`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`ACERTA PHARMA B.V.,
`Patent Owner.
`_____________________
`
`Case IPR2023-00478
`Patent 10,272,083 B2
`_____________________
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`TABLE OF CONTENTS
`
`Page
`
`
`TABLE OF AUTHORITIES ................................................................................... iv
`LIST OF EXHIBITS ............................................................................................... vii
`GLOSSARY OF ABBREVIATIONS ....................................................................... x
`I.
`INTRODUCTION ........................................................................................... 1
`II. MANDATORY NOTICES .............................................................................. 3
`III. REQUIREMENTS FOR REVIEW ................................................................. 4
`IV. THE ʼ083 PATENT .......................................................................................... 5
`A.
`Specification .......................................................................................... 5
`B.
`Claims .................................................................................................... 6
`C.
`Prosecution history ................................................................................ 8
`EFFECTIVE FILING DATE ......................................................................... 12
`V.
`VI. LEVEL OF ORDINARY SKILL .................................................................. 13
`VII. CLAIM CONSTRUCTION .......................................................................... 13
`A.
`“A method of treating a mantle cell lymphoma (MCL) in a
`human subject suffering therefrom comprising the step of orally
`administering, to the human subject” (claim 8) .................................. 14
`“a compound of Formula (II):…” (claims 8-9) ................................... 16
`“wherein the Mantle Cell Lymphoma (MCL) increases
`monocytes and NK cells in peripheral blood after treatment with
`Formula (II) for a period selected from the group consisting of
`about 14 days, about 28 days, and about 56 days” (claim 10) ............ 17
`VIII. TECHNICAL BACKGROUND ................................................................... 18
`IX. GROUNDS REFERENCES .......................................................................... 21
`A.
`Barf (EX1005) ..................................................................................... 21
`1.
`Prior-art status ........................................................................... 21
`2.
`Exemplary disclosures .............................................................. 23
`Barf-PCT (EX1006) ............................................................................ 25
`B.
`Cheson (EX1008) ................................................................................ 26
`C.
`X. ANALYSIS OF GROUNDS FOR TRIAL .................................................... 27
`
`B.
`C.
`
`-i-
`
`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`b.
`
`c.
`
`A. Ground 1: Claims 8-12 and 19-20 would have been obvious over
`Barf and Cheson. ................................................................................. 27
`1.
`Claim 8 ...................................................................................... 27
`a.
`“A method of treating a mantle cell lymphoma
`(MCL) in a human subject suffering therefrom
`comprising the step of” ................................................... 27
`“orally administering, to the human subject, … a
`BTK inhibitor, wherein the BTK inhibitor is a
`compound of Formula (II) … or a pharmaceutically-
`acceptable salt, hydrate, or solvate thereof.” .................. 28
`“a dose of 100 mg twice daily” ...................................... 28
`i.
`A 100 mg dose would have been obvious. ........... 29
`(1) Barf discloses and claims a range that
`encompasses the claimed dose. .................. 29
`(2) A POSA practicing Barf would have
`arrived at a 100 mg dose by conducting
`a routine dose-finding study. ..................... 34
`Twice-daily dosing would have been obvious. .... 40
`ii.
`Claim 9 ...................................................................................... 44
`2.
`Claim 10 .................................................................................... 44
`3.
`Claim 11 .................................................................................... 47
`4.
`Claim 12 .................................................................................... 48
`5.
`Claim 19 .................................................................................... 49
`6.
`Claim 20 .................................................................................... 49
`7.
`Ground 2: Claims 8-12 and 19-20 would have been obvious over
`Barf-PCT and Cheson. ........................................................................ 49
`1.
`Claim 8 ...................................................................................... 50
`a.
`“A method of treating a mantle cell lymphoma
`(MCL) in a human subject suffering therefrom
`comprising the step of” ................................................... 50
`“orally administering, to the human subject, … a
`BTK inhibitor, wherein the BTK inhibitor is a
`compound of Formula (II) … or a pharmaceutically-
`acceptable salt, hydrate, or solvate thereof.” .................. 50
`
`B.
`
`b.
`
`-ii-
`
`

`

`C.
`
`IPR2023-00478 (10,272,083 B2)
`
`“a dose of 100 mg twice daily” ...................................... 51
`c.
`Claim 9 ...................................................................................... 52
`2.
