`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`v.
`MERCK SERONO S.A.,
`Patent Owner.
`
`___________________
`
`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,713,947
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`TABLE OF CONTENTS
`
`I.
`
`C.
`D.
`
`STATEMENT OF PRECISE RELIEF REQUESTED AND REASONS
`THEREFOR (37 C.F.R. § 42.22(A)) .............................................................. 1
`INTRODUCTION .......................................................................................... 1
`II.
`III. THE ’947 PATENT AND ITS PROSECUTION HISTORY ........................ 7
`A.
`Specification of the ’947 patent ............................................................ 8
`B.
`Challenged claims ................................................................................. 8
`C.
`The ’947 patent prosecution history ...................................................... 9
`IV. STATE OF THE ART BEFORE DECEMBER 22, 2004 ............................ 13
`A. MS is a chronic disease with no known cure ......................................13
`B.
`Immunosuppression was a common treatment strategy; lymphocyte
`count was a common measure for assessing response to treatment ....15
`Treatment of MS required cyclical drug therapies ..............................17
`Cladribine, a known immunosuppressant, was used to treat MS before
`December 2004 ....................................................................................19
`Oral cladribine compositions and dosages for treating MS were known
`in the art ...............................................................................................21
`Petitioner’s ground relies specifically on the following publications .22
`1.
`Bodor (EX1022) ....................................................................... 22
`2.
`Stelmasiak (EX1013) ............................................................... 24
`PERSON OF ORDINARY SKILL IN ART ................................................ 28
`V.
`VI. CLAIM CONSTRUCTION ......................................................................... 29
`A.
`“total dose of cladribine” .....................................................................29
`B.
`“an induction period” ..........................................................................29
`C.
`“a maintenance period” .......................................................................30
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(B)) ...... 33
`VII.
`VIII. GROUND 1: THE CLAIMS WOULD HAVE BEEN OBVIOUS OVER
`BODOR AND STELMASIAK .................................................................... 33
`A.
`Claim 36 ..............................................................................................33
`
`E.
`
`F.
`
`- i -
`
`

`

`1.
`
`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`A POSA would have had a reason to combine Bodor and
`Stelmasiak to arrive at the claimed methods ........................... 33
`A POSA would have had a reasonable expectation of success 43
`2.
`Each limitation of claim 36 is disclosed in the art ................... 45
`3.
`Claim 38 ..............................................................................................55
`B.
`Claim 39 ..............................................................................................55
`C.
`Claim 41 ..............................................................................................56
`D.
`Claim 42 ..............................................................................................57
`E.
`Claim 43 ..............................................................................................58
`F.
`Claims 44 and 45 .................................................................................59
`G.
`Claim 46 ..............................................................................................60
`H.
`IX. NO OBJECTIVE
`INDICIA WEIGH AGAINST THE STRONG
`OBVIOUSNESS SHOWING HERE ........................................................... 60
`THE FACTS AND LAW WEIGH AGAINST DISCRETIONARY DENIAL
`UNDER § 325(D). ........................................................................................ 61
`XI. FINTIV DOES NOT SUPPORT DISCRETIONARY DENIAL. ................ 65
`XII. GENERAL PLASTIC DOES NOT SUPPORT DISCRETIONARY DENIAL.
` ...................................................................................................................... 67
`XIII. CERTIFICATION AND STANDING (37 C.F.R. § 42.104(A)) ................. 68
`XIV. MANDATORY NOTICES (37 C.F.R. § 42.8(A)(1)) .................................. 68
`
`
`X.
`
`
`
`
`
`- ii -
`
`

`

`
`
`Exhibit #
`
`1001
`
`1002
`1003
`1004
`1005
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`EXHIBIT LIST
`
`
`Description
`
`De Luca, G., et al., “Cladribine Regimen for Treating Multiple
`Sclerosis,” U.S. Patent No. 7,713,947 B2 (filed June 18, 2007; issued
`May 11, 2010)
`Declaration of Aaron Miller, M.D.
