Trials@uspto.gov
`571-272-7822
`
`Paper 8
`Entered: March 28, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00050
`Patent 8,377,903 B2
`
`
`
`
`
`
`
`
`
`Before ERICA A. FRANKLIN, ULRIKE W. JENKS, and
`TINA E. HULSE, Administrative Patent Judges.
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`571-272-7822
`
`Paper 8
`Entered: March 28, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`TWI PHARMACEUTICALS, INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00050
`Patent 8,377,903 B2
`
`
`
`
`
`
`
`
`
`Before ERICA A. FRANKLIN, ULRIKE W. JENKS, and
`TINA E. HULSE, Administrative Patent Judges.
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`
`INTRODUCTION
`I.
`TWi Pharmaceuticals, Inc. (“Petitioner”) filed a Petition requesting an
`inter partes review of claims 17, 19, 20, and 22–29 of U.S. Patent No.
`8,377,903 B2 (Ex. 1002, “the ’903 patent”). Paper 1 (“Petition” or “Pet.”).
`Merck Serono SA (“Patent Owner”) filed a Preliminary Response to the
`Petition. Paper 6 (“Prelim. Resp.”).
`We have authority to determine whether to 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 not institute an inter
`partes review of the challenged claims.
`Real Parties-in-Interest
`A.
`Petitioner identifies itself as a real parties-in-interest. Pet. xiii. Patent
`Owner identifies 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.” Paper 4, 1.
`Related Matters
`B.
`The parties explain that the ’903 patent has been asserted in Merck
`KGaA, Merck Serono SA, and Ares Trading SA v. Accord Healthcare, Inc.,
`1-22-cv-00974-GBW (D. Del.). Pet. xiii; Paper 4, 1. Petitioner notes that it
`is not a party to that district court proceeding. Pet. xiii. Patent Owner also
`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.
`
`2
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`The parties also identify as a related matter the petition filed in
`IPR2022-00049, which challenges claims of U.S. Patent No. 7,713,947 B2.
`Pet. xiii; Paper 4, 1.
`
`The ’903 Patent
`C.
`The ’903 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. The Specification explains,
` Four courses of the disease are individualized: relapsing-
`remitting (RR), secondary progressive (SP), primary progressive
`(PP) and progressive relapsing (PR) multiple sclerosis.
` More than 80% of patients with MS will initially display a RR
`course with clinical exacerbation of neurological symptoms,
`followed by a recovery that may or may not be complete.
` During RRMS, accumulation of disability results from
`incomplete recovery from relapses. Approximately, half of the
`patients with RRMS switch to a progressive course, called
`SPMS, 10 years after the diseased onset.
`Id. at 1:48–58 (citation omitted).
`The ’903 patent explains that there have been studies regarding the
`intravenous or subcutaneous administration of cladribine to treat multiple
`sclerosis (“MS”). Id. at 2:28–49. Those studies provided evidence that
`cladribine had positive effects in patients with MS but some adverse effects,
`“such as increased incidence of infections related to compromised immune
`function or myelosuppression, were observed with the highest doses.” Id. at
`2:50–63. Another study directed to the oral administration of cladribine
`observed the same side effects but to a lesser degree than subjects
`administered with cladribine intravenously. Id. at 3:3–16. However, the
`’903 patent states that “the therapeutic efficacy of the oral regimen above
`
`3
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`versus the i.v. infusion therapy was questioned” and there was a group of
`subjects that did not respond to the treatment. Id. at 3:17–21.
`According to the ’903 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 MS lesions 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
`Cladribine treatment between the treatment periods is also
`desirable.
`Id. at 3:22–30. In view of this, the ’903 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.” Id. at 3:34–37. The ’903 patent states that each of the
`induction and the maintenance periods may last up to about four months. Id.
`at 4:58–59, 5:11–12.
`
`Illustrative Claim
`D.
`Petitioner challenges claims 17, 19, 20, and 22–29 of the ’903 patent.
`Claim 17, set forth below, is the only the independent claim challenged and
`is illustrative of the claimed subject matter.