`Claim 10 .................................................................................... 53
`3.
`Claim 11 .................................................................................... 53
`4.
`Claim 12 .................................................................................... 53
`5.
`Claim 19 .................................................................................... 54
`6.
`Claim 20 .................................................................................... 54
`7.
`There are no probative secondary considerations. .............................. 54
`1.
`The results submitted during prosecution fail to
`demonstrate probative unexpected results. ............................... 55
`a.
`A daily dose of 200 mg acalabrutinib (100 mg BID)
`does not produce probative unexpected results. ............. 55
`Acalabrutinib’s twice-daily dosing does not produce
`probative unexpected results. ......................................... 59
`The results in the specification fail to demonstrate
`probative unexpected results. .................................................... 64
`XI. DISCRETIONARY FACTORS ..................................................................... 66
`A.
`The Board should not deny review under §314(a). ............................. 67
`B.
`The Board should not deny review under §325(d). ............................ 67
`XII. CONCLUSION .............................................................................................. 69
`CERTIFICATE OF COMPLIANCE........................................................................ 70
`CERTIFICATE OF SERVICE ................................................................................. 71
`
`b.
`
`2.
`
`-iii-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) ................................................ 68
`AK Steel Corp. v. Sollac & Ugine,
`344 F.3d 1234 (Fed. Cir. 2003) .......................................................................... 31
`Amgen Inc. v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) .................................................................... 31, 47
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) .......................................................................... 21
`Boehringer Ingelheim Pharms. Inc. v. Mylan Pharms. Inc.,
`803 F. App’x 397 (Fed. Cir. 2020) ................................................... 33, 34, 35, 37
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) .......................................................................... 22
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ............................................................................ 30
`Found. Med., Inc. v. Guardant Health, Inc.,
`IPR2019-00652, Paper 12 (PTAB Aug. 19, 2019) ......................................passim
`Fresenius Kabi USA, LLC v. Chugai Seiyaku Kabushiki Kaisha,
`IPR2021-01288, Paper 30 (PTAB Feb. 23, 2022) .............................................. 30
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 61
`Genzyme Therapeutic Prods. Ltd. P’ship v. Biomarin Pharm. Inc.,
`825 F.3d 1360 (Fed. Cir. 2016) .......................................................................... 34
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 64
`
`-iv-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ................................................................ 1, 30, 51
`Jansen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) .............................................................. 14, 15, 16
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ............................................................................ 65
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 44
`Ex Parte Mann,
`No. 2015-003571, 2016 WL 7487271 (PTAB Dec. 21, 2016) .......................... 22
`McNeil-PPC, Inc. v. L. Perrigo Co.,
`337 F.3d 1362 (Fed. Cir. 2003) .................................................................... 65, 66
`Merck & Co. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ...................................................................... 34, 39
`Minton v. Nat’l Ass’n of Secs. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 17
`Novartis Pharm. Corp. v. W.-Ward Pharm. Int’l Ltd.,
`923 F.3d 1051 (Fed. Cir. 2019) .......................................................................... 50
`Novartis Pharm. Corp. v. Accord Healthcare Inc.,
`387 F. Supp. 3d 429 (D. Del. 2019) .................................................................... 16
`Oticon Med. AB v. Cochlear Ltd.,
`IPR2019-00975, Paper 15 (PTAB Oct. 16, 2019) .............................................. 68
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .................................................................... 45, 53
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .............................................................. 56, 62, 66
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) .................................................................... 14, 15
`
`-v-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 45
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1289 (Fed. Cir. 2010), vacated on other grounds,
`374 F. App’x 35 (Fed. Cir. 2010), reinstated in-relevant-part,
`649 F.3d 1276 (Fed. Cir. 2011) .......................................................................... 27
`Valeant Pharms. Int’l, Inc. v. Mylan Pharms. Inc.,
`955 F.3d 25 (Fed. Cir. 2020) .............................................................................. 30
`Statutes
`U.S.C. Title 35 ........................................................................................................... 5
`35 U.S.C. §102(a)(2) ................................................................................................ 21
`35 U.S.C. §102(d)(2)................................................................................................ 22
`35 U.S.C. §314(a) .............................................................................................. 66, 67
`35 U.S.C. §325(d) ........................................................................................ 66, 67, 69
`Other Authorities
`37 C.F.R. §42.8(b) ..................................................................................................... 3
`37 C.F.R. §42.104 ...................................................................................................... 4
`37 C.F.R §42.104(b)(3) ............................................................................................ 13
`
`Interim Procedure for Discretionary Denials in AIA Post-Grant
`Proceedings with Parallel District Court Litigation,
`(USPTO Dir. June 21, 2022) ............................................................................... 67
`MPEP § 2111.04 .......................................................................................... 17, 18, 19
`MPEP § 2154.01(b).................................................................................................. 22
`MPEP § 2154.01(c) .................................................................................................. 21
`
`Request for Comments on USPTO Initiatives To Ensure the
`Robustness and Reliability of Patent Rights,
`87 Fed. Reg. 60,130 (Oct. 4, 2022) ...................................................................... 2
`
`-vi-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`LIST OF EXHIBITS
`
`1008
`
`1009
`
`No. Description
`1001 U.S. Patent No. 10,272,083 to Hamdy et al. (the “ʼ083 patent”)
`1002 Declaration of John P. Fruehauf, M.D., Ph.D.
