Strongbridge Dublin LimitedDownload PDFPatent Trials and Appeals BoardOct 19, 20212021003775 (P.T.A.B. Oct. 19, 2021) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 16/253,515 01/22/2019 Fredric Jay COHEN STRG0004-201T-US 9689 159061 7590 10/19/2021 GLOBAL PATENT GROUP - STRG Global Patent Group LLC P.O. Box 1636 Canóvanas, PR 00729 EXAMINER SZNAIDMAN, MARCOS L ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 10/19/2021 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): admin@globalpatentgroup.com lwilson@globalpatentgroup.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte FREDRIC JAY COHEN ____________ Appeal 2021-003775 Application 16/253,515 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims 32 and 33 (Appeal Br. 5). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant†to refer to “applicant†as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as “Strongbridge Dublin Limited . . . a wholly owned subsidiary of Strongbridge Biopharma plc.†(Appellant’s November 13, 2020, Appeal Brief (Appeal Br.) 3). Appellant further notes that “[o]ther wholly owned subsidiaries of Strongbridge Biopharma pk include Strongbridge U.S. Inc. Cortendo AB and Cortendo Cayman†and that “Avenue Venture Opportunities Fund, L.P. holds a security interest in the subject patent application†(id.). Appeal 2021-003775 Application 16/253,515 2 STATEMENT OF THE CASE Appellant’s disclosure relates to “a method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also being administered an organic anion transporter-1 (OAT1) inhibitor and/or an organic anion transporter-3 (OAT3) inhibitor†(Spec.2, Abstract). Appellant’s claims 32 and 33 are reproduced below: 32. A method of treating a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, wherein the subject is exhibiting one or more signs of dichlorphenamide toxicity as a result of increase in exposure of dichlorphenamide caused by the subject being co-administered: (i) an organic anion transporter-1 (OAT1) substrate that is dichlorphenamide, or a pharmaceutically acceptable salt thereof, at an initial dosage of up to 200 mg daily to treat a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants, and (ii) an organic anion transporter-1 (OAT1) inhibitor that is probenecid to treat gout and/or hyperuricemia, wherein the one or more signs of dichlorphenamide toxicity is chosen from paresthesia, cognitive disorder, dysgeusia, confusional state, hypersensitivity reactions, anaphylaxis reactions, hypokalemia, metabolic acidosis, falls, amnesia, cardiac failure, condition aggravated, convulsion, fetal death, hallucination, nephrolithiasis, pancytopenia, psychotic disorder, renal tubular necrosis, stupor, syncope, and tremor, 2 Appellant’s January 22, 2019, Specification. Appeal 2021-003775 Application 16/253,515 3 the method comprising: administering a reduced dose of dichlorphenamide, or a pharmaceutically acceptable salt thereof, once daily to the subject, wherein the reduced dose is less than the initial dose; and continuing administration of the OAT1 inhibitor. (Appeal Br. 18–19.) 33. A method of treating a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, wherein the subject is also in need of treatment with an organic anion transporter-1 (OAT1) inhibitor that is probenecid to treat gout and/or hyperuricemia, the method comprising: administering the OAT1 inhibitor to the subject; and subsequently administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to the subject at a reduced dose to compensate for the expected increase in exposure resulting from co-administration of the OAT1 inhibitor and the OAT1 substrate dichlorphenamide, or a pharmaceutically acceptable salt thereof, wherein the reduced dose is relative to what the subject would be administered if the subject was not being administered the OAT1 inhibitor. (Id. at 19.) Grounds of rejection before this Panel for review: Claim 33 stand rejected under 35 U.S.C. § 112(b). Appeal 2021-003775 Application 16/253,515 4 Claims 32 and 33 stand rejected under 35 U.S.C. § 103 as unpatentable over the combination of Keyevis3 and Probenecid.4 Definiteness: ISSUE Does the preponderance of evidence support Examiner’s conclusion that the phrase “wherein