`17. A method of
`treating relapsing-remitting multiple
`sclerosis or early secondary progressive multiple sclerosis
`comprising the oral administration of a formulation comprising
`cladribine to an individual having relapsing-remitting multiple
`sclerosis or early secondary progressive multiple sclerosis
`following the sequential steps below:
`(i) an induction period lasting from about 2 months to
`about 4 months wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg;
`
`4
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`(ii) a cladribine-free period lasting from about 8 months to
`about 10 months, wherein no cladribine is administered;
`(iii) a maintenance period lasting from about 2 months to
`about 4 months, wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`maintenance period is about 1.7 mg/kg; and
`(iv) a cladribine-free period wherein no cladribine is
`administered.
`Ex. 1001, 18:7–26. Dependent claims 19, 20, and 22–29 recite additional
`limitations to the method of claim 17. Dependent claims 19 and 22–24
`recite time periods for the induction period, cladribine-free period, and
`maintenance period. Dependent claims 20, 25, and 26 recite doses.
`Dependent claim 27 recites that the formulation is administered 1–7 days per
`month during the induction period. Dependent claim 28 recites that certain
`steps of claim 17 are repeated. Dependent claim 29 requires the formulation
`of claim 17 to be administered in combination with interferon-beta.
`Asserted Grounds of Unpatentability
`E.
`Petitioner asserts that claims 17, 19, 20, and 22–29 are unpatentable
`on the following three grounds:
`Claims Challenged
`32 U.S.C. §1 Reference(s)
`17, 19, 20, 22–29
`102(e)
`Bodor2
`17, 19, 20, 22–29
`103(a)
`Bodor, knowledge of a POSITA3
`
`
`1 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.
`2 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,” i.e., “person having ordinary
`skill in the art.”
`
`5
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`Claims Challenged
`17, 19, 20, 22–29
`
`32 U.S.C. §1 Reference(s)
`103(a)
`Bodor, Rice4
`
`Petitioner also relies upon the Declaration of Benjamin M. Greenberg,
`M.D. (Ex. 1005).
`
`II. ANALYSIS
`Person of Ordinary Skill in the Art
`A.
`The level of skill in the art is a factual determination that provides a
`primary guarantee of objectivity in an obviousness analysis. Al-Site Corp. v.
`VSI Int’l Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999) (citing Graham v. 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)).
`Petitioner asserts that “[a] person having ordinary skill in the art at the
`time of the alleged invention would have a Doctor of Medicine and at least
`two-years’ experience treating neurological conditions and prescribing
`immunotherapies to treat neurological conditions.” Pet. 8 (citing
`Ex. 1005 ¶¶ 1–14, 17–19). Patent Owner does not dispute Petitioner’s
`definition for one of ordinary skill in the art but “reserves the right to
`challenge Petitioner’s definition of a POSA at a later stage in this
`proceeding, should the Board institute trial.” Prelim. Resp. 7.
`Because Petitioner’s uncontested definition of one of ordinary skill in
`the art is reasonable and consistent with the ’903 patent and the prior art of
`record, we adopt Petitioner’s definition for purposes of this Decision.
`
`
`4 Rice et al., Cladribine and progressive MS: Clinical and MRI outcomes of
`a multicenter controlled trial, NEUROLOGY, 54(5):1145–1155 (2000)
`(Ex. 1008, “Rice”).
`
`6
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`
`Claim Construction
`B.
`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.,
`415 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 language itself, 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 ¶¶ 34–35).
`Patent Owner notes Petitioner’s assertion in its challenge of the claims
`that “limitations regarding treatment of or administering to patients having
`‘RRMS or early SPMS’ have no patentable weight.” Prelim. Resp. 7
`(quoting Pet. 27–28). Patent Owner disagrees because the portion of the
`preamble regarding the oral administration of cladribine to an individual
`having RRMS or early SPMS is limiting. Id. at 7–8.
`Based upon our review of the current record and our analysis of the
`issues, 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
`
`7
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`that are in controversy need be construed, “and only to the extent necessary
`to resolve the controversy.”).
`Anticipation by Bodor
`C.
`Petitioner asserts that claims 17, 19, 20, and 22–29 are anticipated by
`Bodor. Pet. 27–42. Patent Owner disagrees. Prelim. Resp. 21–41.
`“A claim is anticipated only if each and every element as 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)).
`Bodor
`1.
` 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 teaches that “[c]ladribine is an antimetabolite which has use
`in the treatment of lymphoproliferative disorders” and as “a modality for the
`treatment of a variety of autoimmune conditions including . . . multiple
`sclerosis.” Id. at 1:46–54. 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.” Id. at 1:61–
`63.
