USINO. GOV
`7S
`571-272-7822.
`
`Paper 10
`Entered: March 28, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`
`V.
`
`MERCK SERONOSA,
`Patent Owner.
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`Before ERICA A. FRANKLIN, ULRIKE W. JENKS, and
`TINA E. HULSE, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of /nter Partes Review
`35 US.C. $314
`
`
`7S
`571-272-7822.
`
`Paper 10
`Entered: March 28, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`
`V.
`
`MERCK SERONOSA,
`Patent Owner.
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`Before ERICA A. FRANKLIN, ULRIKE W. JENKS, and
`TINA E. HULSE, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`DenyingInstitution of /nter Partes Review
`35 US.C. $314
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`I.
`
`INTRODUCTION
`
`TWi1Pharmaceuticals, Inc. (“Petitioner”) filed a Petition requesting an
`
`inter partes review ofclaims36, 38, 39, and 41-48 of U.S. Patent No.
`
`7,713,947 B2 (Ex. 1001, “the ’947 patent”). Paper 1 (“Petition” or “Pet.”).
`
`Merck Serono SA (“Patent Owner”) filed a Preliminary Responseto the
`
`Petition. Paper 6 (Prelim. Resp.”’).
`
`Wehaveauthority to determine whetherto institute an inter partes
`
`review. 35 U.S.C. § 314 (2018). Upon considering the parties’ arguments
`
`and evidence, we determine that Petitioner has not established a reasonable
`
`likelihood that it would prevail in showing the unpatentability of at least one
`
`claim challenged in the Petition. Accordingly, we do notinstitute an inter
`
`partes review ofthe challenged claims.
`
`A,
`
`Real Parties-in-Interest
`
`Petitioner identifies itself as a real parties-in-interest. Pet. xii. Patent
`
`Owneridentifies Merck Serono SA, Merck KGaA, and Ares Trading SA as
`
`real parties-in-interest, stating that “Merck Serono SA and Ares Trading SA
`
`are wholly owned subsidiaries of Merck KGaA.” Paper4, 1.
`
`B.
`
`Related Matters
`
`Theparties explain that the 947 patent has been asserted in Merck
`
`KGaA, Merck Serono SA, and Ares Trading SA v. Accord Healthcare, Inc.,
`
`]-22-cv-00974-GBW (D. Del.). Pet. xii1; Paper 4, 1. Petitioner notesthat it
`
`is not a party to the district court proceeding. Pet. xi. Patent Owneralso
`
`identifies Merck KGaA, Merck Serono SA, and Ares Trading SA v. Hopewell
`
`Pharma Ventures, Inc., No. 1:22-cv-1365-GBW (D. Del.) as a related
`
`matter. Paper 4, 1.
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`The parties also identify as a related matter the petition filed in
`
`IPR2022-00050, which challenges claims of U.S. Patent No. 8,377,903 B2.
`
`Pet. xiii; Paper 4, 1.
`
`C.
`
`The °947 Patent
`
`The ’947 patent“relates to the use of multiple doses of Cladribine for
`
`the treatment of multiple sclerosis, especially relapsing-remitting multiple
`
`sclerosis or early secondary progressive multiple sclerosis.” Ex. 1001, 1:17—
`
`20. Cladribine is a chlorinated purine analogue 2-chloro-2‘deoxyadenosine
`
`analogue (2-DcA).
`
`/d. at 2:24—25. The ’947 patent explains that there have
`
`been studies regarding the intravenous or subcutaneous administration of
`
`cladribine to treat multiple sclerosis (“MS”).
`
`/d. at 2:28—49. Those studies
`
`provided evidencethat cladribine had positive effects in patients with MS,
`
`but some adverseeffects “such as increased incidence of infections related to
`
`compromised immunefunction or myelosuppression, were observed with
`
`the highest doses.” /d. at 2:50-63.
`
`Another study directed to the oral administration of cladribine
`
`observed the sameside effects but to a lesser degree than subjects
`
`administered with cladribine intravenously.
`
`/d. at 3:3-16. However, the
`
`Specification states that “the therapeutic efficacy of the oral regimen above
`
`versus the 1.v. infusion therapy was questioned”and there was a group of
`
`subjects that did not respond to the treatment. /d. at 3:17-21.
