‘Trialscauspto. gov
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`571-272-7822
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`Paper 10
`Entered: September 22, 2023
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HOPEWELL PHARMA VENTURES,INC.,
`Petitioner,
`
`V.
`
`MERCK SERONOS.A.,
`Patent Owner.
`
`IPR2023-00480
`Patent 7,713,947 B2
`
`Before ZHENYU YANG, ROBERT A. POLLOCK, and TIMOTHYG.
`MAJORS, Administrative Patent Judges.
`
`MAJORS, Administrative Patent Judge.
`
`DECISION
`Granting Institution ofInter Partes Review
`35 US.C. $314
`
`
`
`571-272-7822
`
`Paper 10
`Entered: September 22, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`HOPEWELL PHARMA VENTURES,INC.,
`Petitioner,
`
`V.
`
`MERCK SERONOS.A.,
`Patent Owner.
`
`IPR2023-00480
`Patent 7,713,947 B2
`
`Before ZHENYU YANG, ROBERT A. POLLOCK, and TIMOTHYG.
`MAJORS, Administrative Patent Judges.
`
`MAJORS, Administrative Patent Judge.
`
`DECISION
`Granting Institution ofInter Partes Review
`35 US.C. $314
`
`
`
`IPR2023-00480
`Patent 7,713,947 B2
`
`I.
`
`INTRODUCTION
`
`Hopewell Pharma Ventures, Inc. (“Petitioner” or “Hopewell”) filed a
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`Petition (Paper 2, “Pet”’) requesting interpartes review ofclaims 36, 38, 39,
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`and 41—46 of U.S. Patent No. 7,713,947 B2 (Ex. 1001, “the ’947 patent”).
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`Pet. 1,33. Merck Serono S.A. (“Patent Owner”or “Merck’’) filed a
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`Preliminary Response (Paper8, “Prelim. Resp.”).
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`Under 35 U.S.C. § 314(a), an interpartes review maynotbeinstituted
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`unless it is determinedthat there is a reasonable likelihoodthat the petitioner
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`will prevail with respect to at least one ofthe claims challenged in the
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`petition. Considering the parties’ arguments and evidence, for the reasons
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`set forth below, we concludethat Petitioner demonstrates a reasonable
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`likelihood ofprevailing with respectto at least one ofthe °947 patent’s
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`challenged claims. Wedecline to deny the Petition on the basis ofdiscretion
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`under 35 U.S.C. § 325(d) as sought by Patent Owner. Wetherefore institute
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`an interpartes review onall challenged claims. See SAS Inst. Inc. v. lancu,
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`138 S. Ct. 1348, 1355 (2018).
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`Anyfindings and conclusionsat this stage are preliminary and based
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`on the current record. This is not a final decision on the patentability ofthe
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`challenged claims. Any suchfinal decision will be based on a complete
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`record developed throughtrial.
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`W.
`
`A.
`
`BACKGROUND
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`Real Parties-in-Interest
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`Petitioner identifies itself and the following entities as real parties-in-
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`interest: Hopewell Pharma Ventures LLC; Levy SPV, LLC; GLS Capital
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`Partners Fund I, LP; GLS Capital Partners GP, LLC; and GLS Capital, LLC.
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`Pet. 68-69. Merck identifies itself along with Merck KGaA and Ares
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`Trading SA asthereal parties-in-interest. Paper 3, 1.
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`
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`IPR2023-00480
`Patent 7,713,947 B2
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`B.
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`RelatedMatters
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`The parties identify the following lawsuits involving assertionsofthe
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`947 patent: Merck KGaA et al. v. AccordHealthcare, Inc. et al. , 1-22-cv-
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`00974 (D. Del. ); Merck KGaA et al. v. Hopewell Pharma Ventures, Inc. , 1-
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`22-cv-01365 (D. Del); Merck KGaA et al v. Aurobindo Pharma USA,Inc. et
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`al. , 1-23-cv-00039 (D. Del.). Pet. 69; Paper3, 1.
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`The parties also identify other related matters before the Board.
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`Pet. 69-70; Paper 3, 1-2. Those matters include IPR2023-00481, filed by
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`Hopewell, challenging U.S. Patent No. 8,377,903 (“the ’903 patent’), in
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`which weinstitute trial concurrent with this decision.' Paper3, 1.
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`Additionally, the parties identify IPR2023-00049 andIPR2023-00050,
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`whichwerefiled by a different petitioner (TWi Pharmaceuticals, Inc.