`Curriculum Vitae for Aaron Miller, M.D.
`File History for U.S. Patent No. 7,713,947
`Intentionally Left Blank
`Noseworthy, J.H., et al., “Multiple Sclerosis,” The New England
`Journal of Medicine, 343(13):938-952 (2000)
`Neuhaus, O., et al., “Immunomodulation in multiple sclerosis: from
`immunosuppression to neuroprotection,” TRENDS in
`Pharmaceutical Sciences, 24(3):131-138 (2003)
`Weiner, H.L., et al., “Immunotherapy of Multiple Sclerosis,” Annals
`of Neurology, 23(3):211-222 (1988)
`Wingerchuk, D.M., et al., “Biology of Disease, Multiple Sclerosis:
`Current Pathophysiological Concepts,” Laboratory Investigation,
`81(3):263-281 (2001)
`Kurtzke, J.F., “Rating neurologic impairment in multiple sclerosis:
`An expanded disability status scale (EDSS),” Neurology, 33:1444-
`1452 (1983)
`Intentionally Left Blank
`Whitaker, J.N., “Rationale for Immunotherapy in Multiple
`Sclerosis,” Annals of Neurology, 36:S103-S107 (1994)
`Stelmasiak, Z., et al., “A pilot trial of cladribine (2-
`chlorodeoxyadenosine) in remitting-relapsing multiple sclerosis,”
`Medical Science Monitor, 4(1):4-8 (1998)
`Beutler, E., et al., “The treatment of chronic progressive multiple
`sclerosis with cladribine,” Proceedings of the National Academy of
`Sciences, USA 93:1716-1720 (1996)
`Tortorella, C., et al., “Cladribine Ortho Biotech Inc,” Current
`Opinion in Investigational Drugs, 2(12):1751-1756 (2001)
`Langtry, H.D., et al., “Cladribine, A Review of its Use in Multiple
`Sclerosis,” BioDrugs, 9(5):419-433 (1998)
`
`- iii -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`
`Description
`
`Rudick, R.A., et al., “Management of Multiple Sclerosis,” The New
`England Journal of Medicine, 337(22):1604-1611 (1997)
`Rice, G.P.A., et al., “Cladribine and progressive MS, Clinical and
`MRI outcomes of a multicenter controlled trial,” Neurology,
`54:1145-1155 (2000)
`Barkhof, R., et al., “Limited duration of the effect of
`methylprednisolone on changes on MRI in multiple sclerosis,”
`Neuroradiology, 36:382-387 (1994)
`Pirko, I. and Rodriguez, M., “Pulsed Intravenous
`Methylprednisolone Therapy in Progressive Multiple Sclerosis: Need
`for a Controlled Trial,” Archives of Neurology, 61:1148-1149 (2004)
`Weiner, H.L., et al., “Intermittent cyclophosphamide pulse therapy in
`progressive multiple sclerosis: Final report of the Northeast
`Cooperative Multiple Sclerosis Treatment Group,” Neurology,
`43:910-918 (1993)
`Bodor, N. and Dandiker, Y., “Oral Formulations of Cladribine,”
`International Publication No. WO 2004/087101 A2 (filed March 26,
`2004; published October 14, 2004)
`Grieb, P., et al., “Effect of Repeated Treatments with Cladribine (2-
`Chlorodeoxyadenosine) on Blood Counts in Multiple Sclerosis
`Patients,” Archivum Immunologiae Experimentalis, 43:323-327
`(1995)
`Schultz, T.W., et al., “Cyclodextrine Cladribine Formulations,” U.S.
`Patent No. 6,194,395 B1 (filed February 25, 1999; issued February
`27, 2001)
`File History for U.S. Patent No. 8,377,903
`Beutler, E., “Use of Substituted Adenine Derivatives for Treating
`Multiple Sclerosis,” U.S. Patent No. 5,506,214 B2 (filed February
`18, 1993; issued April 9, 1996)
`Docket Report, Merck KGaA et al. v. Hopewell Pharma Ventures,
`Inc., Case No. 1:22-cv-01365-GBW (D.Del.)