`
`According to the ’947 patent:
`
`it would be desirable to have a method for treating multiple
`sclerosis comprising the oral administration of Cladribine that
`would permit the same or improved effect on MSlesions while
`decreasing the occurrence and/or severity adverse events.
`In
`addition, as MS is a chronic disease, it would be desirable to
`decrease the occurrence and/or severity adverse events in such a
`way that re-treatments are possible. A sustained benefit of
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`Cladribine treatment between the treatment periods is also
`desirable.
`
`Id. at 3:22-30. In view ofthis, the 947 patent describes the “use of
`
`Cladribine for the preparation of a pharmaceutical formulation for the
`
`treatment of multiple sclerosis, wherein the preparation is to be the orally
`
`administered.” /d. at 3:34—37.
`
`D.
`
`Illustrative Claim
`
`Petitioner challenges claims 36, 38, 39, and 41-48 of the ’947 patent.
`
`Claim 36, set forth below,is the only the independent claim challenged and
`
`is illustrative of the claimed subject matter.
`
`36. A method of treating multiple sclerosis comprising the
`oral 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 reached at the end of the
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg;
`(11) a cladribine-free period lasting from about 8 months
`to about 10 months, wherein no cladribine is administered;
`(111) 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.
`
`Ex. 1001, 19:14—30. Dependent claims 38 and 41-43 recite time periods for
`
`the induction period, cladribine-free period, and maintenanceperiod.
`
`Dependentclaims 39 and 44—46recite doses. Dependent claim 47 recites
`
`that certain steps of claim 36 are repeated. Dependent claim 48 recites that
`
`the formulation of claim 36 is administered in combination with interferon-
`
`beta.
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`Ef.
`
`Asserted Grounds of Unpatentability
`
`Petitioner asserts that claims 36, 38, 39, and 41-48 are unpatentable
`
`
`
`
`
`on the following three grounds:
`
`
`
`Bodor?
`36, 38, 39, 41-48
`
`
`Bodor, knowledge of a POSITA?
`36, 38, 39, 41-48
`
`
`Bodor, Rice*
`36, 38, 39, 41-48
`Petitioner also relies upon the Declaration of Benjamin M. Greenberg,
`
`MLD. (Ex. 1005).
`
`II.
`
`ANALYSIS
`
`A.—Person of Ordinary Skill in the Art
`
`The level of skill in the art is a factual determination that provides a
`
`primary guarantee of objectivity in an obviousness analysis. A/-Site Corp.v.
`
`VST Int’l Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999) (citing Graham vy. John
`
`Deere Co., 383 U.S. 1, 17-18 (1966)); Ryko Mfg. Co. v. Nu-Star, Inc.,
`
`950 F.2d 714, 718 (Fed. Cir. 1991)).
`
`' The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284 (2011), amended 35 U.S.C. §§ 102 and 103, effective March 16,
`2013. Because the application from which the ’947 patent issued has an
`effective filing date before that date, the pre-AIA version of § 103 applies.
`7 US 7,888,328 B2, issued Feb. 15, 2011 (Ex. 1029, “Bodor’).
`3 “POSITA”refers to “person of ordinary skill in the art.” The parties and
`this Decision similarly refer to a “PHOSITA,”L.e., “person having ordinary
`skill in the art.”
`* Rice et al., Cladribine andprogressive MS: Clinical and MRI outcomes of
`a multicenter controlled trial, NEUROLOGY, 54(5):1145—1155 (2000)
`(Ex. 1008, “Rice”).
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`Petitioner asserts that “[a] person of ordinary skill in the art at the time
`
`of the alleged invention would have a Doctor of Medicine and at least two-
`
`years’ experiencetreating neurological conditions and prescribing
`
`immunotherapiesto treat neurological conditions.” Pet. 8 (citing
`
`Ex. 1005 4 1-14, 17-19). Patent Ownerdoes not dispute Petitioner’s
`
`definition for one of ordinary skill in the art at this stage in the proceeding.
`
`Prelim. Resp. 7.
`
`BecausePetitioner’s uncontested definition of one of ordinary skill in
`
`the art is reasonable and consistent with the °947 patent and the priorart of
`
`record, we adoptPetitioner’s definition for purposes of this Decision.
`
`B.
`
`Claim Construction
`
`The Board applies the same claim construction standard that would be
`
`used to construe the claim in a civil action under 35 U.S.C. § 282(b).