`
`Bodor states that oral delivery of cladribine had been “plagued by low
`bioavailability.” Id. at 2:10–11. However, Bodor further states that “[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 solid oral dosage form.” Id. at 3:25–28. According to
`Bodor, “[t]his product is a complex cladribine-cyclodextrin complex, and the
`
`8
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`solid oral dosage form containing it improves oral bioavailability and/or
`achieves lower interpatient and/or intrapatient variation of the drug.” Id. at
`3:28–31.
`Bodor explains that “[t]herapeutically effective dosages described in
`the literature include those for . . . multiple sclerosis (from about 0.04 to
`about 1.0 mg/kg/day.” Id. at 12:55–59 (citing U.S. Patent No. 5,506,214).
`Bodor notes that the route of administration for such dosages taught in the
`literature, i.e., intravenous administration, should be taken into
`consideration. Id. at 13:9–11. According to Bodor, “even optimal
`bioavailability from oral dosage forms is not expected to approach
`bioavailability obtained after intravenous administration.” Id. at 13:13–15.
`Boden envisions,
`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 months of no treatment
`Id. at 13:19–25. Bodor explains that therapeutically effective amounts may
`be easily determined by starting at relatively low dosage amounts and then
`adjusting it in step-wise increments with concurrent evaluation of beneficial
`effect. Id. 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
`evaluations will aid and inform in evaluation whether to increase,
`reduce or continue a particular treatment dose, and/or to alter the
`mode of administration.
`Id. at 14:40–46.
`
`9
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`
`Discussion
`2.
`Petitioner identifies the disclosures in Bodor that it relies on for each
`limitation of independent claim 17 and dependent claims 19, 20, and 22–29.
`Pet. 27–42. In particular, we focus on Petitioner’s reliance on Bodor as
`disclosing a method of treating 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. Id. at 28–39. For the 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. Id. at 29 (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.” Id. (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. Id. (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 of cladribine. Pet. 29. According to Petitioner, a skilled artisan
`would have inferred that Bodor’s description of a range of dosages is a
`teaching to “account for patient weight in determining the therapeutically
`effective amount of cladribine.” Id. at 30. In particular, Petitioner contends
`that the skilled artisan would have understood from Bodor’s dosing schedule
`
`10
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`that “lighter patients would receive less drug (e.g., 100 mg over 10 days),
`whereas heavier patients would receive more drug (e.g., 140 mg over 14
`days).” Id. at 29.
`Beyond asserting that Bodor provides an inference for a weight-based
`dosing schedule, Petitioner contends that Bodor anticipates a 1.7 mg/kg total
`dosage for a patient having an average human weight of 70 kilograms who is
`treated for twelve days. Id. at 32–33. Petitioner asserts such a patient would
`be administered 120 mg of cladribine, which results in 1.71 mg/kg. Id.
`Petitioner provides other examples involving hypothetical patients weighing
`more or less than 70 kg, wherein the number of treatment days is increased
`or decreased in a manner that would also result in the patients receiving a
`dosage that reaches about 1.7 mg/kg. See id. at 33.
`For the maintenance period total dosage limitation, Petitioner asserts
`that Bodor teaches a 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. 38–40. According to Petitioner, “[b]ecause Bodor did 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.” Id. at 38–39 (citing Ex. 1005 ¶¶ 117–118).
`Further, Petitioner asserts that Patent Owner agreed that 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 same total dose of cladribine being administered
`
`11
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`to the patient in both the induction phase and the maintenance phase.” Id. at
`39 (citing Ex. 1004, 156; Ex. 1005 ¶ 123).
`Turning to Patent Owner’s arguments, among other things, Patent
`Owner asserts 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. 22. Patent Owner contends that “[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.” Id. at 27. Patent Owner asserts that Bodor instead discloses a
`method of treating MS with “fixed oral doses” of cladribine, i.e., 10 mg
`daily, for five to seven days. Id. (citing Ex. 1029, 13:19–25, 18:65–66,
`20:15–17). According to Patent Owner, “[b]ecause Bodor does not disclose
`any relationship between dosage and patient weight, the disclosed doses of
`100, 120, and 140 mg (10 mg for 10, 12, or 14 days, respectively) are flat for
`all patients and not weight-adapted.” Id.
`Patent Owner asserts 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 contends that it is “[o]nly by rewriting Bodor with
`hindsight knowledge of the claimed dosing regimen, and ignoring Bodor’s
`express teaching of flat, 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.” Id.
