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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`Petitioner
`
`v .
`
`PHARMACYCLICS LLC,
`Patent Owner.
`
`U.S. Patent No. 9,795,604 to Byrd et al.
`Issue Date: October 24, 2017
`Title: Methods of Treating and Preventing Graft Versus Host Disease
`
`
`
`Inter Partes Review No.: IPR2019-00865
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`PETITIONER’S REPLY BRIEF
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`TABLE OF CONTENTS
`
`
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`THE CLAIMED PATIENT OUTCOMES SHOULD NOT BE GIVEN
`PATENTABLE WEIGHT ............................................................................... 2
`
`’085
`1: ANTICIPATION BASED ON THE
`III. GROUND
`PUBLICATION ............................................................................................... 6
`
`A.
`
`Claim 1 .................................................................................................. 6
`
`B.
`
`C.
`
`Claims 4, 13, and 15 .............................................................................. 9
`
`Claims 6–8, 29–31, 44–46, and 51–53 ................................................10
`
`1.
`
`2.
`
`’085 Publication Explicitly Discloses Patient
`The
`Outcomes ..................................................................................10
`
`The ’085 Publication Inherently Discloses Patient
`Outcomes ..................................................................................11
`
`D.
`
`Claims 9 and 10 ...................................................................................13
`
`E.
`
`Claims 24, 28, 35, 39, 43, 50, and 55 ..................................................13
`
`IV. GROUND 2: OBVIOUSNESS OVER THE ’085 PUBLICATION ............14
`
`A.
`
`Claim 1 ................................................................................................14
`
`B.
`
`Claims 4, 13, and 15 ............................................................................16
`
`V. GROUND 3: OBVIOUSNESS OVER THE ’085 PUBLICATION IN
`VIEW OF SHIMABUKURO-VORNHAGEN AND HERMAN .................18
`
`VI. GROUND 4: OBVIOUSNESS OVER THE ’085 PUBLICATION IN
`VIEW OF SHIMABUKURO-VORNHAGEN AND UCKUN ....................21
`
`VII. PATENT OWNER’S ALLEGED OBJECTIVE INDICIA DO NOT
`OVERCOME THE CLEAR SHOWING OF OBVIOUSNESS ...................24
`
`i
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`

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`VIII. CONSTITUTIONALITY ..............................................................................26
`
`IX. CONCLUSION ..............................................................................................26
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`
`
`
`
`ii
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`

`

`TABLE OF AUTHORITIES
`
`
`CASES
`
`
`
`
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`
`
` PAGE(S)
`
` Arthrex, Inc. v. Smith & Nephew, Inc.,
`2020 U.S. App. LEXIS 9026 (Fed. Cir. Mar. 23, 2020) .................................... 26
`
`Biomarin Pharm. Inc. v. Genzyme Therapeutic Prods. LP,
`IPR2013-00534, Paper 81 (P.T.A.B. Feb. 11, 2015) .......................................... 23
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ...................................................................passim
`
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .......................................................................... 14
`
`Cubist Pharms., Inc. v. Hospira, Inc.,
`805 F.3d 1112 (Fed. Cir. 2015) .......................................................................... 17
`
`Endo Pharms., Inc. v. DepoMed, Inc.,
`IPR2014-00652, Paper 68 (P.T.A.B. Sept. 16, 2015)................................... 24, 25
`
`Georgetown Rail Equip. Co. v. Holland, L.P.,
`867 F.3d 1229 (Fed. Cir. 2017) ............................................................................ 5
`
`Hewlett-Packard Co. v. Mustek Sys., Inc.,
`340 F.3d 1314 (Fed. Cir. 2003) .......................................................................... 11
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .................................................................... 17, 18
`
`Impax Labs. Inc. v. Aventis Pharms. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ...................................................................... 8, 13
`
`Impax Labs. Inc. v. Aventis Pharms. Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) ........................................................................ 8, 9
`
`In re Copaxone Consolidated Cases,
`906 F.3d 1013 (Fed. Cir. 2018) .................................................................... 3, 4, 5
`
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) .......................................................................... 12
`
`iii
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`