`1003 Declaration of Sylvia Hall-Ellis, Ph.D.
`1004
`Prosecution History of U.S. Patent No. 10,272,083
`(Application No. 15/112,968)
`1005 U.S. Patent No. 9,758,524 to Barf, et al. (“Barf”)
`1006
`PCT International Publication No. WO2013/010868 to Barf, et al.
`(“Barf-PCT”)
`1007 U.S. Provisional Application No. 61/509,397 to Barf, et al.
`(“Barf Provisional”)
`Bruce D. Cheson, et al., Advancements in the Treatment of B-Cell
`Malignancies (International Conference on Malignant Lymphoma),
`CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY, Vol. 11, Issue 9,
`Supplement 12 (Sept. 2013) (“Cheson”)
`Ranjana H. Advani, et al., Bruton Tyrosine Kinase Inhibitor Ibrutinib
`(PCI-32765) Has Significant Activity in Patients With
`Relapsed/Refractory B-Cell Malignancies, J. CLINICAL ONCOLOGY,
`31(1):88-94 (Jan. 2013) (“Advani”)
`John C. Byrd, et al., Acalabrutinib (ACP-196) in Relapsed Chronic
`Lymphomatic Leukemia, N. ENGL. J. MED. 374(4):323-32 (Jan. 2016)
`(“Byrd”)
`1011 U.S. Provisional Application No. 61/929,742
`1012 U.S. Provisional Application No. 61/974,665
`1013 U.S. Provisional Application No. 62/035,777
`1014
`Stefano A. Pileri, et al., Mantle cell lymphoma, HAEMATOLOLGICA
`94(11):1488-92 (2009) (“Pileri”)
`1015 M. Dreyling, et al., How to manage mantle cell lymphoma, LEUKEMIA
`28:2117-31 (2014) (“Dreyling”)
`1016
`IMBRUVICA™ (ibrutinib) Prescribing Information (2014)
`1017 U.S. Food and Drug Administration Office of Clinical Pharmacology
`Review of IMBRUVICA™ (ibrutinib), Application No. NDA 205552
`(Jan. 2014)
`
`1010
`
`-vii-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`1019
`
`1020
`
`1022
`
`No. Description
`1018 Akintunde Akinleye, et al., Ibrutinib and novel BTK inhibitors in
`clinical development, J. OF HEMATOLOGY & ONCOLOGY 6:59 (2013)
`(“Akinleye”)
`Claire V. Hutchinson, et al., Breaking good: the inexorable rise of
`BTK inhibitors in the treatment of chronic lymphocytic leukaemia,
`BRITISH J. OF HAEMATOLOGY 166:12-22 (2014) (“Hutchinson”)
`Jennifer R. Brown, et al., Phase 1 Study Of Single Agent CC-292, a
`Highly Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, In
`Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL), BLOOD
`122(21):1630 (2013) (“Brown”)
`1021 Daniel W. Pierce, et al., Target Engagement, Pathway Inhibition, and
`Efficacy Of The Bruton’s Tyrosine Kinase (Btk) Inhibitor CC-292,
`BLOOD 122(21):4169 (2013) (“Pierce”)
`Simon Rule, et al., A Phase I Study Of The Oral Btk Inhibitor ONO-
`4059 In Patients With Relapsed/Refractory B-Cell Lymphoma, BLOOD
`122(21):4397 (2013) (“Rule”)
`1023
`Prosecution History of U.S. Patent No. 9,758,524
`1024 U.S. Food and Drug Administration, Good Review Practice: Clinical
`Review of Investigational New Drug Applications (Dec. 2013) (“FDA
`2013 Good Review Practice”)
`1025 U.S. Patent No. 7,732,454 (“Verner”)
`1026
`International Conference on Harmonisation; Dose-Response
`Information to Support Drug Registration; Guideline; Availability, 59
`Fed. Reg. 55,972 (Nov. 9, 1994)
`1027 U.S. Food and Drug Administration, Guidance for Industry - S9
`Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010)
`(“S9 Guidance”)
`1028 U.S. Food and Drug Administration, Guidance for Industry -
`Estimating the Maximum Safe Starting Dose in Initial Clinical Trials
`for Therapeutics in Adult Healthy Volunteers (July 2005) (“MSSD
`Guidance”)
`Erica K. Evans, et al., Inhibition of Btk with CC-292 Provides Early
`Pharmacodynamic Assessment of Activity in Mice and Humans, J.
`PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 346:219-228
`(Aug. 2013) (“Evans”)
`
`1029
`
`-viii-
`
`

`

`1032
`
`1033
`
`1034
`
`1035
`1036
`
`No. Description
`1030
`Tjeerd Barf, et al., Irreversible Protein Kinase Inhibitors: Balancing
`the Benefits and Risks, J. MED. CHEM. 55:6243-62 (2012) (“Barf
`2012”)
`1031 Amit Mahipal, et al., Risks and Benefits of Phase 1 Clinical Trial
`Participation, CANCER CONTROL 21:193-99 (July 2014) (“Mahipal”)
`Sarah Brumskill, et al., Conference Scene: Recent developments in the
`understanding and treatment of hematological malignancies, INT’L J.
`HEMATOLOGIC ONCOLOGY, Vol. 2, No. 5, published online at
`https://doi.org/10.2217/ijh.13.52 (Oct. 8, 2013) (“Brumskill”)
`Toshio Yoshizawa, et al., ONO-4059—a Potent and Selective
`Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent,
`Twice Daily (BD) Dosing and Dosing with Food Results in Sustained,
`High Trough Levels of ONO-4059, Translating into 100% Tumour
`Remission in a TMD-8 Xenograft Model, BLOOD, 124(21):4502 (2014)
`(“Yoshizawa”)
`Plaintiffs’ Initial Infringement Contentions to Defendant Sandoz Inc.,
`C.A. No. 22-154-GBW-SRF (Consolidated) (D. Del. Sept. 26, 2022)
`CALQUENCE® (acalabrutinib) Prescribing Information (2017)
`Jan de Jong, et al., Effect of CYP3A perpetrators on ibrutinib exposure
`in healthy participants, PHARMACOLOGY RESEARCH & PERSPECTIVES,
`Vol. 3, Issue 4 (2015) (“de Jong”)
`1037 Dominique Levêque, Evaluation of Fixed Dosing of New Anticancer
`Agents in Phase I Studies, ANTICANCER RESEARCH 28:3075-78 (2008)
`(“Levêque”)
`ZYDELIG® (idelalisib) Prescribing Information (2014)
`TASIGNA® (nilotinib) Prescribing Information (2007)
`JAKAFI™ (ruxolitinib) Prescribing Information (2011)
`LYNPARZA™ (olaparib) Prescribing Information (2014)
`Betty Y. Chang, et al., Egress of CD191CD51 cells into peripheral
`blood following treatment with the Bruton tyrosine kinase inhibitor
`ibrutinib in mantle cell lymphoma patients, BLOOD 122(14):2142
`(2013) (“Chang”)
`1043 Yan Bao, et al., Tyrosine Kinase Btk Is Required for NK Cell
`Activation, J. Biological Chemistry 287(28):23769 (2012)
`
`
`1038
`1039
`1040
`1041
`1042
`
`IPR2023-00478 (10,272,083 B2)
`
`
`
`
`-ix-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`GLOSSARY OF ABBREVIATIONS
`
`BCR ...................................................................................................... B-cell receptor
`BID, b.i.d., BD ........................................................................ twice a day (bis in die)
`BTK, Btk ............................................................................ Bruton’s Tyrosine Kinase
`CLL ............................................................................. chronic lymphocytic leukemia
`EC50, IC50 ...................................... half-maximal effective/inhibitory concentration
`FDA .................................................................... U.S. Food and Drug Administration
`MCL ........................................................................................ mantle-cell lymphoma
`MPEP ........................................................... Manual of Patent Examining Procedure
`NHL ................................................................................... non-Hodgkin’s lymphoma
`NK ................................................................................................ natural killer [cells]
`nM .............................................................................................................. nanomolar
`ORR ............................................................................................ overall response rate
`PCT ................................................................................... Patent Cooperation Treaty
`PI3K ................................................................................... phosphoinositide 3-kinase
`POSA ....................................................................... person of ordinary skill in the art
`QD ......................................................................................... once a day (quaque die)
`µM ............................................................................................................. micromolar
`SLL ................................................................................. small lymphocytic leukemia
`
`-x-
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`

`

`I.