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`(“TWi’)), challenging the 947 and ’903 patents.” /d. at 1-2; Pet. 69.
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`C.
`
`The ’947 Patent & Technology Background
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`The ’947 patent, titled “Cladribine Regimen for Treating Multiple
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`Sclerosis,” issued on May 11, 2010. Ex. 1001, codes (45), (54). The
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`application that matured into the ’947 patent wasfiled December 20, 2005,
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`and claims the priority benefit of a provisional patent application filed
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`December22, 2004.
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`/d. at codes (22), (60).3
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`! TPR2023-00482 involved the sameparties (or their RPIs) anda patent on
`related subject matter, but that case terminated on August 16, 2023, before
`institution due to settlement. [PR2023-00482, Paper12.
`* The Board deniedinstitution on the TWi-filed petitions. See IPR2023-
`00049, Paper 10; IPR2023-00050, Paper8.
`3 Although not concedingthat the 947 patentis entitledto claim priority to
`the date this provisional application wasfiled (Pet. 7-8 n.3), Petitioner
`applies that date (December 22, 2004) in explaining the state ofthe art at
`that time and for its obviousness analysis. /d. at 2-4, 13-28. In determining
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`3
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`IPR2023-00480
`Patent 7,713,947 B2
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`According to the ’947 patent, the “invention relates to the use of
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`multiple doses of Cladribine for the treatment ofmultiple sclerosis,
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`especially relapsing-remitting multiple sclerosis or early secondary
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`progressive multiple sclerosis.” Ex. 1001, 1:17—20.
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`Cladribine is a chlorinated purine analogue, 2-chloro-
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`2’ deoxyadenosine(also known as 2-CdA). Jd. at 2:24—-27. Cladribine was
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`knownin the priorart, as wereoral, i.v., and subcutaneous formulations
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`including it. See, e.g., id. at 6:20—25 (noting oral formulations described in,
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`for example, WO 2004/087101, which 1s the Bodorreference asserted in this
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`proceeding). As background, the ’947 patentalso notesthat cladribine has
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`been suggested previously as useful for treating multiple sclerosis. /d. at
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`2:24—3:21 (discussing prior studies on cladribine’s use, in various forms
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`including delivery via oral and subcutaneousroutes, in patients with multiple
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`sclerosis); see also Pet. 19-21; Ex. 1002 4] 33-52 (testimony ofDr. Aaron
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`Miller on studies by Beutler, Stelmasiak, Rice, and others).
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`Asdescribed in the ’947patent, “[mJultiple sclerosis (MS) is the most
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`knownchronic inflammatory demyelinating disease ofthe central nervous
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`system in humans.” Ex. 1001, 1:25—27. “Overtime, MS mayresult in the
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`accumulation ofvarious neurological disabilities” and “[c]linical disability
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`in MSis presumed to be aresult ofrepeated inflammatory injury with
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`subsequent loss ofmyelin and axons, leading to tissue atrophy.” /d. at 1:30—
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`34. The patent states that “MSis manifestedin physical symptoms(relapses
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`and disability progression), Central Nervous System (CNS) inflammation,
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`brain atrophy and cognitive impairment.” /d. at 1:35—37.
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`whetherPetitioner has shown a reasonable likelihood that it would prevail
`herein, we will likewise apply that date.
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`4
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`IPR2023-00480
`Patent 7,713,947 B2
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`Before December 2004, it was known that lymphocytes(or T cells),
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`whichcells are part ofthe body’s acquired immunesystem,play a role in the
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`pathophysiology ofMS. Ex. 1002 4928-29. According to Dr. Miller,
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`“[platients with MS ‘harborT cells that react with CNS autoantigens’” and,
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`“[a|lthough these T cells (a type of lymphocyte) may ‘remain dormantfor
`299
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`decades, at some point they are activated in the periphery,’”
`eee
`cells to “‘migratethrough the blood-brain barrier to the brain and spinal
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`allowing the
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`cord.’” /d. (citing Ex. 1044, 1-3; Ex. 1007, 131). “Oncethese T cells are
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`reactivatedin theCNS.. . they ‘release pro-inflammatory Th1 cytokines
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`and orchestrate the destruction ofthe myelin sheath by various types of
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`immune cells.’” /d. (citing Ex. 1007, 131). As Dr. Miller further explains,
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`inflammation and resulting demyelination creates “lesions” in the affected
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`tissues that can be detected and monitored. Ex. 1002 99 15, 24, 27
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`(discussing detection of active/enhancing lesions using MRI).