`
`37 C.F.R. § 100(b) (2019). Under that standard, claim terms “are generally
`
`given their ordinary and customary meaning”as understood by a person of
`
`ordinary skill in the art at the time of the invention. Phillips v. AWH Corp.,
`
`A415 F.3d 1303, 1312-13 (Fed. Cir. 2005) (en banc) (quoting Vitronics Corp.
`
`v. Conceptronic, Inc.,90 F.3d 1576, 1582 (Fed. Cir. 1996)). “In determining
`
`the meaning of the disputed claim limitation, we look principally to the
`
`intrinsic evidence of record, examining the claim languageitself, the written
`
`description, and the prosecution history, if in evidence.” DePuy Spine, Inc.
`
`v. Medtronic Sofamor Danek, Inc., 469 F.3d 1005, 1014 (Fed. Cir. 2006)
`
`(citing Phillips, 415 F.3d at 1312-17).
`
`Petitioner “asserts that all claim terms should be given their plain and
`
`ordinary meaning.” Pet. 25 (citing Ex. 1005 9 34-35). Patent Owner does
`
`not assert any claim construction at this preliminary stage. Prelim. Resp. 7.
`
`
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`IPR2023-00049
`Patent 7,713,947 B2
`
`Based upon our review of the current record, we determine that no
`
`claim terms require express construction for purposes of deciding whether to
`
`institute an inter partes review of the challenged claims. See Nidec Motor
`
`Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed.
`
`Cir. 2017) (stating only those terms that are in controversy need be
`
`construed, “and only to the extent necessary to resolve the controversy.”).
`
`C.
`
`Anticipation by Bodor
`
`Petitioner asserts that claims 36, 38, 39, and 41-48 are anticipated by
`
`Bodor. Pet. 27-41. Patent Ownerdisagrees. Prelim. Resp. 22—40.
`
`“A claim is anticipated only if each and every elementas set forth in
`
`the claim is found, either expressly or inherently described, in a single prior
`
`art reference.” Schering Corp. v. Geneva Pharms, 339 F.3d 1373, 1379
`
`(Fed. Cir. 2003) (quoting Verdegaal Bros., Inc. v. Union Oil Co. of Cal., 814
`
`F.2d 628, 631 (Fed. Cir. 1987)).
`
`1.
`
`Bodor
`
`Bodor“relates to a composition comprising a complex cladribine-
`
`cyclodextrin complex formulated into a solid oral dosage form and to a
`
`method for enhancing the oral bioavailability of cladribine.” Ex. 1029,
`
`1:17—20. Bodor teachesthat “[c]ladribine is an antimetabolite which has use
`
`in the treatment of lymphoproliferative disorders.” /d. at 1:46—47.
`
`According to Bodor, “[o]ral delivery of drugs is often preferred to parenteral
`
`delivery for a variety of reasons, foremost patient compliance, or for cost or
`
`therapeutic considerations.” /d. at 1:61-63.
`
`Bodorstates that oral delivery of cladribine had been “plagued by low
`
`bioavailability.” /d. at 2:10-11. However, Bodorexplainsthat “[i]t has now
`
`been found that amorphous cyclodextrins can be combined with cladribine
`
`to form a particularly advantageous product which can be incorporated into a
`
`
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`IPR2023-00049
`Patent 7,713,947 B2
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`solid oral dosage form.” /d. at 3:25—28. According to Bodor,“[t]his product
`
`is a complex cladribine-cyclodextrin complex, and the solid oral dosage
`
`form containing it improvesoral bioavailability and/or achieves lower
`
`interpatient and/or intrapatient variation of the drug.” /d. at 3:28-31.
`
`Bodor explainsthat “[t]herapeutically effective dosages described in
`
`the literature include those for .. . multiple sclerosis (from about 0.04 to
`
`about 1.0 mg/kg/day.” /d. at 12:55—59 (citing U.S. Patent No. 5,506,214).
`
`Bodornotesthat the route of administration for such dosages taught in the
`
`literature, i.e., intravenous administration, should be taken into
`
`consideration. /d. at 13:9-11. According to Bodor,“even optimal
`
`bioavailability from oral dosage formsis not expected to approach
`
`bioavailability obtained after intravenous administration.” /d. at 13:13-15.
`
`Bodenenvisions,
`
`for the treatment of multiple sclerosis, 10 mg of cladribine in the
`instant complex cladribine-cyclodextrin complex in the instant
`solid dosage form would be 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 monthsof no treatment.