`

`King Pharmaceuticals, Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 12
`
`Lectrosonics, Inc. v. Zaxcom, Inc.,
`IPR2018-01129, Paper 33, 33 (P.T.A.B. Jan. 24, 2020) .................................... 24
`
`Minton v. Nat’l Assoc. of Securities Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) ........................................................................ 3, 4
`
`Mobotix Corp. v. ComCam Int’l., Inc.,
`IPR2015-00093 Paper 21 (P.T.A.B. Apr. 28, 2016) .......................................... 26
`
`OSI Pharms. LLC v. Apotex Inc.,
`939 F.3d 1375 (Fed. Cir. 2019) .......................................................................... 15
`
`Pharmastem Therapeutics, Inc. v. Viacell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) .................................................................... 17, 23
`
`Prometheus Labs. Inc. v. Roxane Labs., Inc.,
`No. 2013 U.S. Dist. LEXIS 135284 (D.N.J. Sept. 23, 2013) ............................... 4
`
`Texas Instruments Inc. v. ITC,
`988 F.2d 1165 (Fed. Cir. 1993) ............................................................................ 4
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 24
`
`OTHER AUTHORITIES
`
`37 C.F.R. 42.22(a)(2) ............................................................................................... 26
`
`37 C.F.R. 42.23(a) .................................................................................................... 26
`
`37 C.F.R. 42.120(a) .................................................................................................. 26
`
`MPEP 2111.04(I) ....................................................................................................... 4
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`
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`
`
`iv
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`

`

`TABLE OF EXHIBITS
`
`1005
`
`1007
`
`1010
`
`1011
`
`1012
`
`1004
`
`Exhibit
`Ex #
`1001 U.S. Patent No. 9,795,604 B2 (“the ’604 Patent”)
`1002 U.S. Patent Pub. No. 2015/0140085 A1 (“the ’085 Publication ”)
`Shimabukuro-Vornhagen et al., “The role of B cells in the pathogenesis
`1003
`of graft-versus-host disease,” BLOOD, Volume 114, No. 24, pp. 4919–
`4927, December 3, 2009 (“Shimabukuro-Vornhagen”)
`Herman et al., “Bruton tyrosine kinase represents a promising therapeutic
`target for treatment of chronic lymphocytic leukemia and is effectively
`targeted by PCI-32765,” BLOOD, Volume 117, No. 23, pp. 6287–6296,
`June 9, 2011 (“Herman”)
`Uckun et al., “Bruton’s tyrosine kinase as a molecular target in treatment
`of leukemias and lymphomas as well as inflammatory disorders and
`autoimmunity,” EXPERT OPINION ON THERAPEUTIC PATENTS, Volume 20,
`No. 11, pp. 1457–1470, November 2010 (“Uckun”)
`1006 Declaration of James L. M. Ferrara M.D., D.Sc.
`Goldstein et al., “Induction of Costimulatory Molecules B7-1 and B7-2 in
`Murine B Cells: the CBA/N Mouse Reveals a Role for Bruton’s Tyrosine
`Kinase in CD4- Mediated B7 Induction,” MOLECULAR IMMUNOLOGY,
`Volume 33, No. 6, pp. 541–551, 1996 (“Goldstein”)
`1008 Declaration of Sylvia D. Hall-Ellis, Ph.D.
`July 22, 2016 Amendment and Response in Appl. No. 14/523,650
`1009
`Barak et al., “Cytokine Dysregulation in Chronic Graft Versus Host
`Disease,” LEUKEMIA AND LYMPHOMA, Volume 17, pp. 169–173, 1995
`(“Barak”)
`PCT No. PCT/US2013/047958
`Cetkovic-Cvrlje, “Dual targeting of Bruton’s tyrosine kinase and Janus
`kinase 3 with rationally designed inhibitors prevents graft-versus-host
`disease (GVHD) in a murine allogeneic bone marrow transplantation
`model,” BRITISH JOURNAL OF HAEMATOLOGY, Volume 126, pp. 821–827,
`2004
`1013 U.S. Patent No. 7,514,444 B2
`Provisional Patent Application No. 61/666,562 and filing receipt
`1014
`Honigberg et al., “The Bruton tyrosine kinase inhibitor PCI-32765 blocks
`B-cell activation and is efficacious in models of autoimmune disease and
`B-cell malignancy,” PROCEEDINGS OF THE NATIONAL ACADEMY OF
`SCIENCES OF THE USA, Volume 107, No. 29, pp. 13075–13080, July 20,
`2010
`
`1015
`
`v
`
`