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`According to the ’947 patent, MS1s “considered to be a multi-phasic
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`disease and periodsof clinical quiescence (remissions) occur between
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`exacerbations. Remissionsvary in length and maylast several years but are
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`infrequently permanent.” Ex. 1001, 1:43-46. Moreover,the patentstates,
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`[flour coursesofthe disease are individualized: relapsing-remitting (RR),
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`secondary progressive (SP), primary progressive (PP) and progressive
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`relapsing (PR) multiplesclerosis.” /d. at 1:47-50. “Morethan 80% of
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`patients with MS will initially display a RR course with clinical exacerbation
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`of neurological symptoms, followed by recovery that may or may not be
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`complete.” /d. at 1:51—56 (noting that disability arises from incomplete
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`recovery from relapses). “Approximately, half ofthe patients with RRMS
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`switch to a progressive course, called SPMS, 10 years after the disease[]
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`onset.” /d. at 1:57—62 (noting that worseningofdisability in the progressive
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`IPR2023-00480
`Patent 7,713,947 B2
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`phase results from “accumulation ofresidual symptomsafter exacerbation
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`but also from insidious progression between exacerbations”).
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`There is no known cure for MS. Ex. 1002 4 22 (citing Ex. 1024, 35).
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`Because MSis a chronic autommunedisease, Dr. Miller explains, patients
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`ordinarily require ongoing care and repeated treatments designed toalter or
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`suppress the immunesystem. Ex. 1002 953 (citing Ex. 1008, 211-213).
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`Dr. Miller identifies Figure 1 ofWeiner (Ex. 1008), which is reproduced
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`below.
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`Si
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`
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`nnyASNNNNNNODNTONALTMURAaNNNNNNLRRAN
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`fOAL SAQUASES ANO TREATMENT OF MULTIPLE SOLENOSIS
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`
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`ARISLIPSPEL:SDEPEPE,hhbebbs
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`
`
`
`
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`we
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`
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`SSSISINNERnn
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`Ex. 1008, 212, Fig. 1. Figure 1, above,is titled a “clinical course and
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`treatment ofmultiple sclerosis” and shows acommon MSdisease course,
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`with the horizontal axis representing time and the vertical axis the level of
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`disability. /d. (capitalization omitted). The figure includesan early “attack”
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`followed by multiple “relapses,” shown byvertical bars of different heights
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`on the left half ofthe figure; then, at the time represented by a vertical
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`dashed line near the middle ofthefigure, the onset of a progressive phase of
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`the disease with persistent disability steadily increasing as shownby the
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`upwardly sloping line as one movesto the figure’s right. /d. (including,
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`below the horizontalaxis, a treatmentstrategy (e. g., improve recovery from
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`IPR2023-00480
`Patent 7,713,947 B2
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`attack, etc.) for the disease stage). According to Dr. Miller, as reflected in
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`the figure above,“different therapies are designed to treat acute attacks,
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`preventor decrease the numberofrelapses, and preventonset of or halt the
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`progressive phase.” Ex. 1002 453 (citing Ex. 1008, 212-213).
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`AsDr. Miller further explains, “[b]ecause ofthe role the immune
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`system plays in the underlying pathophysiology ofMS, [administering]
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`immunosuppressive drugs was “[t|he most commontherapeutic approach’
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`for treating MS before December 2004.” Jd. 416 (citing Ex. 1013, 4;
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`Ex. 1007, 131); see also id. | 30 (“Because ofthe role autoantigen-specific
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`T lymphocytes were knowntoplay in MS, suppressing these lymphocytes
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`wasa target of [prior] MS therapies’). According to Dr. Miller, “[b]ecause
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`cladribine caused ‘prolonged, profound suppression of lymphocyte counts,’
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`researchers began studying it in MS.” /d. 416 (citing Ex. 1016, 420).
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`Indeed, Dr. Miller testifies that “[i]n early studies, cladribine was shown to
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`“modulat[e] autoimmuneprocesses involving lymphocyte abnormalities
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`such as MS’ and ‘impressively decrease]’ relapse rates” in MSpatients. /d.
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`(citing Ex. 1018, 1146; Ex. 1013, 5,7). Dr. Miller testifies that, “[d]uring
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`treatment, neurologists commonly assessed the therapeutic effect of
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`cladribine by monitoring a patient’s lymphocyte count, with a sustained
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`reduction of lymphocytes, e.g., below 1000 [cells]/uL, being characteristic
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`of a treatment response.” /d. (citing Ex. 1018, 1146; Ex. 1013, 5; Ex. 1014,
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`1717).