`
`IPR2023-00478 (10,272,083 B2)
`
`
`INTRODUCTION
`Petitioner requests inter partes review of claims 8-12 and 19-20 of U.S.
`
`Patent No. 10,272,083 (the “’083 patent”). These claims are directed to treating
`
`mantle-cell lymphoma (“MCL”) by orally administering 100 mg twice daily of
`
`acalabrutinib, a known inhibitor of Bruton’s Tyrosine Kinase (“BTK”). As shown
`
`below and by Petitioner’s expert, Dr. Fruehauf (EX1002), all challenged claims
`
`would have been obvious to a person of ordinary skill in the art (“POSA”) by the
`
`ʼ083 patent’s effective filing date on January 21, 2015, based on two grounds.
`
`First, all challenged claims would have been obvious over Barf (EX1005)
`
`and Cheson (EX1008). Infra §X.A. Barf is an issued patent with an effective
`
`filing date in 2011, whose sole independent claim recites a method of treating MCL
`
`with acalabrutinib. EX1005, 150:2-32. Barf’s claim 12 narrows this method by
`
`reciting a dosing range that overlaps with the ʼ083 patent’s claimed 100 mg dose
`
`(id., 151:14-16), triggering “a presumption of obviousness.” Iron Grip Barbell Co.
`
`v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004). Moreover, a POSA
`
`would have arrived at the claimed dose through routine experimentation by
`
`conducting a dose-finding study focused on maximizing BTK occupancy, which
`
`was successfully done for previous BTK inhibitors. EX1002 ¶¶15, 127-42.
`
`Administering the claimed dose twice daily would have been obvious over
`
`Cheson’s teaching that “BTK inhibitors are being evaluated in a twice-daily
`
`-1-
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`

`

`IPR2023-00478 (10,272,083 B2)
`
`
`schedule in an attempt to overcome the synthesis of new BTK molecules,” which
`
`“appeared to be more effective” in clinical trials. EX1008, 4, 10; EX1002 ¶16.
`
`Second, to the extent Patent Owner attempts to disqualify Barf as prior art,
`
`all challenged claims would have been obvious over Barf-PCT (EX1006) and
`
`Cheson. Infra §X.B. Barf-PCT is the international application counterpart to Barf,
`
`published in 2013. EX1006, 1. Thus, Barf-PCT provides the same disclosures as
`
`Barf—including acalabrutinib, treating MCL, and the overlapping dosing range.
`
`Id., 35:16-36:2, 22:15-16, 20:24-25; EX1002 ¶17.
`
`During prosecution, the Examiner repeatedly found the claims prima facie
`
`obvious and allowed them only after the applicants alleged unexpected results.
`
`Infra §IV.C. As shown below, however, the alleged results were neither probative
`
`nor unexpected. Infra §X.C. Thus, the Examiner’s basis for allowance was
`
`incorrect, and the challenged claims are unpatentable.
`
`Patent Owner is currently asserting these claims against generic drug makers
`
`of acalabrutinib, including Petitioner. Instituting review and canceling the
`
`challenged claims will thus promote the Office’s objective to ensure that the patent
`
`“system, as a whole, does not unnecessarily delay generic and biosimilar
`
`competition, which provide cost savings to Americans when they purchase
`
`pharmaceutical products.” 87 Fed. Reg. 60,130, 60,131 (Oct. 4, 2022).