the reduced dose [of dichlorphenamide] is relative to what the subject would be administered if the subject was not being administered the OAT1 inhibitor[, probenecid],†recited in Appellant’s claim 33, is indefinite? ANALYSIS Appellant’s claim 33 is reproduced above. The method of Appellant’s claim 33 requires the administration of dichlorphenamide to a patient receiving probenecid for treatment of gout and/or hyperuricemia. The method of Appellant’s claim 33, further requires that dichlorphenamide is administered to the patient “at a reduced dose to compensate for the expected increase in exposure resulting from co- administration of the OAT1 inhibitor and the OAT1 substrate dichlorphenamide, or pharmaceutically acceptable salt thereof†(see Appellant’s claim 33). Appellant’s claim 33 further defines the “reduced dose†as an amount that is “relative to what the [patient] would be administered if the subject was not being administered the OAT1 inhibitor†3 KEVEYISTM, dichlorphenamide tablets, for oral use, Highlights of Prescribing Information, reference ID: 3803244, revised August 2015. 4 PROBENECID, probenecid tablet, film coated, Mylan Pharmaceuticals Inc., ID: RM0156A11, revised March 2006. Appeal 2021-003775 Application 16/253,515 5 (id.). As Appellant explains, “dichlorphenamide is an OAT1 substrate and as such, the dosage of the dichlorphenamide needs to be adjusted because of the co-administration†of the OAT1 inhibitor, probenecid (Appeal Br. 9). For the foregoing reasons, we are not persuaded by Examiner’s interpretation of Appellant’s claim 33 or the conclusions Examiner drew from this incorrect interpretation of Appellant’s claimed method (see Ans.5 4 (Examiner finds that Appellant’s “claim [33] requires that the dose of dichlorphenamide administered to the subjects that are also being administered probenecid, to be compared to the dose of dichlorphenamide administered to subjects that are not being administered probenecid.â€); see also id. at 3–5 (citing Keveyis)). CONCLUSION The preponderance of evidence fails to support Examiner’s conclusion that the phrase “wherein the reduced dose [of dichlorphenamide] is relative to what the subject would be administered if the subject was not being administered the OAT1 inhibitor[, probenecid],†recited in Appellant’s claim 33, is indefinite. The rejection of claim 33 under 35 U.S.C. § 112(b) is reversed. Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? 5 Examiner’s March 25, 2021, Answer. Appeal 2021-003775 Application 16/253,515 6 FACTUAL FINDINGS (FF) FF 1. Keyevis discloses prescribing information for dichlorphenamide tablets, for oral use (see Keyevis; see generally Ans. 5). FF 2. Keyevis discloses that dichlorphenamide “is an oral carbonic anhydrase inhibitor indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants†(Keyevis § Full Prescribing Information: 1. Indications and Usage; see also Ans. 5). FF 3. Keyevis discloses that “[d]ichlorphenamide, a dichlorinated benzenedisulfonamide, is known chemically as 4, 5-dichloro-1,3- benzenedisulfonamide†(Keyevis § Full Prescribing Information: 11. Description; see Ans. 6 (Examiner finds that dichlorphenamide is a sulfonamide.)). FF 4. Keyevis discloses that dichlorphenamide is administered at an initial dosage of “50 mg twice daily,†wherein “[t]he initial dose may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction)†and “[t]he maximum recommended dose is 200 mg daily†(Keyevis § Full Prescribing Information: 2. Dosage and Administration; see also Ans. 5). FF 5. Keveyis discloses that dichlorphenamide “is contraindicated in . . . [h]ypersensitivity to dichlorphenamide or other sulfonamides†(Keveyis § Full Prescribing Information: 4. Contraindications). FF 6. Keveyis discloses: Fatalities associated with the administration of sulfonamides have occurred due to adverse reactions including Stevens- Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other Appeal 2021-003775 Application 16/253,515 7 blood dyscrasias. Pulmonary involvement can occur in isolation or as part of a systemic reaction. [Dichlorphenamide] should be discontinued at the first appearance of skin rash or any sign of immune-mediated or idiosyncratic adverse reaction. (Keves § Full Prescribing Information: 5.1 Hypersensitivity / Anaphylasix / Idiosyncratic Reactions; see Ans. 6). FF 7. “Probenecid is a uricosuric and renal tubular transport blocking agent,†with a “chemical name for probenecid is 4- [(dipropylamino)sulfonyl]benzoic acid†(Probenecid § Description). FF 8. Probenecid discloses that “[p]robenecid tablets are indicated for the treatment of the hyperuricemia associated with gout and gouty arthritis†(Probenecid § Indications and Usage; see Ans. 6). FF 9. Probenecid discloses that “[p]robenecid . . . has been reported to inhibit the renal transport of many other compounds including . . . sulfonamides†(Probenecid § Clinical Pharmacology). FF 10. Probenecid discloses: Probenecid produces an insignificant increase in free sulfonamide plasma concentrations, but a significant increase in total sulfonamide plasma levels. Since probenecid decreases the renal excretion of conjugated sulfonamides, plasma concentrations of the latter should be determined from time to time when a sulfonamide and probenecid are coadministered for prolonged periods. Probenecid may prolong or enhance the action of oral sulfonylureas and thereby increase the risk of hypoglycemia. (Probenecid § Drug Interactions; see also Ans. 6.) ANALYSIS Based on the combination of Keyevis and Probenecid, Examiner concludes that, before the effective filing date of Appellant’s claimed Appeal 2021-003775 Application 16/253,515 8 invention, it would have been prima facie obvious to those of ordinary skill in this art “to administer to a subject suffering from both: primary hyperkalemic periodic paralysis and gout a composition comprising a therapeutically effective amount of dichlorphenamide (for the treatment of primary hyperkalemic periodic paralysis) and a therapeutically effective amount of probenecid (for the treatment of gout).†(Ans. 6–7; see FF 1–10). We find no error in Examiner’s conclusion of obviousness. The evidence on this record supports a finding that probenecid produces “a significant increase in total sulfonamide plasma levels†and, thus, “plasma [sulfonamide] concentrations . . . should be determined from time to time when a sulfonamide and probenecid are coadministered for prolonged periods†(see FF 10). The evidence on this record supports a finding that dichlorphenamide is a sulfonamide that is useful in the treatment of primary hyperkalemic periodic paralysis or primary hypokalemic periodic paralysis at an initial dosage of “50 mg twice daily,†wherein “[t]he maximum recommended dose is 200 mg daily†(FF 1–4). The evidence of record further recognizes that dichlorphenamide may be associated with hypersensitivity reactions (see FF 6). Keyevis, however, recognizes that individuals may respond differently to dichlorphenamide and, therefore, discloses that “[t]he initial dose may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction)†(FF 4). Thus, we find no error in Examiner’s conclusion that, before the effective filing date of Appellant’s claimed invention, it would have been prima facie obvious to those of ordinary skill in this art to monitor the patients for signs and/or symptoms of toxicity caused by dichlorphenamide as described by the KEYEVIS TM prescribing information . . . and as described by the Appeal 2021-003775 Application 16/253,515 9 PROBENECID Prescribing Information . . . and if necessary reduce the amount of dichlorphenamide (a sulfonamide) being administered (i.e. less than the initial dose), in order to avoid dichlorphenamide side effects. (Ans. 7; see FF 1–10.) Appellant’s characterization of probenecid as an OAT1 inhibitor and dichlorphenamide as an OAT1 substrate does not change the art recognized interaction between these two drugs (see Appeal Br. 10; cf. FF 1–10). For the foregoing reasons, we are not persuaded by Appellant’s contention that “Appellant unexpectedly found that dichlorphenamide is a substrate of the OAT1 transporter and thus may cause clinically significant drug interactions if co-administered with an OAT1 inhibitor, such as probenecid, in view of the increased systemic exposure of the OAT1 substrate dichlorphenamide†(Appeal Br. 11). For the foregoing reasons, we are not persuaded by Appellant’s