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`The ’947 patent describes, in an example, a treatment regimen for
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`patients with MS. Ex. 1001, 14:19—16:23 (Example 1). Ina study on sixty
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`patients with relapsing forms ofMS, the patients were sorted intothree
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`groups: for the first year, Group 1 patients received placebo for 4 months
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`followed by 8 months ofno treatment; Group2patients received daily oral
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`
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`IPR2023-00480
`Patent 7,713,947 B2
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`administration of cladribine(10 mg tablets) for about 5 days a month for
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`2 months, followed by placebo for 2 months, and 8 months ofno treatment
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`(“total dose of about 1.75 mg/kg’); and Group 3 patients received daily oral
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`administration of cladribine(10 mg tablets, as above) for about 5 days a
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`month for 4 months followed by 8 months ofno treatment (“total dose of
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`about 3.5 mg/kg”). /d. Inthe second year(starting month 13), the patent
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`disclosesthat all three groups receivedoral cladribine for about 5 days a
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`month for 2 monthsat the lowerdose(1.e., total of “about 1.75 mg/kg” over
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`the 2 months) followed by 10 months ofnotreatment.* /d. (disclosing, inter
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`alia, that lymphocyte markers are monitored and that “[p]atients in Groups 2
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`and 3 have a decreasein brain lesions”); see also Ex. 1001, 5:52-6:12
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`(disclosing that “[e]fficacy” ofcladribine for MS treatment can be measured
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`by, for example, frequency ofrelapses, reduction ofMRI-detectable lesions,
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`or improvements in clinical assessments, like the “Expanded Disability
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`Status Scale (EDSSY’).
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`D.
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`Illustrative Claims
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`Claim 36, reproduced below,is the only independent claim challenged
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`in this proceeding. Itreads:
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`36. A method oftreating multiple sclerosis comprising theoral
`administration of a formulation comprising cladribine following
`the sequential steps below:
`(1) 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 reachedat the end ofthe
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg;
`(11) a cladribine-free period lasting from about 8 monthsto
`about 10 months, wherein no cladribine is administered;
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`* The ’947 patent indicates that the course oftreatment continuesinto a third
`year (starting at month 25) that essentially repeats the regimen given during
`the secondyear. Ex. 1001, 16:4—9.
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`
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`IPR2023-00480
`Patent 7,713,947 B2
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`(111) a maintenanceperiod lasting from about 2 monthsto
`about 4 months, wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end ofthe
`maintenance period is about 1.7 mg/kg; [and]
`(iv) a cladribine-free period wherein no cladribine is
`administered.
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`Ex. 1001, 19:14—30. Illustrating some ofthe challenged dependentclaims,
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`claim 39 depends from claim 36 and adds“wherein the total dose of
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`cladribine reached at the end ofthe induction period is about 1.7 mg/kg,”
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`claim 41 depends from claim 36 and adds “wherein the cladribine-free
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`period (11) lasts about 10 months,” and claim 45 depends from claim 36 and
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`adds “wherein the formulation is orally administered at a daily dose of
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`10 mg cladribine.” /d. at 20:5—7, 20:11—12, 20:20-22.
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`E.
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`Prior Art and Asserted Ground
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`Petitioner asserts that claims36, 38, 39, and 41-46 are unpatentable
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`based on the following ground:
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` 36, 38, 39, 41-46
`
`103
`
`Bodor,° Stelmasiak’
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`Petitioner also submits testimony from Aaron E. Miller, M.D.,in
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`support ofits challenge. Ex. 1002 (Miller Decl. ).
`
`> The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284, 285—88 (2011), revised 35 U.S.C. §§ 102, 103 effective March 16,
`2013. The 947 patent issued from an application filed before March 16,
`2013, so pre-AIA §§ 102 and 103 apply. Ex. 1001, code (22).
`° Bodoret al., WO 2004/087101 A2, published Oct. 14, 2004 (“Bodor”
`(Ex. 1022)).
`7 Zbigniew Stelmasiak, A pilot trial ofcladribine (2-chlorodeoxyadenosine)
`in remitting-relapsing multiple sclerosis, 41:1 Med. Sci. Monit. (March 1,
`1998) (“Stelmasiak”’ (Ex. 1013)).
`
`
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`IPR2023-00480
`Patent 7,713,947 B2
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`I. ANALYSIS
`
`A.—Legal Standards
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`“Tn an [interpartes review], the petitioner has the burden from the
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`onset to show with particularity why the patent it challengesis
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`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
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`Cir. 2016) (citing 35 U.S.C. § 312(a)(3)).