`

`1016
`
`1017
`
`1022
`
`Advani et al., “Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765)
`Has Significant Activity in Patients With Relapsed/Refractory B-Cell
`Malignancies,” JOURNAL OF CLINICAL ONCOLOGY, Volume 31, No. 1, pp.
`88–94, January 1, 2013
`Dolgin, “Precision therapies take aim at non-Hodgkin’s lymphoma”
`NATURE, Volume 563, S46–S47, November 14, 2018
`1018 U.S. Patent No. 8,476,284 B2
`1019 U.S. Patent No. 8,497,277 B2
`1020 Orange Book Listing for Ibrutinib 420 mg Capsules
`1021 April 22, 2016 Office Action in Appl. No. 14/523,650
`Auphan et al., “Immunosuppression by Glucocorticoids: Inhibition of NF-
`κB Activity Through Induction of IκB Synthesis,” SCIENCE, Volume 270,
`pp. 286–290, October 13, 1995
`1023 Curriculum Vitae of Dr. James L. M. Ferrara M.D., D.Sc.
`Koreth et al., “Current and Future Approaches for Control of Graft-
`Versus-Host Disease,” EXPERT REVIEWS IN HEMATOLOGY, Volume 1, No.
`1, pp. 111–128, 2008
`Sarantopoulous et al., “Altered B-cell Homeostasis and Excess BAFF in
`Human Chronic Graft-Versus-Host Disease,” BLOOD, Volume 113, No.
`16, pp. 3865–3874, April 16, 2009
`Cutler et al., “Rituximab Prophylaxis Prevents Corticosteroid-Requiring
`Chronic GVHD After Allogeneic Peripheral Blood Stem Cell
`Transplantation: Results of a Phase 2 Trial,” BLOOD, Volume 122, No. 8,
`pp. 1510–1517, August 22, 2013
`NCCN Clinical Practice Guidelines in Oncology, Hematopoietic Cell
`Transplantation (HCT): Pre-Transplant Recipient Evaluation and
`Management of Graft Versus Host Disease, Version 1.2020, October 30,
`2019
`1028 April 27, 2017 Response and Amendment in Appl. No. 14/523,650
`1029 October 14, 2014 Specification Filed in Appl. No. 14/523,650
`1030 March 13, 2020 Deposition Transcript of John Koreth M.B.B.S., D. Phil.
`
`1024
`
`1025
`
`1026
`
`1027
`
`
`
`
`
`
`
`
`
`
`
`vi
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`

