claims methods of treating cGVHD by
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`administering a therapeutically effective amount of ibrutinib, including a daily oral
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`dose of 420 mg. Ex. 1001, 39:27–40:12. The ’604 patent contains eight examples,
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`including pre-clinical and clinical data demonstrating ibrutinib’s efficacy in treating
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`cGVHD. Ex. 1001, 64:32–75:22.
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`Petitioner challenges independent claims 1 and 55. Pet., 11. These claims
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`read as follows:
`
`A method of treating chronic graft versus host
`1.
`disease (GVHD) comprising administering to a patient
`having chronic GVHD a therapeutically effective amount
`of a compound of the structure:
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`12
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`thereby treating the chronic GVHD in the patient.
`Ex. 1001, claim 1.
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`
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`55. A method of treating chronic graft versus host
`disease (GVHD) comprising administering to a patient
`having chronic GVHD about 420