`
`Id. at 13:19-25. Bodor explains that therapeutically effective amounts may
`
`be easily determinedbystarting at relatively low dosage amounts and then
`
`adjusting it in step-wise increments with concurrent evaluation of beneficial
`
`effect. /d. at 13:37-40. According to Bodor,
`
`A practitioner will appreciate that the complexes, compositions,
`dosage forms and methods described herein are to be in
`concomitance with continuous clinical evaluations by a skilled
`practitioner
`.
`.
`.
`to determine subsequent
`therapy.
`Such
`evaluationswill aid and inform in evaluation whetherto increase,
`reduce or continue a particular treatment dose, and/orto alter the
`modeof administration.
`
`Id. at 14:40-46.
`
`
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`IPR2023-00049
`Patent 7,713,947 B2
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`2.
`
`Discussion
`
`Petitioner identifies the disclosures in Bodorthatit relies on for each
`
`limitation of independent claim 36 and dependentclaims 38-39, 41-46, and
`
`48. Pet. 27-41. In particular, we focus on Petitioner’s reliance on Bodoras
`
`disclosing a method oftreating multiple sclerosis comprising administering
`
`orally a cladribine formulation in: (a) an induction period, 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; and (b) a maintenance period, wherein the
`
`total dose of cladribine reached at the end of the maintenance period is about
`
`1.7 mg/kg.
`
`/d. at 28-39. Forthe total dose of cladribine in the induction
`
`period, Petitioner directs us to Bodor’s disclosure of administering a 10 mg
`
`tablet of cladribine daily for 10 to 14 days.
`
`/d. at 28 (citing Ex. 1029,
`
`13:19-25; 17:52-67). According to Petitioner, “Bodor further teaches that a
`
`patient’s weight is considered when dosing the ‘therapeutically effective
`
`amount’ of cladribine.” /d. (citing Ex. 1029, 12:53-64). Petitioner also
`
`relies on Bodor’s reference to a dosage of about 0.04 to about 1.0 mg/kg/day
`
`for cladribine, while recognizing that dosage is for subcutaneous
`
`administration.
`
`/d. (citing Ex. 1029, 12:55-59, 4:36-46).
`
`Additionally, Petitioner asserts that a skilled artisan “would have
`
`inferred that Bodor teaches considering patient weight to determine the
`
`therapeutically effective dose” from Bodor’s teaching to administer 10 mg
`
`daily for 10-14 days, which corresponds to a dosage range from 100 to
`
`140 mg ofcladribine. Pet. 29. According to Petitioner, a skilled artisan
`
`would have inferred that Bodor’s description of a range of dosagesis a
`
`teaching to “account for patient weight in determining the therapeutically
`
`effective amount of cladribine.” /d.
`
`In particular, Petitioner contends that
`
`the skilled artisan would have understood from Bodor’s dosing schedule that
`
`
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`IPR2023-00049
`Patent 7,713,947 B2
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`“lighter patients would receive less drug (e.g., 100 mg over 10 days),
`
`whereasheavier patients would receive more drug (e.g., 140 mg over 14
`
`days).” Id.
`
`Beyondasserting that Bodor provides an inference for a weight-based
`
`dosing schedule, Petitioner contends that Bodor anticipates a 1.7 mg/kgtotal
`
`dosage for a patient having an average human weight of 70 kilograms who is
`
`treated for twelve days.
`
`/d. at 31. Petitioner asserts such a patient would be
`
`administered 120 mg ofcladribine, which results in 1.71 mg/kg. /d. at 31-
`
`32. Petitioner provides other examples involving hypothetical patients
`
`weighing more or less than 70 kg, wherein the numberof treatment daysis
`
`increased or decreased in a manner that would also result in these patients
`
`receiving a dosage that reaches about 1.7 mg/kg. See id. at 32.
`
`For the maintenance period total dosage limitation, Petitioner asserts
`
`that Bodor teachesa total dosage of 1.7 mg/kg in this maintenance period for
`
`the same reasons Petitioner asserted for that dosage in the induction period.
`
`Pet. 38. According to Petitioner, “[b]ecause Bodordid not teach different
`
`dosages for a subsequent cladribine administration round, a PHOSITA
`
`would infer that the same dosages would be administered to the patient in
`
`both the first cladribine administration round and the second administration
`
`round.” /d. (citing Ex. 1005 4¥ 117-118).