`

`TABLE OF ABBREVIATIONS
`
`Dec.
`
`HCT
`
`Definition
`Abbreviation
`Acute Graft Versus Host Disease
`aGVHD
`Bone Marrow Transplant
`BMT
`Bruton’s Tyrosine Kinase
`BTK
`Chronic Graft Versus Host Disease
`cGVHD
`Challenged Claims Claims 1, 4, 6–10, 13, 15, 24, 28–31, 35, 39, 43–46, 50–53, and 55
`Chronic Lymphocytic Leukemia
`CLL
`September 26, 2019 Decision Granting Institution of Inter Partes
`Review (Paper 8)
`Hematopoietic Cell Transplant
`National Comprehensive Cancer Network Guidelines on aGVHD
`and cGVHD
`Petition (Paper No. 2)
`Patent Owner Response (Paper No. 13)
`Small Lymphocytic Lymphoma
`
`NCCN Guidelines
`
`Pet.
`POR
`SLL
`
`
`
`
`vii
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`I.
`
`INTRODUCTION
`
`Addressing Petitioner’s four Grounds of unpatentability, Patent Owner
`
`acknowledges many of the underlying facts, leaving only a few issues for resolution.
`
`Regarding Ground 1, Patent Owner says relatively little. The ’085 Publication
`
`expressly recites that ibrutinib can be administered in a therapeutically effective
`
`amount for treating diseases, including GVHD. The reference provides preclinical
`
`and clinical data for ibrutinib and discloses the same 420 mg/day dosage recited in
`
`certain dependent claims. Faced with these clear disclosures, Patent Owner argues
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`that the ’085 Publication is not enabled. But the reference is presumed enabled, and
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`the law does not require proof of efficacy.
`
`Patent Owner’s arguments directed to Ground 2 fare no better, since clinical
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`trial results are not required for a reasonable expectation of success.
`
`Grounds 3 and 4, which independently supported institution, are founded on
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`the known mechanisms of action for treating cGVHD as well as ibrutinib’s known
`
`mechanisms of action. Patent Owner’s expert, Dr. Koreth, admitted the key facts.
`
`He admitted that both B cells and T cells were known to be implicated in cGVHD.
`
`He admitted that, in a first mechanism of action, ibrutinib was known to irreversibly
`
`bind to BTK in B cells, thus blocking activation of T cells. And he admitted that, in
`
`a second mechanism of action, ibrutinib was known to inhibit production of
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`inflammatory cytokines known to play an important role in cGVHD. Further, Patent
`
`
`
`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`Owner does not dispute the pre-2013 knowledge that ibrutinib is a BTK inhibitor,
`
`BTK inhibitors were known to prevent severe GVHD, and drugs for treating
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`aGVHD were also known to treat cGVHD. Patent Owner instead argues there was
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`no certainty that ibrutinib would treat cGVHD because other drugs had inconsistent
`
`results and toxicity concerns. But that is not the standard. Properly considered, all
`
`Challenged Claims are unpatentable based, independently, on all four Grounds.
`
`II. THE CLAIMED PATIENT OUTCOMES SHOULD NOT BE GIVEN
`PATENTABLE WEIGHT
`
`Patent Owner’s first argument is purely legal and directed to the patient
`
`outcomes in dependent claims 6–8, 29–31, 44–46, and 51–53, each of which depends
`
`from claim 1. Claim 1 recites “thereby treating the chronic GVHD in the patient,”
`
`and the parties agree that “treating” means lessening the severity, causing regression,
`
`relieving a condition, or stopping symptoms. See (Pet., 16; POR, 15). The noted
`
`dependent claims specify that the patient achieves a partial response, a complete
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`response, or reduction in severity.
`
`Petitioner demonstrated that the “thereby treating” phrase in claim 1 is a non-
`
`limiting statement of intended purpose, and the dependent claims simply express the
`
`intended result of the recited method. The Board agreed based “on the record now
`
`before us.” (Dec., 8). That record has not changed; thus, the Board should adopt its
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`initial conclusion.
`
`2
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`
`To be sure, Patent Owner’s legal argument remains incorrect. Efficacy
`
`language stating “the intended result of administering” a drug “does not … limit the
`
`claim.” Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375–76
`
`(Fed. Cir. 2001). Also, a “thereby” clause “in a method claim is not given patentable
`
`weight when it simply expresses the intended result of a process step positively
`
`recited.’” Minton v. Nat’l Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381
`
`(Fed. Cir. 2003). Patent Owner contends these rules should not apply since this case
`
`involves methods of treatment with pharmaceuticals. Patent Owner misinterprets the
`
`law, and its cited cases are inapplicable. Both Bristol-Myers and Minton remain good
`
`law, and both apply here.
`
`In Bristol-Myers the claim recited a “method for treating a cancer patient …
`
`said method being associated with reduced hematologic toxicity.” 246 F.3d at 1375–
`
`76. The Federal Circuit held that this “expression does not result in a manipulative
`
`difference in the steps of the claim” because the “steps of the … method are
`
`performed in the same way regardless whether or not the patient experiences a
`
`reduction in hematologic toxicity.” Id. at 1375. The Federal Circuit reached the same
`
`result in In re Copaxone Consolidated Cases, 906 F.3d 1013, 1023 (Fed. Cir. 2018).
`
`The claims recited a method “comprising administering … a therapeutically
`
`effective regimen of … glatiramer acetate … the regimen being sufficient so as to
`
`thereby alleviate the symptom of the patient.” Id. at 1023–24. Citing Bristol-Myers,
`
`3
`
`

