Trials@uspto.gov
`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 SERONO SA,
`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
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`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 SERONO SA,
`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
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2023-00049
`Patent 7,713,947 B2
`
`INTRODUCTION
`I.
`TWi Pharmaceuticals, Inc. (“Petitioner”) filed a Petition requesting an
`inter partes review of claims 36, 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 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 ’947 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 the 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
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`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.
`
`The ’947 Patent
`C.
`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). Id. 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”). 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
`Specification states that “the therapeutic efficacy of the oral regimen above
`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 ’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 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
`
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`IPR2023-00049
`Patent 7,713,947 B2
`Cladribine treatment between the treatment periods is also
`desirable.
`Id. at 3:22–30. In view of this, 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.” Id. at 3:34–37.
`Illustrative Claim
`D.
`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:
` (i) an induction period lasting from about 2 months to
`about 4 months wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`induction period is from about 1.7 mg/kg to about 3.5 mg/kg;
` (ii) a cladribine-free period lasting from about 8 months
`to about 10 months, wherein no cladribine is administered;
` (iii) a maintenance period lasting from about 2 months to
`about 4 months, wherein said formulation is orally administered
`and wherein the total dose of cladribine reached at the end of the
`maintenance period is about 1.7 mg/kg;
` (iv) a cladribine-free period wherein no cladribine is
`administered.
`Ex. 1001, 19:14–30. Dependent claims 38 and 41–43 recite time periods for
`the induction period, cladribine-free period, and maintenance period.
`Dependent claims 39 and 44–46 recite 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.
`
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`IPR2023-00049
`Patent 7,713,947 B2
`Asserted Grounds of Unpatentability
`E.
`Petitioner asserts that claims 36, 38, 39, and 41–48 are unpatentable
`on the following three grounds:
`Claims Challenged
`32 U.S.C. §1 Reference(s)
`36, 38, 39, 41–48
`102(e)
`Bodor2
`36, 38, 39, 41–48
`103(a)
`Bodor, knowledge of a POSITA3
`36, 38, 39, 41–48
`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)).
`
`
`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.”
`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”).
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`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’ 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 at this stage in the proceeding.
`Prelim. Resp. 7.
`Because Petitioner’s uncontested definition of one of ordinary skill in
`the art is reasonable and consistent with the ’947 patent and the prior art of
`record, we adopt Petitioner’s definition for purposes of this Decision.
`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 does
`not assert any claim construction at this preliminary stage. Prelim. Resp. 7.
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`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.”).
`Anticipation by Bodor
`C.
`Petitioner asserts that claims 36, 38, 39, and 41–48 are anticipated by
`Bodor. Pet. 27–41. Patent Owner disagrees. Prelim. Resp. 22–40.
`“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.” Id. 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.” 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 explains 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
`
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`Patent 7,713,947 B2
`solid oral dosage form.” Id. at 3:25–28. According to Bodor, “[t]his product
`is a complex cladribine-cyclodextrin complex, and the 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.
`
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`
`Discussion
`2.
`Petitioner identifies the disclosures in Bodor that it relies on for each
`limitation of independent claim 36 and dependent claims 38–39, 41–46, and
`48. Pet. 27–41. 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 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.” 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. In particular, Petitioner contends that
`the skilled artisan would have understood from Bodor’s dosing schedule that
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`IPR2023-00049
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`“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.
`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 31. Petitioner asserts such a patient would be
`administered 120 mg of cladribine, which results in 1.71 mg/kg. Id. at 31–
`32. 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 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 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. 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. (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
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`Patent 7,713,947 B2
`to the patient in both the induction phase and the maintenance phase.” Id. at
`(citing Ex. 1004, 156; Ex. 1005 ¶ 123).
`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. 27. 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. 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. at 27.
`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 a total oral dosage of cladribine in an induction period or a
`maintenance period based upon the weight of a patient.
`
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`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. 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 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 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. Id. at 13:19–25.
`Whether administered for 10 days or up to 14 days during the treatment
`period, the daily dosage remains a flat 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
`skilled practitioner (physician or veterinarian) to determine subsequent
`therapy. Such evaluation will aid and inform in evaluating whether to
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`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 weights and treatment durations that support calculations
`resulting in 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
`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
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`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 does not necessarily stay the same.
`Rather, the dosage may require adjustments in view of ongoing and
`continuous clinical evaluation.
`Moreover, for the same reasons discussed regarding Bodor’s
`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 one that is equivalent to 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 36, or its dependent claims, claims 38, 39, and 41–48, are anticipated
`by Bodor.
`D. Obviousness over Bodor and Knowledge in the Art
`Petitioner asserts that claims 36, 38, 39, and 41–48 would have been
`obvious over the combined teachings of Bodor and the common knowledge
`of one of ordinary skill in the art. Pet. 41–49. Patent Owner disagrees.
`Prelim. Resp. 40–54. We incorporate our description and discussion of
`Bodor in Section II.C. 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
`invention was made to a person having ordinary skill in the art to which the
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`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.
`For this obviousness challenge, Petitioner again relies on Bodor as
`disclosing every limitation of the challenged claims. Pet. 41. 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. at 41–42.
`To begin, we focus on the total dosage limitations recited in
`independent claim 36, 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 44–48. 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 44–45.
`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
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`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. at 45 (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.” Pet. 45 (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. 45 (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. at 46 (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 and adjust that dosage. Id. (citing Ex. 1029, 13:31–40). Petitioner
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`IPR2023-00049
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`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. at 46–47.
`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
`(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, 49. In particular, Patent Owner
`asserts that “Petitioner’s suggestion to ‘fine tun[e]’ by ‘trial and error’ is
`plagued by hindsight.” Id. at 47. 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 47–48. Patent Owner asserts
`also that Petitioner’s reliance on Rice in this single-reference ground
`challenge is improper. Id. at 42.
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`IPR2023-00049
`Patent 7,713,947 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 treatment of MS or what
`specific combination (if any) would result in a safe and effective MS
`treatment method.” Id. at 48. According to Patent Owner, Petitioner’s
`obviousness challenge involves “merely throw[ing] metaphorical darts at a
`board in hopes of arriving at a successful result [when] the prior art gave
`either no indication of which parameters were critical or no direction as to
`which of many possible choices is likely to be successful” and should be
`rejected as improperly relying on hindsight. Id. 48–49 (quoting In re
`Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat. Litig., 676
`F.3d 1063, 1070 (Fed. Cir. 2012)).
`Having considered the arguments and the evidence on the current
`record, we determine that Petitioner has not shown sufficiently for institution
`that Bodor discloses each limitation of the challenged claims expressly or
`inherently for the reasons discussed regarding the anticipation ground. It is
`only by employing a strategy that exemplifies treatment of patients having
`specifically selected weights and specifically selected treatment durations
`that Petitioner is able to show that Bodor’s method of treating MS with
`10 mg of the cladribine complex daily arrives at about a total dosage of
`1.7 mg/kg at the end of a treatment period. Indeed, Petitioner recognizes
`that Bodor’s teachings do not always arrive at that total dosage. Pet. 45.
`Insofar as Petitioner relies on Bodor, in view of the asserted common
`knowledge of a skilled artisan at the time of the invention, to demonstrate
`that “it would have been obvious for a PHOSITA to make the total dosage at
`the end of the induction period and at the end of the maintenance period to
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`IPR2023-00049
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`be 1.7 mg/kg,” id. at 45, we determine that showing is also insufficient for
`institution. In particular, we agree with Patent Owner that Petitioner’s
`obviousne
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