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`A claim is unpatentable under 35 U.S.C. § 103 if the differences
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`between the claimed invention andthe priorart are such that the claimed
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`invention as a whole would have been obviousat the time the invention was
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`made to a person having ordinary skill in the relevant art. KSR /nt’l Co.v.
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`Teleflex Inc. , 550 U.S. 398, 406 (2007). The question of obviousness is
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`resolved on the basis ofunderlying factual determinations including: (1) the
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`scope and content ofthe priorart; (2) any differences between the claimed
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`subject matter andthepriorart; (3) the level of ordinary skill in the art; and
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`(4) secondary considerations ofnonobviousness when presented. Grahamy.
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`John Deere Co., 383 U.S. 1, 17-18 (1966).
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`Moreover, “[a]n obviousness determination requires finding both that
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`a Skilled artisan would have been motivated to combine the teachingsofthe
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`prior art references to achieve the claimed invention, and that the skilled
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`artisan would have had a reasonable expectation of successin doing so.”
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`CRFD Research, Inc. v. Matal, 876 F.3d 1330, 1340 (Fed. Cir. 2017)
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`(internal quotation marksand citation omitted).
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`B.
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`Level ofOrdinary Skill in the Art
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`In determining the level of skill in the art, we consider the problems
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`encounteredin the art, the art’s solutions to those problems, the rapidity with
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`whichinnovations are made,the sophistication ofthe technology, andthe
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`10
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`educational level of active workersin the field. Custom Accessories, Inc. v.
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`Jeffrey-Allan Indus., Inc. , 807 F.2d 955, 962 (Fed. Cir. 1986).
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`Petitioner proposesthat the person ofordinary skill in the art
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`(“POSA”) would havea “high”level of skill. Pet.28. In more detail,
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`Petitioner contends:
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`A POSA here would have drawn upon the knowledge and
`experience ofrelated disciplines of a multi-disciplinary team that
`might lie outside the POSA’s primary training.... A POSA for
`the °947patent would have the knowledge of multiple
`disciplines, such as immunology, biochemistry, and human
`physiology and anatomy, and also typically [would] be a
`clinician with experience and/ortraining in neurology... . The
`POSAtypically would be a medical doctor with a specialty in
`neurology, specifically in treating autormmunedisorders of the
`nervous system, such as multiple sclerosis, andtypically at least
`2 years of experience with admmistering treatments to patients
`and evaluating results of such treatments, as well as experience
`or knowledge in related research and development.
`
`Id. at 28-29 (citing Ex. 1002 49 20-21).
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`Patent Ownerdoesnot contest Petitioner’s definition for the POSA.
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`Prelim. Resp. 5. For purposes ofthis decision, we apply Petitioner’s
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`proposed POSAlevel, which appears consistent with the skill level reflected
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`in the priorart.
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`C.
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`Claim Construction
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`In interpartes review, we construe claims using the same claim
`
`construction standard used to construe claims in a civil action before the
`
`courts under 35 U.S.C. § 282(b), including construing claims in accordance
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`with the ordinary and customary meaning as understood by the POSA and
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`the patent’s prosecution history. 37 C.F.R. § 42.100(b). Weneed only
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`construetermsthat are in controversy and only as needed to resolve the
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`11
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`matters in dispute. Realtime Data, LLC v. lancu, 912 F.3d 1368, 1375 (Fed.
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`Cir. 2019).
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`Petitioner proposes constructionsfor the following terms: (a) “total
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`dose of cladribine”; (b) “an induction period”; and(c) “maintenance period.”
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`Pet. 29-33. There is no disputeat this stage that turns on interpretation of a
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`“total dose of cladribine,”’ and we see, as pointed out by Petitioner, that
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`“total dose”is defined in the °947 patent. Ex. 1001, 4:19—26 (defining “total
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`dose” as the “cumulative dose,”1.e., “the total dose of Cladribine
`
`administered during the treatment, 1.e. the dose reachedat the end ofthe
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`treatmentthat is calculated by adding the daily doses”). We need not further
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`addressthe interpretation ofthisterm at this time.
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`Wediscuss the terms “induction period” and “maintenance period”in
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`greater detail below,starting with the “maintenance period,” which is the
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`focus ofthe parties’ claim construction arguments.
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`1.