`Docket Report, Merck KGaA et al. v. Accord Healthcare, Inc., Case
`No. 1:22-cv-00974-GBW (D.Del.)
`United States District Courts - National Judicial Caseload Profile,
`June 2022
`Curriculum Vitae for Nancy E. Adams, Ed.D.
`
`Exhibit #
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`1030
`
`- iv -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`
`Description
`
`Romine, J. S., et al., “A Double-Blind, Placebo-Controlled,
`Randomized Trial of Cladribine in Relapsing-Remitting Multiple
`Sclerosis,” Proceedings of the Association of American Physicians,
`111(1):35-44 (1999)
`Docket Report, Merck KGaA et al. v. Aurobindo Pharma USA, Inc.,
`et al., Case No. 1:23-cv-00039-GBW (D.Del.)
`Bloom, P.M., “Treatment of Multiple Sclerosis with
`Lymphocytapheresis and Chemo-Immunosuppression,” U.S. Patent
`No. 4,964,848 (filed June 27, 1988; issued October 23, 1990)
`Intentionally Left Blank
`Intentionally Left Blank
`Lassmann, H., et al., “Heterogeneity of multiple sclerosis
`pathogenesis: implications for diagnosis and therapy,” TRENDS in
`Molecular Medicine, 7(3):115-121 (March 2001)
`Lublin, F. D., et al., “Defining the clinical course of multiple
`sclerosis: Results of an international survey,” Neurology, 46:907-911
`(1996)
`Casanova, B., et al., “High clinical inflammatory activity prior to the
`development of secondary progression: a prospective 5-year follow-
`up study,” Multiple Sclerosis, 8:59-63 (2002)
`Publisher's Record for Stelmasiak (EX1013)
`Declaration of Nancy E. Adams, Ed.D.
`Intentionally Left Blank
`Shurkovich, S., et al., “Randomized study of antibodies to INF-γ and
`TNF-α in secondary progressive multiple sclerosis,” Multiple
`Sclerosis, 7:277-84 (2001)
`Khoury, S. J., “Multiple Sclerosis: What Have We Learned From
`Magnetic Resonance Imaging Studies?,” Archives of Internal
`Medicine, 158:565-73 (1998)
`Roitt, I. M., “Essential Immunology, Sixth Edition,” Blackwell
`Scientific Publications, 1-29 (1988) (Excerpt)
`Filippi, M., et al., “The effect of cladribine on T1 'black hole'
`changes in progressive MS,” Journal of Neurological Sciences,
`176:42-44 (2000)
`Romine, J. S., et al., “Cladribine: Use in Therapy of Multiple
`Sclerosis,” Biodrugs, 7(5):386-93 (1997)
`
`Exhibit #
`
`1031
`
`1032
`
`1033
`
`1034
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`1040
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`- v -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`Exhibit #
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`
`Description
`
`Selby, R., et al., “Safety and Tolerability of Subcutaneous Cladribine
`Therapy in Progressive Multiple Sclerosis,” Canadian Journal of
`Neurological Sciences, 25:295-99 (1998)
`Liliemark, J., “The Clinical Pharmacokinetics of Cladribine,”
`Clinical Pharmacokinetics, 32(2):120-31 (1997)
`Barkhof, F., et al., “Limited duration of the effect of
`methylprednisolone on changes on MRI in multiple sclerosis,”
`Neuroradiology, 36:382-387 (1994)
`Chumlea, W.C., “Total body water data for white adults 18 to 64
`years of age: The Fels Longitudinal Study,” Kidney International,
`56:244-252 (1999)
`U.S. Patent and Trademark Office, Memorandum, Interim Procedure
`for Discretionary Denials in AIA Post-Grant Proceedings with
`Parallel District Court Litigation (June 21, 2022)
`
`
`
`
`- vi -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`TABLE OF ABBREVIATIONS
`
`Definition
`Multiple sclerosis
`Relapsing-remitting multiple sclerosis
`Central nervous system
`Expanded disability status scale
`Scripps neurologic scoring scale
`Intravenous methylprednisolone
`
`Abbreviation
`MS
`RRMS
`CNS
`EDSS
`SNRS
`IVMP
`
`
`
`
`
`
`
`
`- vii -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`TABLE OF AUTHORITIES
`
`Cases
`Abbott Labs. v. Andrx Pharm., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ............................................................................22
`ACCO Brands Corp. v. Fellowes, Inc.,
`813 F.3d 1361 (Fed. Cir. 2016) ............................................................................37