`Based upon our review of the arguments and evidence, we agree with
`Patent Owner that Petitioner has not demonstrated a reasonable likelihood of
`establishing that Bodor expressly or inherently discloses a method of
`treating MS with an oral dosage of cladribine, wherein the total dose of
`cladribine reached at the end of the induction period and at the end of the
`
`12
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`maintenance period is from about 1.7 mg/kg, or any amount that is weight-
`based.
`As Patent Owner correctly observes, Bodor’s discussion of weight-
`based dosages relied upon by Petitioner expressly refers to “[t]herapeutically
`effective dosages described in the literature,” i.e., in the prior art. See
`Ex. 1029, 12:55–59; Pet. 28; Prelim. Resp. 27. 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 we see, 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 that it envisions 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. Id. at
`13:19–25. Whether administered for 10 days or up to 14 days during the
`treatment period, the daily dosage remains a fixed amount.
`Even when explaining that the invention “provides a method to 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. Id. at 13:35–
`37; 14:54–57. Bodor explains that “[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.” Id. at 14:54–57. Bodor further explains that the methods
`“are to be used in concomitance with continuous clinical evaluations by a
`
`13
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`skilled practitioner (physician or veterinarian) to determine subsequent
`therapy. Such evaluation will aid and inform in evaluating whether to
`increase, reduce or continue a particular treatment dose, and/or to alter the
`mode of administration.” Id. 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 involve a strategic
`selection of patient weight and treatment duration that support a calculation
`that yields a 1.7 mg/kg total dosage for the treatment period. We agree with
`Patent Owner that 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. In 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 what Petitioner refers to as the maintenance
`period, would necessarily be at the same dosage administered in the first
`round. According to Petitioner, a skilled artisan would infer that the same
`
`14
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`dosages would be administered to the patient in both the first and second
`rounds of treatment, because Bodor did not teach different dosages for a
`subsequent cladribine administration round. Pet. 38. However, as noted
`above, Bodor provides an instruction that its methods are to be used with
`continuous clinical evaluations for beneficial effect to determine any need
`for adjusting a particular treatment dose. Ex. 1029, 14:43–57. In other
`words, the dosage amount administered is not necessarily a static one.
`Rather, dosage may require adjustments in view of ongoing and continuous
`clinical evaluation. Moreover, for the same reasons discussed regarding
`Bodor’s initial or induction therapy, Petitioner has not persuasively
`identified disclosures in Bodor that a subsequent round of Bodor’s therapy
`would be based on the weight of the patient or that the total dose of
`cladribine reached at the end of that period would necessarily be about 1.7
`mg/kg.
`For at least the foregoing reasons, we find that Petitioner has not
`shown a reasonable likelihood of prevailing on its assertion that independent
`claim 17, or its dependent claims, claims 19, 20, and 22–29, are anticipated
`by Bodor.
`D. Obviousness over Bodor and Knowledge in the Art
`Petitioner asserts that claims 17, 19, 20, and 22–29 would have been
`obvious over the combined teachings of Bodor and the common knowledge
`of one of ordinary skill in the art. Pet. 42–50. Patent Owner disagrees.
`Prelim. Resp. 41–54. We incorporate our description of Bodor in Section
`II.C.1. here.
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`
`15
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`invention was made to a person having ordinary skill in the art to which the
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007).
`“An obviousness determination requires finding both ‘that a skilled
`artisan would have been motivated to combine the teachings of the prior art
`references to achieve the claimed invention, and that the skilled artisan
`would have had a reasonable expectation of success in doing so.’” CRFD
`Research, Inc. v. Matal, 876 F.3d 1330, 1340 (Fed. Cir. 2017) (quoting
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367–
`1368 (Fed. Cir. 2016)).
`
`Discussion
`1.
`As in its anticipation challenge, Petitioner asserts here also that Bodor
`alone discloses every limitation of the challenged claims. Pet. 42.
`According to Petitioner, even if we are not persuaded that a skilled artisan
`would have made the inferences regarding Bodor’s treatment method alleged
`by Petitioner for the anticipation ground, the challenged claims are still
`unpatentable as obvious over Bodor and in view of the common knowledge
`of a PHOSITA. Id.