`

`
`the Federal Circuit held that the latter clause “does not change the express dosing
`
`amount or method already disclosed in the claims” and “is therefore non-limiting.”
`
`Petitioner’s Reply Brief
` IPR2019-00865
`
`Id. at 1024.
`
`The same is true here. Regardless of the claimed patient outcome, the method
`
`is performed the same way: the physician administers a “therapeutically effective
`
`amount” of ibrutinib to a patient having cGVHD. What happens after administration
`
`is a result of the drug’s biological effect on the disease. See id.; Texas Instruments
`
`Inc. v. ITC, 988 F.2d 1165, 1172 (Fed. Cir. 1993) (A clause that “merely states the
`
`result of the limitations” “adds nothing to the patentability or substance of the
`
`claim.”).
`
`
`
`The Federal Circuit’s Minton decision likewise applies. Courts and the MPEP
`
`continue to rely on Minton for the proposition that a “whereby clause in a method
`
`claim is not given weight when it simply expresses the intended result of a process
`
`step positively recited.” MPEP 2111.04(I); Minton, 336 F.3d at 1381; Prometheus
`
`Labs. Inc. v. Roxane Labs., Inc., No. 2013 U.S. Dist. LEXIS 135284, *13–*16
`
`(D.N.J. Sept. 23, 2013) (citing Minton and Bristol-Myers); Ex Parte Abraham, 2019
`
`PAT. APP. LEXIS 7531, *7 (P.T.A.B. Sept. 6, 2019) (quoting Minton).
`
`Patent Owner’s cases are inapposite. In Allergan Sales v. Sandoz, the
`
`applicant distinguished the prior art during prosecution based on the claimed
`
`efficacy, and the Examiner relied on the wherein clauses in allowing the claims. 935
`
`4
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`F.3d 1370, 1375–76 (Fed. Cir. 2019). Here, the applicant never relied on the efficacy
`
`limitations for patentability. Instead, they were added “[s]ubsequently” after the
`
`Examiner allowed the claims. (POR, 11); see (EX1028, 3–5, 8). Allergan Sales
`
`distinguishes Bristol-Myers on this very basis. 935 F.3d at 1376; see also Copaxone,
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`906 F.3d at 1024 (“the disputed claim terms were not necessary or relevant to the
`
`examiner’s approval”); Georgetown Rail Equip. Co. v. Holland, L.P., 867 F.3d 1229
`
`(Fed. Cir. 2017) (the claim terms were not relied on during prosecution); Abraham,
`
`2019 PAT. APP. LEXIS 7531, at *10 (distinguishing Allergan Sales).
`
`Likewise, LA Biomedical v. Eli Lilly is distinguishable. 849 F.3d 1049 (Fed.
`
`Cir. 2017). The claims recited administering a drug and “arresting or regressing” a
`
`condition according to an open-ended dosing protocol. Because the “arresting or
`
`regressing” language was not in a preamble or wherein clause, the claims were “not
`
`comparable” to claims “in which statements of general purpose … have been held
`
`to carry no patentable weight.” Id. at 1061. Also, the open-ended administration
`
`protocol was “different from cases in which the claims contain express dosage
`
`amounts as material claim limitations.’” Id. This case is like those distinguished in
`
`LA Biomedical. Here, the Challenged Claims recite administering a “therapeutically
`
`effective amount” of ibrutinib, with several containing an express dosage (420 mg),
`
`and the result (“treating”) is recited in a “thereby” clause.
`
`5
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`
`The Board should conclude that the recited patient outcomes carry no
`
`patentable weight. (Dec., 8). If the Board finds otherwise, the claims are still
`
`unpatentable as anticipated and obvious, as discussed in the Petition and in Section
`
`III.C below.
`
`III. GROUND 1: ANTICIPATION BASED ON THE ’085 PUBLICATION
`
`Patent Owner addresses Ground 1 only on pages 53–56 of the POR. Below,
`
`Petitioner demonstrates the flaws in Patent Owner’s position and identifies
`