`
`Further, Petitioner asserts that Patent Owneragreedthat a skilled
`
`artisan would have administered the same dosage in Bodor’s maintenance
`
`period as that administered in the induction period when Patent Owner
`
`argued, in response to a rejection by the Examiner, that “the teachings of
`
`[Bodor] would suggest that the same dosing regimen be applied to the
`
`patient .
`
`.
`
`. result[ing] in the sametotal dose of cladribine being administered
`
`10
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`
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`IPR2023-00049
`Patent 7,713,947 B2
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`to the patient in both the induction phase and the maintenance phase.” /d. at
`
`(citing Ex. 1004, 156; Ex. 1005 § 123).
`
`Amongother things, Patent Ownerasserts that Bodor does not
`
`disclose expressly or inherently a weight-based, total induction period
`
`cladribine dose of about 1.7 or 1.7—3.5 mg/kg. Prelim. Resp. 27. Patent
`
`Ownercontendsthat “[w]hile Bodor mentions weight-based cladribine
`
`dosages for treating MS in the context of prior art .
`
`.
`
`. it never teaches dosing
`
`its oral cladribine formulation based on body weight.” /d. Patent Owner
`
`asserts that Bodor instead discloses a methodof treating MS with “fixed oral
`
`doses”of cladribine,i.e., 10 mg daily, for five to seven days.
`
`/d. (citing
`
`Ex. 1029, 13:19-25, 18:65—-66, 20:15—17). According to Patent Owner,
`
`“Tb]ecause Bodordoesnot disclose any relationship between dosage and
`
`patient weight, the disclosed doses of 100, 120, and 140 mg (10 mgfor 10,
`
`12, or 14 days, respectively) are flat for all patients and not weight-adapted.”
`
`Id. at 27.
`
`Patent Ownerasserts that Petitioner improperly relies on hindsight to
`
`arrive at the claimed about 1.7 or 1.7—3.5 mg/kg dosage limitations. Prelim.
`
`Resp. 31. Patent Owner contendsthat it is “[o|Jnly by rewriting Bodor with
`
`hindsight knowledgeof the claimed dosing regimen, and ignoring Bodor’s
`
`express teaching offlat, fixed-dose dosing .
`
`.
`
`. can Petitioner argue a POSA
`
`would infer the claimed total induction period dose of about 1.7 or 1.7-
`
`3.5mg/kg from Bodor.” /d.
`
`Based upon our review of the arguments and evidence, we agree with
`
`Patent Ownerthat Petitioner has not demonstrated a reasonable likelihood of
`
`establishing that Bodor expressly or inherently discloses a method of
`
`treating MS with a total oral dosage of cladribine in an induction period or a
`
`maintenance period based upon the weightof a patient.
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`11
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`IPR2023-00049
`Patent 7,713,947 B2
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`As Patent Ownercorrectly observes, Bodor’s discussion of weight-
`
`based dosagesrelied upon by Petitioner expressly refers to “[t]herapeutically
`
`effective dosages described in the literature,” 1.e., in the prior art. See
`
`Ex. 1029, 12:55—-59; Pet. 28; Prelim. Resp. 26. In that passage, Bodor
`
`describes the prior art dosage approach for MS was“from about 0.04 to
`
`about 1.0 mg/kg/day.” Ex. 1029, 12:57—59 (citing U.S. Patent
`
`No. 5,506,214). Petitioner has not shown, nor do wesee, any description in
`
`Bodor implementing that weight-based dosage approach for Bodor’s
`
`treatment method. Instead, after recognizing the prior art approach, Bodor
`
`expressly discloses a method of treating MS by orally administering 10 mg
`
`of the cladribine-cyclodextrin complex for a period of five to seven days in
`
`the first month, and five to seven days in the second month. /d. at 13:19-25.
`
`Whether administered for 10 days or up to 14 days during the treatment
`
`period, the daily dosage remainsa flat amount.
`
`Even when explaining that the invention “provides a methodto tailor
`
`the administration/treatment,” Bodor does not refer to any consideration of
`
`the weight of a patient. Ex. 1029, 13:31-40. Rather, Bodor describes
`
`tailoring the administration/treatment“to the particular exigencies specific to
`
`a given mammal,” as Bodor’s treatment method is intended for use with
`
`human and non-human subjects, e.g., domesticated animals.