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`maintenanceperiod
`
`The parties’ argument on the term “maintenance period” concerns a
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`comparison between the total amount ofcladribine reachedat the end ofthe
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`induction and maintenance periods. More specifically, whether
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`“maintenance period” should be construed as a retreatment period “during
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`whichthetotal dose of cladribine 1s Jower than the total dose in the
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`induction period’—Petitioner’s position. Pet. 30-33 (emphasis added). Or,
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`whetherthe “total cladribine dosing during a maintenance period can be
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`either the same as or lower than the total dose of cladribine administered
`
`during the induction period”—Patent Owner’s argument. Prelim. Resp. 10.
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`The parties cite intrinsic evidence that allegedly supports their respective
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`interpretations. Pet. 30-33; Prelim. Resp. 6—15.
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`12
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`It is not wholly clear that “maintenance period” must be further
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`interpreted to resolve Petitioner’s challenge. Patent Owner’s interpretation
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`is broader and encompassesPetitioner’s interpretation. Nevertheless, to
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`address the arguments made and give guidancefortrial, we determine that
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`the weight ofthe evidenceon this preliminary record supports Patent
`
`Owner’s interpretation, and we conclude that the dosing of cladribine given
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`during the “maintenance period” can be same as or lower than the total dose
`
`given during the induction period. We explain below.
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`First, the language ofthe claims supports Patent Owner’s
`
`interpretation. Claim 36 expressly recites that the total dose reachedat the
`
`end of the induction period (step (1)) “is from about 1.7 mg/kg to about
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`3.5 mg/kg.” See supra Section II(D). Claim 36, step (111), recites that the
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`total dose of cladribine reachedat the end ofthe maintenanceperiod “‘is
`
`about 1.7 mg/kg.” The plain language of claim 36, thus, indicates that the
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`cladribine dosing given during the induction period andthe maintenance
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`period can be the same—each“about 1.7 mg/kg.” Claim 36 also
`
`encompasses regimens where the maintenance period dosing(e.g.,
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`1.7 mg/kg) is lower comparedto the induction period dosing(e. g.,
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`3.5 mg/kg). But the plain language ofthe claims does not require a lower
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`total dose in the maintenance period. Petitioner’s construction narrowsthe
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`claims and,in effect, asks us to rewrite the lower bound ofthe range recited
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`in claim 36’s induction period stepto be some value higher than “about
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`1.7mg/kg.” Wedecline to do so.
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`Petitioner’s interpretation is also at odds with dependentclaim 39,
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`whichspecifies that the total dose of cladribine reached at the end ofthe
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`induction period “is about 1.7 mg/kg.” Thus, in claim 39, the same dosing
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`amountis recited for the induction and maintenanceperiods(“about
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`1.7 mg/kg,” given the dependency from claim 36). Petitioner does not
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`explain how its proposed “lower than”construction can be reconciled with
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`the express language ofclaim 39.
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`In addition, other claims (not challenged in this proceeding) expressly
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`require that the “total dose of cladribine 1s lower than thetotal dose of
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`cladribine reached at the end ofthe induction period.” See, e.g., Ex. 1001,
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`18:7—24 (claim 20, which is otherwise substantially identical to claim 36,
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`apart from using the “lowerthan”language not the language “about 1.7
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`mg/kg” for the maintenance period) (emphasis added). The patent applicant,
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`thus, knew howtodraft independentclaims requiring the maintenance
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`period dosing be lower. But that language was not used in independent
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`claim 36, whichinstead sets forth the amount of cladribine reached at the
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`end of the maintenanceperiod using different, numerical terms. Under such
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`circumstances, Petitioner does not persuade us that we should construe claim
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`36 to insert a “lower than” requirement.
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`Second, the Specification ofthe ’947 patent supports Patent Owner’s
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`interpretation. Petitioner cites a definition of “Maintenance Treatment”that
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`describes a maintenanceperiod in whichthetotal cladribine dosageis
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`“orally administered at a lower dose than the Cladribine doseorally
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`administered during the induction treatment.” Ex. 1001, 5:6-11.* Thatthe
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`maintenance period dosing may be lower than the induction period dosingis
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`uncontroversial. The question is whether it must always be so. And the
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`Specification answers this question: “no.” Indeed, the ’947 patent includes
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`an example wherethe cladribine dose reached at the end ofthe induction
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`8 Petitioner’s declarant, Dr. Miller, testifies that “[t]he ’947 patent does not
`explicitly define ‘maintenance period.’” Ex. 1002 4 70.