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`IPR2019-01469, Paper 6 (P.T.A.B. Feb. 13, 2020) ...................................... 61, 63
`Agrofresh Solutions, Inc. v. Lytone Enterprise, Inc.,
`IPR2021-00451, Paper 11 (P.T.A.B. July 27, 2021) ...........................................64
`Amgen Inc, v. Hoechst Marion Roussel, Inc.,
`314 F.3d 1313 (Fed. Cir. 2003) ............................................................................13
`Amneal Pharms., LLC v. Supernus Pharms., Inc.,
`IPR2013-00368, Paper 8 (P.T.A.B. Dec. 17, 2013) ............................................61
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, Paper 11 (P.T.A.B. Mar. 20, 2020) ............................. 65, 66, 67
`Becton, Dickinson & Co. v. Baxter Corp. Englewood,
`998 F.3d 1337 (Fed. Cir. 2021) ............................................................................52
`Biogen Idec, Inc. v. GlaxoSmithKline LLC,
`713 F.3d 1090 (Fed. Cir. 2013) ............................................................................31
`Code200, UAB v. Bright Data Ltd.,
`IPR2022-00861, IPR2022-00862, Paper 18 (P.T.A.B. Aug. 23, 2022) ....... 67, 68
`Duramed Pharm., Inc. v. Watson Labs., Inc.,
`413 F. App’x 289 (Fed. Cir. 2011) ......................................................................34
`E.I. DuPont de Nemours & Company v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ........................................................... 39, 41, 42, 43
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ..............................................................................39
`Gen. Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (P.T.A.B. Sept. 6, 2017) ..................................... 67, 68
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) ...................................................................... 40, 43
`
`- viii -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`In re Applied Materials,
`692 F.3d 1289 (Fed. Cir. 2012) ............................................................................40
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) ............................................................................40
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ............................................................................39
`In re Woodruff,
`919 F.2d 1575 (Fed. Cir. 1990) ............................................................................40
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................51
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) ..................................................................... 13, 43
`Micron Tech., Inc. v. Godo Kaisha IP Bridge 1,
`IPR2020-01007, Paper 15 (P.T.A.B. Dec. 7, 2020) ..................................... 66, 67
`Microsoft Corp. v. Multi-Tech Systems, Inc.,
`357 F.3d 1340 (Fed. Cir. 2004) ............................................................................31
`Newell Cos., Inc. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ..............................................................................60
`NOF Corp. v. Nektar Therapeutics,
`IPR2019-01394, Paper 68 (P.T.A.B. July 30, 2021) ...........................................40
`OpenSky Indus., LLC v. VLSI Tech. LLC,
`IPR2021-01064, Paper 17 (P.T.A.B. Dec. 23, 2021) ..........................................67
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) ............................................................................22
`Sand Revolution II, LLC v. Continental Intermodal Group – Trucking LLC,
`IPR2019-01393, Paper 24 (P.T.A.B. June 16, 2020)...........................................66
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) ............................................................................13
`Shenzhen Silver Star Intelligent Tech. Co., Ltd. v. iRobot Corp.,
`IPR2018-00761, Paper 15 (P.T.A.B. Sept. 5, 2018) ............................................68
`Sotera Wireless, Inc. v. Masimo Corporation,
`IPR2020-01019, Paper 12 (P.T.A.B. Dec. 1, 2020) ............................................65