`
`/d. at 13:35—
`
`37; 14:54-57. Bodor explainsthat “[t]herapeutically effective amounts may
`
`be easily determined, for example, empirically by starting at relatively low
`
`amounts and by step-wise increments with concurrent evaluation of
`
`beneficial effect.” /d. at 14:54-57. Bodor further explains that the methods
`
`“are to be used in concomitance with continuousclinical evaluations by a
`
`skilled practitioner (physician or veterinarian) to determine subsequent
`
`therapy. Such evaluation will aid and inform in evaluating whetherto
`
`12
`
`
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`IPR2023-00049
`Patent 7,713,947 B2
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`increase, reduce or continue a particular treatment dose, and/orto alter the
`
`mode of administration.” /d. at 14:43-50. There again, Bodor’s disclosure
`
`regarding a treatment dose does not include any consideration of a patient’s
`
`weight. Thus, Bodor does not support Petitioner’s assertion that a patient’s
`
`weight is considered in Bodor’s method of treating MS with a cladribine
`
`complex, or that a skilled artisan would have inferred such a teaching from
`
`Bodor.
`
`To the extent that Petitioner provides examples to show that under
`
`certain very specific circumstances, Bodor’s total dose of cladribine could
`
`reach an amount that equals about 1.7 mg/kg at the end of a treatment period
`
`for a particular patient, we do not find that showing persuasive in terms of
`
`establishing a reasonable likelihood of prevailing on an anticipation
`
`challenge. It is apparent to us that Petitioner’s examples involvea strategic
`
`selection of patient weights and treatment durations that support calculations
`
`resulting in a 1.7 mg/kg total dosage for the treatment period. We agree
`
`with Patent Ownerthat such a strategy is insufficient to establish inherency
`
`as it demonstrates only the total dose that is possible for some patients. It is
`
`a long-standing principle that inherent anticipation requires the missing
`
`descriptive element to be “necessarily present,” and not merely possibly
`
`present. Jn re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999).
`
`Further, we determine that Petitioner has not identified disclosures in
`
`Bodor that adequately support Petitioner’s assertion that a subsequent round
`
`of Bodor’s therapy, during whatPetitioner refers to as the maintenance
`
`period, would necessarily be at the same dosage administeredin the first
`
`round. Accordingto Petitioner, a skilled artisan would infer that the same
`
`dosages would be administered to the patient in both the first and second
`
`roundsof treatment, because Bodordid not teach different dosages for a
`
`13
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`IPR2023-00049
`Patent 7,713,947 B2
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`subsequent cladribine administration round. Pet. 38. However, as noted
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`above, Bodorprovides an instruction that its methods are to be used with
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`continuousclinical evaluations for beneficial effect to determine any need
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`for adjusting a particular treatment dose. Ex. 1029, 14:43-57. In other
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`words, the dosage amount administered does not necessarily stay the same.
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`Rather, the dosage may require adjustments in view of ongoing and
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`continuousclinical evaluation.
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`Moreover, for the same reasons discussed regarding Bodor’s
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`induction therapy, Petitioner has not persuasively identified disclosures in
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`Bodorthat a subsequent round of Bodor’s therapy would be based on the
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`weight of the patient or that the total dose of cladribine reached at the end of
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`that period would necessarily be one that is equivalent to about 1.7 mg/kg.
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`Forat least the foregoing reasons, we find that Petitioner has not
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`shown a reasonable likelihood of prevailing on its assertion that independent
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`claim 36, or its dependent claims, claims 38, 39, and 41-48, are anticipated
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`by Bodor.
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`D.—Obviousness over Bodor and Knowledgein the Art
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`Petitioner asserts that claims 36, 38, 39, and 41-48 would have been
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`obvious over the combined teachings of Bodor and the common knowledge
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`of one of ordinary skill in the art. Pet. 41-49. Patent Ownerdisagrees.
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`Prelim. Resp. 40-54. Weincorporate our description and discussion of
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`Bodorin Section II.C. here.
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`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
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`differences between the claimed subject matter and the prior art are such that
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`the subject matter, as a whole, would have been obviousat the time the
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`invention was madeto a person having ordinary skill in the art to which the
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`IPR2023-00049
`Patent 7,713,947 B2
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`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
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`(2007).