`additional evidence from trial supporting anticipation of all Challenged Claims.
`
`A. Claim 1
`
`Regarding anticipation, Patent Owner does not contest most of Petitioner’s
`
`supporting evidence, admitting:
`
`• Ibrutinib “was known and had been studied in the treatment of B-cell
`
`malignancies.” (EX1030, 84:25–85:6).
`
`• “[T]he ’085 Publication states that ‘a solid oral dosage form disclosed herein’
`
`[of ibrutinib] could be used to treat … diseases” including “graft versus host
`
`disease.” (EX2055 ¶93).
`
`• There are two primary types of GVHD: aGVHD and cGVHD. (EX1030,
`
`130:18–19; EX2055 ¶136).
`
`• The ’085 Publication discloses administering “ibrutinib” at therapeutically
`
`effective dosages of “420 mg/day.” (EX2055 ¶89).
`
`6
`
`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`Nor does Patent Owner contest the key legal principles:
`
`• A claimed species (cGVHD) is anticipated where the prior art discloses a
`
`genus (GVHD) having “such a defined and limited class that one of ordinary
`
`skill in the art could ‘at once envisage’ each member of the genus.” (Dec., 14–
`
`15).
`
`• The ’085 Publication is presumed enabled. (Id., 17).
`
`Patent Owner’s only argument is that the ’085 Publication “does not enable
`
`treatment” because it is allegedly directed only to “formulations.” (POR, 53).1 That
`
`is incorrect; the ’085 Publication repeatedly describes formulations and their use in
`
`treating diseases. (EX1002, ¶¶[0096], [0098]). For example, the Abstract identifies
`
`“[o]ral pharmaceutical formulations of ibrutinib … and use of these formulations for
`
`
`1 Patent Owner also states that, in 2012, Dr. Ferrara noted the lack of a “long-term
`
`satisfactory regimen for patients who fail front-line steroid-based therapy.” (POR,
`
`54). The POR repeats similar assertions throughout. Dr. Ferrara’s statements,
`
`however, remain true even today. He testified, “there is still a large unmet medical
`
`need and new therapies are needed.” (EX2056 at 81:1–82:13). Also, the NCCN
`
`Guidelines identify ibrutinib as just one of fifteen cGVHD drugs, stating “[t]here is
`
`insufficient evidence to recommend one systemic agent as preferred over another.”
`
`(EX1027 at 24).
`
`7
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`the treatment of diseases.” (Id., Abstract); (EX2055 ¶93) (Dr. Koreth acknowledging
`
`the ’085 Publication “states that ‘a solid oral dosage form disclosed herein’ could be
`
`used to treat” certain diseases, including “graft versus host disease”) (emphasis
`
`added).
`
`Patent Owner argues that the ’085 Publication lacks “working examples” or
`
`clinical data specific to using ibrutinib to treat cGVHD. (POR, 53–54). The law is
`
`not so rigid. A prior art reference is enabling and will anticipate if it describes the
`
`claimed invention such that a POSA can carry out the invention—“proof of efficacy
`
`is not required for a prior art reference to be enabling under section 102.” Impax
`
`Labs. Inc. v. Aventis Pharms. Inc., 468 F.3d 1366, 1383 (Fed. Cir. 2006). Here, the
`
`’085 Publication explicitly discloses methods of treating diseases—including
`
`GVHD—using ibrutinib, and even recommends dosages of 420 mg/day based on
`
`clinical trials where ibrutinib had successfully treated “a variety of B-cell
`
`malignancies.” (EX1002 ¶[0004]). Nothing else is needed to enable the claimed
`
`method.
`
`Impax Laboratories, Inc. v. Aventis Pharmaceuticals, Inc. is distinguishable.
`
`545 F.3d 1312 (Fed. Cir. 2008). The prior art disclosed “hundreds or thousands of
`
`compounds” and included “broad dosage guidelines [that] specifically excluded the
`
`claimed compound.” Id. at 1315. Here, the ’085 Publication specifies the exact
`
`compound (ibrutinib) in a dosage (420 mg/day) disclosed as a “pharmaceutically
`
`8
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`