`
`-2-
`
`

`

`II. MANDATORY NOTICES
`Under 37 C.F.R. §42.8(b), Petitioner states as follows:
`
`IPR2023-00478 (10,272,083 B2)
`
`
`1.
`
`Real party-in-interest. For purposes of this Petition only, the real
`
`party-in-interest is Sandoz Inc.
`
`2.
`
`Related matters. The ’083 patent has been asserted in the following
`
`civil actions: Acerta Pharma BV v. Cipla Ltd., No. 1-22-cv-00162 (D. Del.); Acerta
`
`Pharma BV v. MSN Pharms. Inc., No. 1-22-cv-00163 (D. Del.); Acerta Pharma BV
`
`v. Sandoz Inc., No. 1-22-cv-00164 (D. Del.); Acerta Pharma BV v. Alembic
`
`Pharms. Ltd., No. 1-22-cv-00154 (D. Del.); Acerta Pharma BV v. Natco Pharma
`
`Ltd., No. 1-22-cv-00155 (D. Del.).
`
`No prior IPR petition for the ʼ083 patent has been filed.
`
`The ’083 patent is related to U.S. Patent No. 11,090,302.
`
`3.
`
`Lead and back-up counsel. Petitioner identifies the following:
`
` Lead counsel:
`
`Jovial Wong (Reg. No. 60,115)
`
` Back-up counsel:
`
`Charles B. Klein*
`
` Back-up counsel:
`
`Eimeric Reig-Plessis*
`
` Back-up counsel:
`
`Sharon Lin*
`
`* Counsel to seek pro hac vice admission.
`
`4.
`
`Service information. Petitioner identifies the following:
`
` Email address:
`
`acalabrutinibIPR@winston.com
`
`-3-
`
`

`

` Mailing address:
`
`Winston & Strawn LLP
`
`IPR2023-00478 (10,272,083 B2)
`
`
`1901 L Street NW
`
`Washington, DC 20036
`
` Telephone number:
`
`202-282-5867
`
` Fax number:
`
`
`
`202-282-5100
`
`Please address all correspondence to lead counsel at the address shown
`
`above. Petitioner consents to electronic service at the above-listed email address.
`
`III. REQUIREMENTS FOR REVIEW
`Under 37 C.F.R. §42.104, Petitioner certifies:
`
`a. Grounds for standing. The ’083 patent is available for IPR.
`
`Petitioner is not barred or estopped from requesting review of any claim on any
`
`ground. All fees may be charged to Deposit Account No. 50-1814.
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`b.
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`Identification of challenge. As explained further below, Petitioner
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`requests cancelation of claims 8-12 and 19-20 under the following grounds:
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`-4-
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`IPR2023-00478 (10,272,083 B2)
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`
`Ground
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`Claims
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`Basis1
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`References
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`1
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`2
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`8-12, 19-20
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`103 Barf, Cheson
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`8-12, 19-20
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`103 Barf-PCT, Cheson
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`IV. THE ʼ083 PATENT
`A.
`Specification
`The ʼ083 patent is titled “Methods of treating chronic lymphocytic leukemia
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`and small lymphocytic leukemia using a BTK inhibitor.” EX1001. The
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`“Background of the Invention” explains that BTK is a “protein kinase expressed in
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`B cells” whose function “is well established.” EX1001, 1:14-18. Citing prior art,
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`the specification admits that “[t]he reported role for BTK in the regulation of
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`proliferation and apoptosis [i.e., death] of B cells indicates the potential for BTK
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`inhibitors in the treatment of B cell lymphomas,” and “BTK inhibitors have thus
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`been developed as potential therapies.” Id., 1:28-32.
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`Like the title, the specification focuses on “B cell chronic lymphocytic
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`leukemia (CLL)” (id., 1:34) and “[s]mall lymphocytic leukemia (SLL)” (id., 1:45).
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`1 The ʼ083 patent was filed in 2015 and claims priority to provisional applications
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`filed in 2014 (EX1001, 1), after the effective date of March 16, 2013, for the
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`Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125 Stat. 284,
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`287-88 (2011). Thus, this Petition applies the AIA version of Title 35.
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`IPR2023-00478 (10,272,083 B2)
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`The specification discloses treatments for these conditions by administering a
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`compound of “Formula (II),” i.e., acalabrutinib. Id., 2:37-47. The only recited
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`clinical data is from a study on CLL. Id., 7:24-61, Figs. 2-8. The patent contains
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`no in vivo or clinical data on MCL. EX1002 ¶43.