`Vudu, Inc. v. Ideahub, Inc.,
`IPR2020-01689, Paper 16 (P.T.A.B. Apr. 19, 2021) ...........................................64
`
`- ix -
`
`

`

`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`Statutes
`35 U.S.C. § 103 .......................................................................................................... 1
`35 U.S.C. § 103(a) ...................................................................................................33
`35 U.S.C. § 325(d) ...................................................................................... 61, 63, 65
`Other Authorities
`U.S. Patent and Trademark Office, Memorandum, Interim Procedure for
`Discretionary Denials in AIA Post-Grant Proceedings with Parallel District
`Court Litigation (June 21, 2022) ..........................................................................66
`Regulations
`37 C.F.R. § 42.10(b) ................................................................................................70
`37 C.F.R. § 42.104(a) ...............................................................................................68
`37 C.F.R. § 42.104(b) ..............................................................................................33
`37 C.F.R. § 42.106(a) ...............................................................................................70
`37 C.F.R. § 42.22(a) ................................................................................................... 1
`37 C.F.R. § 42.63(e) .................................................................................................70
`37 C.F.R. § 42.8(a)(1) ..............................................................................................68
`37 C.F.R. § 42.8(b)(2) ..............................................................................................69
`37 C.F.R. § 42.8(b)(3) ..............................................................................................70
`37 C.F.R. § 42.8(b)(4) ..............................................................................................70
`
`
`
`- x -
`
`

`

`I.
`
`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`STATEMENT OF PRECISE RELIEF REQUESTED AND REASONS
`THEREFOR (37 C.F.R. § 42.22(A))
`Hopewell Pharma Ventures, Inc. (“Hopewell”) petitions for inter partes
`
`Review, seeking cancellation of claims 36, 38, 39, and 41-46 of U.S. Patent No.
`
`7,713,947 (“the ’947 patent”; EX1001), assigned to Merck Serono S.A. (“Merck”).
`
`The challenged claims are unpatentable under 35 U.S.C. § 103. This Petition is
`
`supported by the declaration of Dr. Aaron Miller, M.D. (EX1002), an expert in
`
`multiple sclerosis.
`
`II.
`
`INTRODUCTION
`The claims encompass methods of treating multiple sclerosis (“MS”)
`
`comprising “oral administration of a formulation comprising cladribine” following
`
`“the sequential steps” of “an induction period,” “a cladribine-free period,” “a
`
`maintenance period,” and another “cladribine-free period.” EX1001, 19:13-30.
`
`Properly construed, the claims require that a total dose of cladribine administered
`
`in the maintenance period is lower than the total dose of cladribine administered in
`
`an induction period in the claimed method. The prior art would have rendered such
`
`methods obvious.
`
`MS is a chronic autoimmune disease with no known cure. EX1009, 263;
`
`EX1002, ¶¶15, 22. Most patients experience a relapsing-remitting form of MS
`
`(“RRMS”), in which neurological symptoms and signs develop over several days,
`
`plateau, and then usually improve—events known as “relapses.” EX1009, 263;
`
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`EX1002, ¶15. Many RRMS patients go on to develop secondary progressive
`
`multiple sclerosis (“SPMS”), characterized by emerging “progressive neurological
`
`dysfunction.” EX1009, 263; EX1002, ¶15. Therefore, a person of ordinary skill in
`
`the art (“POSA”) would have known before December 2004 that as a rule, an MS
`
`patient typically needs ongoing care. EX1013, 6; EX1009, 263; EX1002, ¶¶15, 53.