`

`Petitioner’s Reply Brief
` IPR2019-00865
`
`
`effective amount” (EX1002 ¶¶[0120], [0030]) based on its “administ[ration] orally
`
`in clinical trials … to obtain the desired therapeutic effect” (id. ¶[0004]). Also, unlike
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`the art in Impax, the ’085 Publication discloses both preclinical and clinical data
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`about ibrutinib (id. ¶[0004] (“oral bioavailability of ibrutinib is reported to be 22.8%
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`in rats”), and discloses “potential adverse side effects” that Dr. Koreth
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`acknowledged were determined through clinical trials (EX1030, 99:8–11). Thus, the
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`’085 Publication provides an enabling disclosure.
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`B. Claims 4, 13, and 15
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`These claims recite treating patients with “steroid dependent/refractory,”
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`“steroid resistant,” or “refractory” cGVHD. The Board preliminarily found them not
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`anticipated, believing the ’085 Publication does not disclose using steroids to treat
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`GVHD or using ibrutinib as a second-line treatment. (Dec., 20). During the trial,
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`however, Patent Owner cross-examined Petitioner’s expert (Dr. Ferrara), and he
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`explained how the ’085 Publication is clear on this point.
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`Dr. Ferrara explained that ¶[0124] of the ’085 Publication discloses ibrutinib
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`as a treatment in combination with steroids. (EX2056, 212:1). He testified that the
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`drugs in ¶[0124] “are all steroids that we use to treat Graft-versus-host disease.” (Id.
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`at 212:6–13). Dr. Ferrara testified that the ’085 Publication discloses “us[ing]
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`ibrutinib to treat Graft-versus-host disease in combination with other drugs … use[d]
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`to prevent and treat Graft-versus-host disease.” (Id.). This includes when steroids—
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`the universally accepted first-line treatment option 2—are not working or where
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`patients are steroid-dependent. One example is in ¶[0121] of the ’085 Publication,
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`which discloses that “[s]uch other drug(s) [e.g., steroids] may be administered …
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`contemporaneously or sequentially with a compound of the present disclosure.”
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`(EX1002, ¶[0121]) (emphasis added). Thus, ibrutinib was disclosed as being given
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`sequentially with steroids, such as when steroids are ineffective. Therefore, based
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`on the developed record, the Board should find these claims anticipated by the ’085
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`Publication.
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`C. Claims 6–8, 29–31, 44–46, and 51–53
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`In its preliminary decision, the Board determined that because the patient
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`outcomes in these dependent claims “‘simply express the intended result’ of the
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`recited method,” they do not have patentable weight. (Dec., 21). That view remains
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`correct for the reasons stated above in Section II. Should the Board alter its
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`preliminary view, these claims are still unpatentable over the ’085 Publication
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`because it discloses the patient outcomes both explicitly and inherently.
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`1.
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`The ’085 Publication Explicitly Discloses Patient Outcomes
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`The ’085 Publication discloses a “method of treating” certain diseases by
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`“administering” ibrutinib (EX1002 ¶[0096]), including treating “graft versus host
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`2 Patent Owner’s expert confirmed this. (EX1030, 10:14–16).
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`disease” (id. ¶[0098]). It states that doses of “420 mg/day” were administered in
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`clinical trials “to obtain the desired therapeutic effect” (id. ¶[0004]), and it describes
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`420 mg/day as a “therapeutically effective amount” (id. ¶[0120]). It defines
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`“treating” as encompassing “inhibiting the disease” and “relieving the disease, i.e.,
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`causing regression of the disease or its clinical symptoms.” (Id. ¶¶[0117]–[0119]).
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`These are the outcomes recited in the dependent claims.
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`2.
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`The ’085 Publication Inherently Discloses Patient Outcomes
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`“Newly discovered results of known processes directed to the same purpose
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`are not patentable because such results are inherent.” Bristol-Myers, 246 F.3d at
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`1376. In Bristol-Myers, a prior art reference disclosed the claimed process for
`
`treating cancer but did not say whether the process was effective in “reducing
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`hematologic toxicity.” Id. at 1372, 1376. That did not matter; the claim was still
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`invalid. The patentee did “no more than claim a result (efficacy)” and “the purpose—
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`treating cancer—is no different from the purpose disclosed by” the prior art. Id. at
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`1377.
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`The prior art method need not actually achieve the result every time. See id.;
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`Hewlett-Packard Co. v. Mustek Sys., Inc., 340 F.3d 1314, 1326 (Fed. Cir. 2003)
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`(“[A] prior art product that sometimes, but not always, embodies a claimed method
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`nonetheless teaches that aspect of the invention.”). What matters is whether the prior