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`The specification does not ascribe any significance to any particular doses,
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`recognizing that “[t]he amounts of BTK inhibitors administered” may vary in “the
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`discretion of the prescribing physician.” EX1001, 42:29-33. The patent states that
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`“an effective dosage is in the range of about 0.001 to about 100 mg per kg body
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`weight per day,” with exemplary ranges spanning 1-500 mg. Id., 42:33-34, 43:12-
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`38. As to frequency, the patent states that dosing may occur as rarely as “once a
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`month” or as often as “six times per day.” Id., 42:50-62.
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`The only mention of dosing for MCL is in a list including 10 other
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`conditions. Id., 4:1-33. For these conditions, the patent recites administration
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`“once daily at a dose selected from the group consisting of 100 mg, 175 mg, 250
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`mg, and 400 mg” or “twice daily at a dose of 100 mg.” Id., 4:16-17, 4:33. No data
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`is provided for these dosing regimens to treat MCL. EX1002 ¶45.
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`B. Claims
`The ʼ083 patent has two independent claims: 1 and 8. Claim 1 and its
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`dependent claims, which Petitioner is not challenging, recite “treating chronic
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`lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).” EX1001,
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`-6-
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`IPR2023-00478 (10,272,083 B2)
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`99:2-3. Claim 8 is the sole independent claim challenged in this Petition and
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`recites a method of treating MCL:
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`8. A method of treating a mantle cell lymphoma (MCL) in a human
`subject suffering therefrom comprising the step of orally administering,
`to the human subject, a dose of 100 mg twice daily of a BTK inhibitor,
`wherein the BTK inhibitor is a compound of Formula (II):
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`or a pharmaceutically-acceptable salt, hydrate, or solvate thereof.
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`
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`Id., 100:39-65.
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`The challenged dependent claims exclude hydrates or solvates (claim 9),
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`recite intended effects of certain treatment durations (claim 10), limit MCL to
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`certain morphologies (claim 11), add combination therapy with an anti-CD20
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`antibody (claim 12), require the free form of acalabrutinib (claim 19), or require a
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`salt form (claim 20).
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`-7-
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`IPR2023-00478 (10,272,083 B2)
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`C.
`Prosecution history
`None of the originally filed claims were specific to treating MCL. Like its
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`issued version, claim 1 recited a treatment for CLL/SLL. EX1004, 4. The only
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`other independent claim (originally numbered 9) was a Markush claim reciting “[a]
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`method of treating a hematological malignancy” that only mentioned MCL as one
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`of 11 conditions. Id., 5.
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`The Examiner rejected the claims as obvious over U.S. Patent Application
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`Publication No. 2013/0338172 (“Smyth ʼ172”) and Barf-PCT, which the Examiner
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`called “Johannes” or “868.” EX1004, 908. The Examiner relied on Smyth ʼ172,
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`which describes an oral formulation of ibrutinib (another BTK inhibitor) because it
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`“is similar to the compound of the instant claims and is used to treat similar
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`disorders.” Id., 909. The Examiner relied on Barf-PCT for acalabrutinib’s
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`structure, stating (erroneously) that “[t]he compound of example 1 is identical to
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`that of the instant claimed formula (II).” Id. The Examiner found “[i]t would have
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`been obvious to include the compound of the 868 into the formulation of the 172 as
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`the compound[s] have the same cores and treat the same conditions.” Id.
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`In response, the applicants amended both independent claims to recite “a
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`human subject suffering” from the recited conditions. Id., 989, 991. For claim 9
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`(which issued as claim 8), “hematological malignancy” was changed to “mantle
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`IPR2023-00478 (10,272,083 B2)
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`cell lymphoma (MCL).” Id., 991. For both claims, the applicants added the dosing
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`regimen, “100 mg twice daily.” Id., 989-91.
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`In their remarks, the applicants revealed a reason for their newfound focus
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`on MCL and the claimed regimen: On October 31, 2017—nearly four years from
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`the earliest claimed priority date—FDA approved acalabrutinib (CALQUENCE®)
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`100 mg twice daily to treat MCL. Id., 994. Thus, the applicants amended then-
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`claim 9 to