`
`Given the autoimmune nature of MS, “the most common therapeutic
`
`approach” to MS before December 2004 was by immunosuppression. EX1013, 4;
`
`EX1007, 131; EX1002, ¶16. Before 2004, cladribine emerged as a useful drug “in
`
`modulating autoimmune processes” involving lymphocyte abnormalities. EX1018,
`
`1146; EX1002, ¶16. Scientists originally developed cladribine for treatment of
`
`leukemia, but quickly repurposed it for treatment of MS due to its demonstrated
`
`ability to, e.g., “impressively decrease[]” relapse rate in patients with RRMS.
`
`EX1013, 5, 7; EX1002, ¶16. A POSA seeking to treat MS would have used the
`
`common strategy of immunosuppression and chosen cladribine because it was
`
`known to “selectively damage lymphocytes” while being “not harmful to normal
`
`bone marrow cells and other cell types,” unlike otherimmunosuppressants (e.g.,
`
`cyclophosphamide, cyclosporine A, chlorambucil). EX1015, 1752; EX1013, 6-7;
`
`EX1002, ¶34. In treating MS with cladribine, neurologists commonly assessed the
`
`effect of cladribine by measuring a patient’s lymphocyte count, with a sustained
`
`decrease in count being characteristic of a treatment response. EX1018, 1146;
`
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`EX1013, 5; EX1014, 1717; EX1002, ¶¶16, 38.
`
`Before December 2004, Bodor, noting a preference of “[o]ral delivery of
`
`[cladribine] … to parental delivery,” described an oral formulation of cladribine
`
`that exhibited “improved cladribine absorption, as reflected by higher
`
`bioavailability.” EX1022, 2, 11-12; EX1002, ¶60. Bodor taught the following
`
`cyclical regimen for treating MS: “10 mg of cladribine … administered once per
`
`day for a period of five to seven days in the first month, repeated for another period
`
`of five to seven days in the second month, followed by ten months of no
`
`treatment.” EX1022, 2, 11-12; EX1002, ¶79. Because MS is a progressive and
`
`incurable disease, a POSA reading Bodor in light of general knowledge in the art
`
`would have understood that there would have been MS patients who would need to
`
`be retreated after the “no-treatment” (cladribine-free) period. EX1002, ¶100. Dr.
`
`Miller prepared a graphic to demonstrate how a POSA would have understood
`
`Bodor’s regimen (EX1002, ¶84):
`
`In following Bodor’s express teachings, a POSA would have orally
`
`
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`administered cladribine for two months (an induction period), following by a ten-
`
`month cladribine-free period. EX1022, 23; EX1002, ¶17. And because a POSA
`
`would have understood that an MS patient typically needs ongoing care, a POSA
`
`would have retreated the patient after the initial induction/cladribine-free cycle, as
`
`Stelmasiak expressly taught, thus arriving at the claimed methods. EX1013, 6;
`
`EX1002, ¶17.
`
`Indeed, before December 2004, Stelmasiak described a trial of oral
`
`cladribine in RRMS, where cladribine was administered according to one of two
`
`regimens. EX1013, Abstract; EX1002, ¶17. Dr. Miller prepared the following
`
`graphic to illustrate how a POSA would have understood Stelmasiak’s regimens
`
`(EX1002, ¶89):
`
`
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`
`
`
`A POSA would have recognized that both regimens were cyclical1: they
`
`included an induction, a cladribine-free, and a maintenance periods. EX1013,
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`Abstract; EX1002, ¶17, 88. Further, a POSA would have appreciated that
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`Stelmasiak’s maintenance period in both regimens included a lower dose of
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`cladribine compared to the induction period (compare 50 mg (maintenance) to 300
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`mg (induction)). EX1013, Abstract; EX1002, ¶89. According to Stelmasiak, the
`
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`1 In a “cyclical” treatment regimen, cycles (or courses) of cladribine
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`administration are repeated at a given interval. EX1026, 11:5-7; EX1002, ¶59.