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`period and the maintenance period is the same (1.75 mg/kg in both periods)
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`or it may alternatively be lower (1.75 mg/kg in the maintenanceperiod and
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`3.5 mg/kg in induction). Ex. 1001, 15:50—16:3 (describing the dosing
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`regimen for Group 2 and Group3 patients versus a placebo group).
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`Petitioner’s claim construction argument neveraddressesthis disclosure in
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`the ’947 patent. There is no adequate basis on this record to construe
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`“maintenance period”in claim 36 such that it wouldexclude the broader
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`maintenance period dosing in the patent’s example.
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`Lastly, the prosecution history does not, on balance, justify
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`interpreting “maintenance period”in the mannerurgedby Petitioner.
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`Petitioner arguesthat, during prosecution ofthe ’947 patent, Patent Owner
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`accepted the Examiner’s finding that the applied prior art did not “teach that
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`the total dose of cladribine reached at the end ofthe maintenance phaseis
`
`/owerthan thetotal dose reachedat the end ofthe induction phase.” Pet.
`
`31-32 (citing Ex. 1004, 248”). According to Petitioner, the Examiner’s
`
`finding and Patent Owner’s alleged acceptanceofit reflect Patent Owner’s
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`own understanding oftheclaimed invention. /d. The flaw with Petitioner’s
`
`argumentis that “the Examiner’s characterization [ofthe art andclaims]
`
`aligned with the scope ofthe then-pending claims”that were subject to the
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`Examiner’s rejection. Prelim. Resp. 11 (citing Ex. 1004, 3-6 (pending
`
`claim 18, for example, expressly included the “lower than” language)).
`
`Claim 36 wasadded via a proposed amendment(as application claim 54)
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`and wasnot, at any time during the ’947 patent’s prosecution, rejected by the
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`Examiner. Ex. 1004, 243 (proposed amendmentadding newclaim 54, dated
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`° Citations to the prosecution histories ofthe °947 and ’903 patents use the
`page numbering addedto the exhibit copy, not the native pagination.
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`Dec. 18, 2009); see also id. at 298 (Notice ofAllowance dated Mar. 22,
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`2010, following applicant’s Dec. 18, 2009, proposed amendment and
`
`remarks). The Examiner, thus, never characterized claim 36 as requiring a
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`“lower” maintenance period dose compared to the induction period dose.
`
`Petitioner also cites statements made during prosecution ofthe child
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`application that matured into the related ’903 patent. Pet. 31-32. According
`
`to Petitioner, Patent Owner“argued that the maintenanceperiodis
`
`characterized by administration of a lowertotal dose of cladribine compared
`
`to the induction period (even for the pending claims that did not expressly
`
`require a /ower dose, e.g., claim 17 and 20).” /d. at 32. Petitioner highlights
`
`argumentraised during prosecution that “one skilled in the art would not
`
`have hadanyreasonto reduce the dosage of cladribine administered
`
`during the ‘maintenance period’ as recited in the claims,” and that Patent
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`Owner madethis argumentfor the group of “claims 1, 4,5, 9, 10, 17, 20 or
`
`21.” /d. (quoting Ex. 1025, 151) (emphasis added by Petitioner). Here, the
`
`prosecution colloquy cited by Petitioner comescloser to supporting
`
`Petitioner’s claim construction position. Immediately before applicant made
`
`the argumentcited above, however, it argued “that nowherein the teachings
`
`of the reference is there any discussion about repeating a treatment courseat
`
`any point in time ateitherthe original dosage or at a lower dosagein a
`
`mannerthat could be construed as a ‘maintenanceperiod’ as defined by the
`
`subject application.” Ex. 1025, 151 (emphasis added); Prelim. Resp. 12—13
`
`(citing same and contending “PO neverargued the maintenance period must
`
`always use a total dose lower than the induction period dose”). The
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`prosecution history ofthe related ’903 patentis, at best for Petitioner,
`
`ambiguouson revealing any narrowed meaningofthe “maintenance period.”
`
`This record doesnot, overall, support Petitioner’sinterpretation on the basis
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`of any alleged disclaimer, disavowal, or estoppel. Continental Circuits LLC
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`v. Intel Corp., 915 F.3d 788, 798 (Fed. Cir 2019) (“[T]o operate as a
`
`disclaimer, the statement in the prosecution history must be clear and
`
`unambiguous, and constitute a clear disavowal of scope.”).