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`art discloses the claimed process steps. Bristol-Myers, 246 F.3d at 1376–78. Here, it
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`does. The ’085 Publication discloses the same process step recited in the claim:
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`administering a therapeutically effective amount of ibrutinib to treat a cGVHD
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`patient. The results—the recited patient outcomes—are inherent to performing that
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`step.
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`The Federal Circuit reached the same conclusion in King Pharmaceuticals,
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`Inc. v. Eon Labs, Inc., 616 F.3d 1267 (Fed. Cir. 2010). The claim recited certain
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`results achieved from administering a drug, and the court found the claim inherently
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`anticipated because the results were “merely … an inherent property of the prior
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`art.” Id. at 1272–73. The court rejected the notion that the prior art must always
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`achieve a “complete restoration” or a “partial response.” Id. at 1276. Rather, to
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`“anticipate, the prior art need only meet the inherently disclosed limitation to the
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`extent the patented method does.” Id. Here, the label for ibrutinib reports a 45%
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`partial response and a 21% complete response. (EX2036, 45). Because there are no
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`differences between the claimed step and the step disclosed in the prior art, the
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`outcomes will not differ either. In re Montgomery, 677 F.3d 1375, 1381 (Fed. Cir.
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`2012) (“[E]ven if the claim includes an efficacy requirement, efficacy is inherent in
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`carrying out the claim steps.”). Thus, the ’085 Publication inherently discloses the
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`claimed patient outcomes.
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`D. Claims 9 and 10
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`Patent Owner does not separately dispute the Board’s findings for claims 9 or
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`10. During trial, Dr. Koreth admitted that patients with CLL would have had a
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`hematopoietic stem cell transplant, per claim 9. (EX1030, 30:4–9). And he admitted
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`that (1) cGVHD is “the most common and serious long-term complication following
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`an allogenic hematopoietic cell transplant (HCT)” (EX2055 ¶14); (2) there are
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`limited diseases that warrant a HCT (EX1030, 29:20–30:3); and (3) a cGVHD
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`patient typically had a HCT (id., 31:2–4), per claim 10.
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`E. Claims 24, 28, 35, 39, 43, 50, and 55
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`The Board preliminarily found these claims anticipated. Patent Owner’s
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`response is that the ’085 Publication does not show efficacy of 420 mg/day for
`
`treating cGVHD. But the law does not require that showing. Instead, the prior art
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`must enable administering the claimed dosage, which the ’085 Publication
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`indisputably does. See Impax, 468 F.3d at 1383 (“[P]roof of efficacy is not required
`
`for a prior art reference to be enabling under section 102.”). Dr. Koreth admitted that
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`the ’085 Publication discloses administering “420 mg/day” of ibrutinib. (EX2055
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`¶89).
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`Also, even if these claims are not anticipated, they were obvious. Dr. Ferrara
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`explained the motivation for using the disclosed dosage (used in treating CLL and
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`SLL) for treating cGVHD, and how a POSA would expect that dosage to be effective
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`since it had been successfully tested in clinical trials. (EX1006 ¶¶98–100).
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`IV. GROUND 2: OBVIOUSNESS OVER THE ’085 PUBLICATION
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`Patent Owner addresses Ground 2 only on POR pages 22–28 (regarding
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`claims 4, 13, and 15) and pages 56–57 (regarding claim 1). Patent Owner does not
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`specifically argue any other Challenged Claims under Ground 2. Therefore,
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`Petitioner likewise does not further address them.
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`A. Claim 1
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`Because claim 1 is anticipated, it is also obvious. (Dec., 25) (quoting Connell
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`v. Sears, Roebuck & Co., 722 F.2d 1542, 1548 (Fed. Cir. 1983) (“anticipation is the
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`epitome of obviousness”)). Alternatively, the ’085 Publication’s disclosure of
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`administering ibrutinib to treat “graft versus host disease” renders claim 1 obvious
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`because that genus has only “two possible disease states – acute and chronic.” (Dec.,
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`25).
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`The Board’s initial findings were confirmed by Patent Owner’s expert during
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`trial. Dr. Koreth agreed that “the major pathophysiologic entities are indeed acute
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`GVHD and chronic GVHD.” (EX1030, 130:18–19). He also admitted that many
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`drugs used to treat aGVHD are also used to treat cGVHD and vice versa. (EX1030,
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`140:22–141:11). This fact is supported by the NCCN Guidelines on GVHD
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`treatment, which Dr. Koreth testified provide “what the consensus is as to what
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`treatment options or specific treatments should be offered.” (EX1030, 20:1–10,
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`22:22–23:11). The NCCN Guidelines show
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`that eight of
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`thirteen drugs
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`recommende