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`induction period was characterized by a drop in lymphocyte count from “2336±595
`
`per µl” to “968±229 per µl.” EX1013, 5; EX1002, ¶40. Notably, the lower dose of
`
`cladribine in the maintenance period, compared to the induction period, was
`
`sufficient to maintain the decreased lymphocyte count. EX1013, FIG. 1; EX1002,
`
`¶90. Stelmasiak concluded that “cladribine favourably compare[d]s with other
`
`immunosuppressants” vis-à-vis side-effects. EX1013, 7; EX1002, ¶101. And it
`
`caused “a very marked” reduction in the relapse rate. EX1013, 5; EX1002, ¶101.
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`Given Stelmasiak’s success, a POSA would have been motivated to use
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`Stelmasiak’s approach involving a lower maintenance cladribine dose, compared
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`to the induction dose, after the induction/cladribine-free periods of Bodor’s cycle,
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`arriving at the claimed regimen. EX1002, ¶¶18, 110.
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`The claims also require that the total dose of cladribine reached at the end of
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`the induction period is “about 1.7 mg/kg to about 3.5 mg/kg.” EX1001, 19:19-20;
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`EX1002, ¶65. The claimed range overlaps with Bodor’s range of about 1.4 mg/kg
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`to about 2 mg/kg, and therefore would have been prima facie obvious. EX1022,
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`23; EX1002, ¶¶83, 107. And the claimed length of the maintenance period (“about
`
`2 months to about 4 months”) and total dose of cladribine reached at the end of the
`
`maintenance period (“about 1.7 mg/kg”) are merely workable ranges that a POSA
`
`would have arrived at by routine experimentation. EX1002, ¶83. Cladribine’s dose
`
`and duration of administration are result-effective variables: the art taught that
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`Case IPR2023-00480
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`“one can tailor the dosage and duration for which [cladribine] is administered to
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`the stage of the disease and the condition of the patient being treated.” EX1026,
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`5:22-252; EX1018, FIG. 4; EX1022, 22:17-19; EX1002, ¶¶91-93. Thus, the
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`claimed total doses of cladribine and the length of administration are not inventive.
`
`A POSA further would have reasonably expected that the
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`immunosuppressive effect of cladribine could be maintained with a lower dose of
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`cladribine during the retreatment because the induction period would have
`
`decreased the patient’s lymphocyte count. EX1013, FIG. 1; EX1002, ¶¶89-90.
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`Thus, a lower dose of cladribine would have been expected to be enough for
`
`maintaining the suppressed lymphocytes count, and a POSA would have used the
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`lowest effective dose to minimize toxicity associated with cladribine. EX1013,
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`FIG. 1, 7; EX1002, ¶¶90-91.
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`Thus, the claimed method would have been obvious to a POSA, and there
`
`are no secondary considerations that weigh against the strong obviousness showing
`
`here. EX1002, ¶141.
`
`III. THE ’947 PATENT AND ITS PROSECUTION HISTORY
`The ’947 patent issued on May 11, 2010, from U.S. Appl. No. 11/722,018,
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`filed as PCT Appl. No. PCT/EP2005/056954 on December 20, 2005, and claims a
`
`
`2 Emphasis is added throughout.
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
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`priority date of December 22, 2004.3
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`Specification of the ’947 patent
`A.
`The patent provides a dosing regimen for using cladribine to treat multiple
`
`sclerosis. EX1001, 3:42-44; EX1002, ¶64. The regimen includes orally
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`administering cladribine following the sequential steps of “an induction treatment,”
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`“a cladribine-free period,” “a maintenance treatment,” and another “cladribine-free
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`period.” Id., 4:3-13. According to the specification, “the total dose of [c]ladribine
`
`reached at the end of the maintenance period is lower than the total dose of
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`[c]ladribine reached at the end of the induction period.” Id., 3:50-4:13.
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` Challenged claims
`B.