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`“An obviousness determination requires finding both ‘that a skilled
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`artisan would have been motivated to combine the teachings of the prior art
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`references to achievethe claimed invention, and that the skilled artisan
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`would have had a reasonable expectation of success in doing so.”” CRED
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`Research, Inc. v. Matal, 876 F.3d 1330, 1340 (Fed. Cir. 2017) (quoting
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`Intelligent Bio-Sys., Inc. v. lumina CambridgeLtd., 821 F.3d 1359, 1367—
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`1368 (Fed. Cir. 2016)).
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`1.
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`Discussion
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`For this obviousness challenge, Petitioner again relies on Bodoras
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`disclosing every limitation of the challenged claims. Pet. 41. According to
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`Petitioner, even if we are not persuadedthat a skilled artisan would have
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`madethe inferences regarding Bodor’s treatment method alleged by
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`Petitioner for the anticipation ground, the challenged claimsarestill
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`unpatentable as obvious over Bodorand in view of the common knowledge
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`of a PHOSITA. /d. at 41-42.
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`To begin, we focus on the total dosage limitations recited in
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`independentclaim 36, and Petitioner’s assertion that it would have been
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`obviousto arrive at a total dosage of 1.7 mg/kg at the end of the induction
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`period and at the end of a maintenance period.
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`/d. at 44-48. According to
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`Petitioner, Bodor’s disclosure of treating patients with 10 mg daily for ten to
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`fourteen daysin a first round of treatment, 1.¢., a total dosage of 100 mg —
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`140 mg, amounts to about 1.7 mg/kg “for numerouspatients and a large
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`section of the patient population.” /d. at 44-45.
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`Petitioner contends, to the extent that Bodor’s 10 mg/day dosing does
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`not always amountto a total dosage of about 1.7 mg/kg dosageat the end of
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`IPR2023-00049
`Patent 7,713,947 B2
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`the induction and maintenanceperiod,“it would have been obvious to a
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`PHOSITAto make the total dosage at the end of the induction period andat
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`the end of the maintenanceperiod to be 1.7 mg/kg because a PHOSITA
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`would be motivated to fine tune dosagesto arrive at a therapeutically
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`effective amount,” as Bodor suggests fine tuning dosages with concurrent
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`evaluation of beneficial effect.
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`/d. at 45 (citing Ex. 1029, 13:31-40).
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`Accordingto Petitioner, the skilled artisan would have been motivated to
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`“start with previously suggested dosage amounts in the medical literature,
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`which Bodorspecifically acknowledges.” Pet. 45 (citing Ex. 1029, 12:65—
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`13:8).
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`Specifically, Petitioner asserts that a skilled artisan would have been
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`motivated to begin by “adjusting for bioavailability” the subcutaneous
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`cladribine dosage of 0.7 mg/kg disclosed in Rice, a journalarticle
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`incorporated by reference in Bodor. /d. at 45—46 (citing Ex. 1008, 1-2, 9);
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`see Ex. 1029, 13:5—8. Petitioner contends that the skilled artisan would have
`
`been motivated to then “evaluate the beneficial effect of this initial dosage
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`and raise the dosage up to 1.7 mg/kg, as suggested by Bodor. .
`
`. to find the
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`therapeutically effective amount.” /d. (citing Ex. 1029, 13:37—40; Ex. 1005
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`4, 161-164).
`
`Petitioner acknowledgesthat Rice also discloses a higher
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`(subcutaneous) dosage of 2.1 mg/kg, Pet. 45 (citing Ex. 1008, 1-2, 9),
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`however, Petitioner contendsthat a skilled artisan would have known that “a
`
`lower dosageis preferable to a higher dose,” especially because Rice
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`describes both dosesas effective, id. at 46 (citing Ex. 1005 4 164).
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`Petitioner contendsthat a skilled artisan “could adjust” Rice’s suggested
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`dosage, through “trial and error,” as Bodor provides motivation to pick a low
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`dosage and adjust that dosage. /d. (citing Ex. 1029, 13:31-40). Petitioner
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`16
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`IPR2023-00049
`Patent 7,713,947 B2
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`also relies on Bodor’s teaching to adjust dosages to support its position that a
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`skilled artisan would have had a reasonable expectation of successin finding
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`a therapeutically effective dosage. /d. at 46-47.