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`Considering the totality ofthe intrinsic evidence and argumentof
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`record, we conclude that, as recited in claim 36, the total dose of cladribine
`
`reachedat the end ofthe “maintenance period”need not be /ower than the
`
`total dose reached at the end ofthe induction period. It may be the same
`
`(i.e., about 1.7 mg/kg) for both periodsas discussed above.
`
`2.
`
`inductionperiod
`
`The parties’ dispute about the meaning of “induction period” flows
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`inescapably from their arguments about the maintenance period. Thatis, if
`
`the maintenance period dose must be /ower, the induction period doseis
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`“higher,” according to Petitioner. Pet. 29-30. Patent Owner, conversely,
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`contends that the induction period’s total cladribine dose may be higher, but
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`it may also be the same as the maintenanceperiod dose. Prelim. Resp. 15.
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`On this record, we agree with Patent Ownerfor the same reasonsdiscussed
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`above concerning the maintenanceperiod.
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`D.—Obviousness over Bodor and Stelmasiak
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`Petitioner contendsthat claims 36, 38, 39, and 41-46 would have been
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`obvious over the combined teachings ofBodor and Stelmasiak. Pet. 33-61.
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`Petitioner contends that Bodor and Stelmasiak are priorart to the
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`°947 patent and Patent Ownerprovides no argumentotherwise. /d. at 22, 24.
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`On this record, we agree that Bodorand Stelmasiak qualify aspriorart.
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`We summarizethe asserted prior art below before turning to the
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`parties’ furtherarguments and ouranalysis.
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`1.
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`Bodor (Ex. 1022)
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`Bodoris an international patent application that wasfiled March 26,
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`2004, and published October 14, 2004. Ex. 1022, codes (22), (43). Bodor
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`relates to “compositions of cladribine and cyclodextrin which are especially
`
`suited for the oral administration of cladribine.” /d. at Abstr.
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`Bodorteachesthat “[o]ral delivery of drugsis often preferred to
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`parenteral delivery fora variety ofreasons.” /d. at 2:9-10. “[F]oremost,”
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`among thereasons given by Bodor, is “patient compliance.” /d. “Patient
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`compliance is enhanced insofar as oral dosage forms alleviate repeated
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`health care providervisits, or the discomfort of injections or prolonged
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`infusion times associated with some active drugs.” /d. at 2:11—13.
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`“However,” Bodorteaches,“to date the oral delivery of cladribine has
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`been plagued by low bioavailability . .. and suboptimalinterpatient
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`variation.” /d. at 2:22—25. Bodor teachesthat “[i]t has now been found that
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`amorphous cyclodextrins can be combined to form a particularly
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`advantageous product which can be incorporatedinto a solid oral dosage
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`form.” /d. at 5:2—4. “This productisa [] cladribine-cyclodextrin complex,
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`and solid oral dosage form containing it improvesoral bioavailability and/or
`
`achieves lowerinterpatient and/or intrapatient variation ofthe drug.” /d. at
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`5:4—7; see also id. at 11:27—12:3 (describing a cladribine and cyclodextrin
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`complex “associated with improved cladribine absorption,as reflected by
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`higher bioavailability and/or lowerinterpatient variation’’).
`
`Bodorteaches that cladribine has “been used as an
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`immunosuppressive agent and as a modality for the treatment of a variety of
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`autoimmune conditions including... multiple sclerosis.” /d. at 2:1—5.
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`Bodordiscloses that “an effective amount ofthe complex cladribine-
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`cyclodextrin... is used (e. g., an amountaffective for the treatment of
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`multiple sclerosis[)].” /d. at 22:11—-15. Bodorfurther teaches that
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`[therapeutically effective dosages described in the literature include those
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`for... multiple sclerosis (from about 0.04 to about 1.0 mg/kg/day (see U.S.
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`Patent No. 5,506,214)).” /d. at 22:17—22 (defining “therapeutically effective
`
`amount’); see alsoid. at 22:27—23:6 (noting “various dosage amounts and
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`dosing regimenshave been reported in the literature for use in the treatment
`
`of multiplesclerosis,” andlisting references). '°
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`Bodordisclosesthat, “[a]t the present time,it is envisionedthat, for
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`the treatment ofmultiple sclerosis, 10 mg of cladribine in the instant [|
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`cladribine-cyclodextrin complexin the instant solid dosage form” would be
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`given.
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`/d. at 23:15—17. Further, Bodorteaches, this dosage form “would be
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`administered onceper day for a period of five to seven daysin thefirst
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`month, repeated for another periodoffive to seven daysin the second
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`month, followed by ten months ofno treatment.” /d. at 23:17—20; see
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