`Independent claim 36 recites:
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`36. A method of treating multiple sclerosis comprising the oral
`administration of a formulation comprising cladribine following the
`sequential steps below:
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`(i) an induction period lasting from about 2 months to about 4 months
`wherein said formulation is orally administered and wherein the total
`dose of cladribine reached at the end of the induction period is from
`about 1.7 mg/kg to about 3.5 mg/kg;
`
`(ii) a cladribine-free period lasting from about 8 months to about 10
`months, wherein no cladribine is administered;
`
`
`3 Petitioner does not concede that the ’947 patent is entitled to this date.
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`Case IPR2023-00480
`U.S. Patent No. 7,713,947
`(iii) a maintenance period lasting from about 2 months to about 4
`months, wherein said formulation is orally administered and wherein
`the total dose of cladribine reached at the end of the maintenance period
`is about 1.7 mg/kg;
`
`(iv) a cladribine-free period wherein no cladribine is administered.
`
`EX1001, 19:13-30; EX1002, ¶¶65, 77. Claims 38, 39, and 41-46 depend from
`
`claim 36 and add limitations such as the length of the induction, cladribine-free,
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`and maintenance periods, as well as cladribine doses. EX1002, ¶66.
`
`C. The ’947 patent prosecution history
`In the only Office Action, the Examiner rejected then-pending claims as
`
`obvious over Bodor and USPN 5,506,214 (“Beutler”), in view of USPN 4,964,848
`
`(“Bloom”). EX1004, 217-27. The Examiner correctly concluded that “effective
`
`treatment of multiple sclerosis requires an intense induction phase with substantial
`
`depletion of blood lymphocytes followed by a more moderate maintenance phase to
`
`hold the cell numbers down.” Id., 224. Incorrectly, however, the Examiner
`
`conflated monocyte and lymphocytes in assessing the claims’ patentability:
`
`“cladribine … functions by killing activated lymphocytes (and in particular,
`
`monocytes),” which, as explained below, ultimately resulted in the Examiner’s
`
`erroneous allowance of the claims. Id., 225. The Examiner further found that
`
`Bodor and Beutler teach every limitation of the claims except that “the total dose
`
`of cladribine reached at the end of the maintenance phase is lower than the total
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`Case IPR2023-00480
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`dose reached at the end of the induction phase.” Id., 223-24.
`
`But, the Examiner relied on Bloom for that claim limitation. Id., 224. The
`
`Examiner also found that “the artisan would have been motivated to use a lower
`
`dose in the maintenance phase that is still sufficient to sustain a therapeutically-
`
`effective immunosuppressive state,” id., 225, and that “each of the recited doses,
`
`treatment durations, and frequencies are clearly result effective parameters that a
`
`person of ordinary skill in the art would routinely optimize.” Id.
`
`In response, Merck, inter alia, introduced a number of new claims. Id., 237-
`
`255. Like the already-pending claims, some of the new claims expressly recited
`
`that “the total dose of cladribine reached at the end of the maintenance period is
`
`lower than the total dose of cladribine reached at the end of the induction period,”
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`while others specified the total dose of cladribine to be “about 1.7 mg/kg.” Id.,
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`238-45, 243.
`
`Merck did not, and could not, dispute that Bodor taught a cyclical treatment
`
`of MS using cladribine, arguing instead that Bodor did not teach “repeated
`
`treatment cycles comprising the administration of cladribine after the 10 month
`
`cladribine free period.” Id., 249. Further, Merck faulted Beutler for failing to teach
`
`this element. Id., 248.
`
`Merck accepted the Examiner’s statement that “neither [Bodor nor Beutler]
`
`teach that the total dose of cladribine reached at the end of the maintenance phase
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`Case IPR2023-00480
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`is lower than the total dose reached at the end of the induction phase,” id., 248, and
`
`argued that none of the cited art taught “lowering treatment dosages with each
`
`successive use of the drug.” Id., 251. But as this petition shows, and Dr. Miller
`
`confirms, the prior art does expressly teach a POSA to adminis