`We begin by focusing on the total dosage limitations recited in
`independent claim 17 and Petitioner’s assertion that it would have been
`obvious to arrive at a total dosage of 1.7 mg/kg at the end of the induction
`period and at the end of a maintenance period. Id. at 45–48. According to
`Petitioner, Bodor’s disclosure of treating patients with 10 mg daily for ten to
`fourteen days in a first round of treatment, i.e., a total dosage of 100 mg –
`140 mg, amounts to about 1.7 mg/kg “for numerous patients and a large
`section of the patient population.” Id. at 45.
`
`16
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`Petitioner contends, to the extent that Bodor’s 10 mg/day dosing does
`not always amount to a total dosage of about 1.7 mg/kg dosage at the end of
`the induction and maintenance period, “it would have been obvious to a
`PHOSITA to make the total dosage at the end of the induction period and at
`the end of the maintenance period to be 1.7 mg/kg because a PHOSITA
`would be motivated to fine tune dosages to arrive at a therapeutically
`effective amount,” as Bodor suggests fine tuning dosages with concurrent
`evaluation of beneficial effect. Id. (citing Ex. 1029, 13:31–40). According
`to Petitioner, the skilled artisan would have been motivated to “start with
`previously suggested dosage amounts in the medical literature, which Bodor
`specifically acknowledges.” Id. (citing Ex. 1029, 12:65–13:8).
`Specifically, Petitioner asserts that a skilled artisan would have been
`motivated to begin by “adjusting for bioavailability” the subcutaneous
`cladribine dosage of 0.7 mg/kg disclosed in Rice, a journal article
`incorporated by reference in Bodor. Id. at 45–46 (citing Ex. 1008, 1–2, 9);
`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
`and raise the dosage up to 1.7 mg/kg, as suggested by Bodor . . . to find the
`therapeutically effective amount.” Id. (citing Ex. 1029, 13:37–40; Ex. 1005
`¶¶ 161–164).
`Petitioner acknowledges that Rice also discloses a higher
`(subcutaneous) dosage of 2.1 mg/kg, Pet. 46 (citing Ex. 1008, 1–2, 9),
`however, Petitioner contends that a skilled artisan would have known that “a
`lower dosage is preferable to a higher dose,” especially because Rice
`describes both doses as effective, id. (citing Ex. 1005 ¶ 164). Petitioner
`contends that a skilled artisan “could adjust” Rice’s suggested dosage,
`through “trial and error,” as Bodor provides motivation to pick a low dosage
`
`17
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`and adjust that dosage. Id. (citing Ex. 1029, 13:31–40). Petitioner also
`relies on Bodor’s teaching to adjust dosages to support its position that a
`skilled artisan would have had a reasonable expectation of success in finding
`a therapeutically effective dosage. Id.
`Additionally, Petitioner contends that it would have been obvious to
`administer the same dosage during both the induction and maintenance
`periods because “it was common practice in the medical arts to prescribe the
`same dose of an immunosuppressant (and other drugs) during a second
`phase as a first phase, absent some compelling reason not to.” Id. at 48–49
`(citing Ex. 1005 ¶¶ 168–170). According to Petitioner, “a PHOSITA would
`have expected success in doing so for the same reason – the medical
`community had studied this dosing regime and found it effective for many
`drugs, including immunosuppressants like cladribine.” Id.
`Patent Owner argues, among other things, that Bodor does not teach
`or suggest weight-based dosing, and that Petitioner has not established any
`motivation to modify Bodor’s teaching to arrive at a method for treating MS
`comprising a total induction period dose of about 1.7 or 1.7–3.5 mg/kg, and
`a maintenance period total dosage of about 1.7 mg/kg, as required by the
`challenged claims. Prelim. Resp. 41, 50. In particular, Patent Owner
`asserts that “Petitioner’s suggestion to ‘fine tun[e]’ by ‘trial and error’ is
`plagued by hindsight.” Id. at 48. According to Patent Owner, “[a]bsent a
`suitable starting point in Bodor, Petitioner relies on Rice but fails to identify
`what would have motivated a POSA to choose Rice from among the various
`cladribine studies as a starting point.” Id. at 48. Patent Owner asserts also
`that Petitioner’s reliance on Rice in this single-reference ground challenge is
`improper. Id. at 43.
`
`18
`
`
`
`IPR2023-00050
`Patent 8,377,903 B2
`Patent Owner continues that Petitioner’s reliance on knowledge in the
`art is unavailing because, “nothing in the prior art taught a POSA how the
`combination of the different variables—dose, length and number of dosing
`period or drug-free periods—would impact the treat
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