contention that “at the time of the present invention, the interaction with dichlorphenamide with an OAT1 inhibitor (such as probenecid) was unknown and unpredictable†(Appeal Br. 10). For the same reasons, we are not persuaded by Appellant’s contention “that the contraindication to administer dichlorphenamide with [probenecid] was discovered by the inventor of the subject patent application upon discovering that dichlorphenamide is [an] OAT1 substrate†(id. at 16). The method set forth in Appellant’s claim 32, reproduced above, requires no more than reducing the dichlorphenamide dosage in patients exhibiting one or more signs of dichlorphenamide toxicity due to a prior co- administration of dichlorphenamide and probenecid for their, respective, art recognized therapeutic utilities (see Appeal Br. 18–19; cf. FF 1–10). Stated Appeal 2021-003775 Application 16/253,515 10 differently, Appellant’s claimed method does not require the co- administration of dichlorphenamide and probenecid that results in signs of dichlorphenamide toxicity. Thus, the preamble of Appellant’s claimed method makes clear that the patient population being treated are those patients suffering from dichlorphenamide toxicity resulting from a previous co-administration of dichlorphenamide and probenecid, for their respective therapeutic utility, else no patient population would fall within the scope of Appellant’s claimed method, specifically, the method comprising: administering a reduced dose of dichlorphenamide, or a pharmaceutically acceptable salt thereof, once daily to the subject, wherein the reduced dose is less than the initial dose; and continuing administration of [probenecid]. (Appeal Br. 19.) Therefore, we are not persuaded by Appellant’s contention that Examiner mistakenly assumed that “subjects being administered dichlorphenamide . . . are subjects also suffering from gout†(Appeal Br. 11). The prior existence of this patient population is implied by the preamble of Appellant’s claimed method, thus Keyevis and Probenecid would have been relevant to those practitioners who co-administered such a combination of drugs for their, respective, therapeutic utilities. For the same reasons, we are not persuaded by Appellant’s contention that Examiner improperly relied upon common sense (Reply Br. 5–8). For the foregoing reasons, we are not persuaded by Appellant’s contention that Examiner failed to identify a reason a person of ordinary skill in this art would have combined Keyevis and Probenecid (see Appeal Br. 11–13). Appeal 2021-003775 Application 16/253,515 11 Appellant contends that dichlorphenamide has “an aromatic core with an attached sulfonamide†(Appeal Br. 15). Stated differently, dichlorphenamide is a sulfonamide conjugated to an aromatic core. Therefore, we are not persuaded by Appellant’s contentions regarding “conjugated sulfonamide[s]†or whether dichlorphenamide falls within the scope of the term “total sulfonamide,†as it is used by Probenecid (see id. at 14–16; cf. FF 10). In addition, we find no evidence on this record supporting Appellant’s counsel’s statements and interpretations of the terms “total sulfonamide†and “conjugated sulfonamide†(see Appeal Br. 14–16). See In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of evidence.â€). For the foregoing reasons, we are not persuaded by Appellant’s contention that “the Office has failed to establish a prima facie case of obviousness and instead bases its rejection on mistaken and unsupported assumptions related to motivation to combine†and “[m]oreover, the prior art actually taught away from the claimed invention†(Appeal Br. 16). CONCLUSION The preponderance of evidence relied upon by Examiner supports a conclusion of obviousness. The rejection of claim 32 under 35 U.S.C. § 103 as unpatentable over the combination of Keyevis and Probenecid is affirmed. Claim 33 is not separately argued and falls with claim 32. Appeal 2021-003775 Application 16/253,515 12 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 33 112(b) Indefiniteness 33 32–33 103 Keyevis, Probenecid 32–33 Overall Outcome 32–33 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv) (2019). AFFIRMED Copy with citationCopy as parenthetical citation