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`Additionally, Petitioner contends that it would have been obvious to
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`administer the same dosage during both the induction and maintenance
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`periods because “it was commonpractice in the medical arts to prescribe the
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`same dose of an immunosuppressant (and other drugs) during a second
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`phaseasafirst phase, absent some compelling reason not to.” /d. at 48
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`(citing Ex. 1005 4] 168-170). According to Petitioner, “a PHOSITA would
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`have expected success in doing so for the same reason — the medical
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`community had studied this dosing regime and foundit effective for many
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`drugs, including immunosuppressantslike cladribine.” /d.
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`Patent Owner argues, among other things, that Bodor does not teach
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`or suggest weight-based dosing, and that Petitioner has not established any
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`motivation to modify Bodor’s teaching to arrive at a method for treating MS
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`comprising a total induction period dose of about 1.7 or 1.7-3.5 mg/kg, and
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`a maintenance period total dosage of about 1.7 mg/kg, as required by the
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`challenged claims. Prelim. Resp. 41, 49. In particular, Patent Owner
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`asserts that “Petitioner’s suggestion to “fine tun[e]’ by ‘trial and error’ is
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`plagued by hindsight.” /d. at 47. According to Patent Owner, “[a]bsent a
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`suitable starting point in Bodor, Petitioner relies on Rice butfails to identify
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`what would have motivated a POSAto choose Rice from amongthe various
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`cladribine studies as a starting point.” /d. at 47-48. Patent Ownerasserts
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`also that Petitioner’s reliance on Ricein this single-reference ground
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`challenge is improper.
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`/d. at 42.
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`17
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`IPR2023-00049
`Patent 7,713,947 B2
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`Patent Owner continuesthat Petitioner’s reliance on knowledgein the
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`art is unavailing because, “nothing in the prior art taught a POSA how the
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`combination of the different variables—dose, length and numberof dosing
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`period or drug-free periods—would impact the treatment of MS or what
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`specific combination (if any) would result in a safe and effective MS
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`treatment method.” /d. at 48. According to Patent Owner, Petitioner’s
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`obviousness challenge involves “merely throw[ing] metaphorical darts at a
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`board in hopesof arriving at a successful result [when] the prior art gave
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`either no indication of which parameters werecritical or no direction as to
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`which of many possible choicesis likely to be successful” and should be
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`rejected as improperly relying on hindsight.
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`/d. 48—49 (quoting Jn re
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`Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig., 676
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`F.3d 1063, 1070 (Fed. Cir. 2012)).
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`Having considered the arguments and the evidence on the current
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`record, we determine that Petitioner has not shownsufficiently for institution
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`that Bodor discloses each limitation of the challenged claims expressly or
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`inherently for the reasons discussed regarding the anticipation ground. It is
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`only by employing a strategy that exemplifies treatment of patients having
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`specifically selected weights and specifically selected treatment durations
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`that Petitioner is able to show that Bodor’s method of treating MS with
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`10 mg ofthe cladribine complex daily arrives at about a total dosage of
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`1.7 mg/kg at the end of a treatment period. Indeed, Petitioner recognizes
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`that Bodor’s teachings do not alwaysarrive at that total dosage. Pet. 45.
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`Insofar as Petitioner relies on Bodor, in view of the asserted common
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`knowledge of a skilled artisan at the time of the invention, to demonstrate
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`that “it would have been obvious for a PHOSITA to makethe total dosage at
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`the end of the induction period and at the end of the maintenance period to
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`IPR2023-00049
`Patent 7,713,947 B2
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`be 1.7 mg/kg,”id. at 45, we determine that showing1s also insufficient for
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`institution. In particular, we agree with Patent Ownerthat Petitioner’s
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`obviousness challenge relies improperly on hindsight, rather than only upon
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`the teachings of Bodor and the asserted knowledgein the art, to reach the
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`total dosage limitations in the challenged claims. Petitioner urges that a
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`skilled artisan would have modified Bodor’s methodof treating MS based
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`upon a flat daily oral dosage of its cladribine-cyclodextrin complex to
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`instead depend upon a dosing schemebased upon the patient’s weight.
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`/d.
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`In support of that contention, Petitioner asserts that “[a] PHOSITA would
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`have been motivated to start with previously suggested dosage amounts in
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`medicalliterature, which Bodor specifically acknowledges.” Id.
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`Specifically, Petitioner refers t
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