DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
Applicant’s response from 1/14/2026 is acknowledged.
Claim Objections
In view of Applicant’s cancellation of claim 27, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112
In view of Applicant’s claim amendments, this rejection is hereby withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments have been carefully considered, but have not been found to be persuasive. The gist of Applicant’s arguments is based on an individual attack of the references of record, where the rejection was made with a combination of references. In response, the Examiner reminds Applicant that it is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000)).
Since a combination with metformin, per the claims as amended, was already addressed in the previous office action, the Examiner accordingly maintains the rejection over the amended claims as well in view of the combination of references.
Claims 2, 14 and 22-29 are pending, and have been examined herewith to the extent of Applicant’s elected species metformin and the broader genus around it of a P-gp inhibitor.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 2, 14, 22-25 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over US 20150361060 A1 to Taylor et al. (“Taylor”, of record), and further in view of US 20190152920 to Valdez et al. (“Valdez”, of record), and Abbasi et al., Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliclazide, metformin, and pioglitazone in vitro and in situ, Res Pharm Sci. 2016 May-Jun;11(3):177–186 (“Abbasi”, of record).
Taylor discloses a therapeutic composition comprising one or more of compounds of disclosed structures, or equivalents thereof, or a stereoisomer thereof, or an analog thereof, or a pharmaceutically acceptable salt thereof, or a bioisostere thereof: and/or compositions thereof, of which a specifically disclosed species is Applicant’s claimed compound RS 194B
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(claim 1, [0006]-[0011], Figures 16 and 21).
Taylor further teaches a method for treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure, or for treating, ameliorating or protecting (preventing) organophosphate (OP) inhibition of an acetylcholinesterase (AChE), comprising: administering to a patient or an individual in need thereof, a compound as set forth in claim 1, wherein optionally the compound or formulation is administered enterally or parenterally, wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally, or administering the compound as set forth in claim 1, using a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, a syringe, a cartridge or a pen or a jet injector. (claim 5). The OP can be pesticide or poison. (col. 6, ll. 65-66).
Applicant has currently amended claim 2, to recite a combination of the claimed compound with metformin, in lieu of the previously claimed a brain efflux transporter inhibitor, or an inhibitor of renal tubular secretion. It is noted, however, that although more narrow, metformin still falls under the guise of a specific brain efflux transporter inhibitor, or an inhibitor of renal tubular secretion. See, e.g., Applicant specification, which provides in relevant part: “[0024] and optionally the brain efflux transporter inhibitor or the inhibitor of renal tubular secretion comprises or is: [0025] (i) metformin”.
Taylor does not disclose a combination with metformin, or alternatively of the broader brain efflux transporter inhibitor, or an inhibitor of renal tubular secretion.
Valdez discloses oxime compounds capable of inactivating OP-based AChE inhibitors, crossing the blood brain barrier (BBB), and/or reactivation of OP-inhibited acetylcholinesterase (AChE) and related methods, systems and compositions for inactivation of one or more OP-based AChE inhibitors, therapeutic and/or prophylactic treatment of an individual, and/or decomposition of OP-based AChE inhibitors for decontamination. (Abstract).
Claim 29 of Valdez is directed to a pharmaceutical composition to treat a condition associated with exposure of an individual to an OP-based AChE inhibitor, the composition comprising at least one compound of claim 1 in a therapeutically effective amount and a pharmaceutically acceptable vehicle. Claim 30 of Valdez is directed to composition of claim 29, further comprising a therapeutically effective amount of at least one efflux inhibitor for an efflux protein.
Per Applicant’s claims 26 and 27, Claim 32 of Valdez is directed to the composition of claim 28, wherein the efflux inhibitor is one selected from the group consisting of verapamil, cyclosporin A, uinidine, quinine, amiodarone, valspodar, elacridar, biricodar, dexverapamil, OC144-093 (ONT-093), LY335979 (zosuquidar), XR9576 (tariquidar), R101933 (laniquidar), GF120918, or any combination thereof.
Claim 25 of Valdez recites: “A method of preventing a condition of an individual, the condition associated with exposure of the individual to an OP-based AChE inhibitor, the method comprising: administering to the individual a therapeutically effective amount of at least one compound of claim 1 capable of inactivating one or more OP-based AChE inhibitor, the administering performed for a time and under a condition to allow contact between the at least one compound and a nervous system and/or vascular system of the individual.”
Per Applicant’s claims 28 and 29, claim 26 of Valdez discloses: “The method of claim 25, wherein the administering a therapeutically effective amount of at least one compound of claim 1 is performed together with at least another one antimuscarinics agent selected from the group consisting of PAM-2, Atropine, Scopolamine, Pirenzepine, Diphenhydramine, Solifenacin or a combination thereof.”
Valdez discloses than an efflux protein includes MDR1 efflux pump which is an ABC efflux transporter. The blockade of BBB P-gp by cerebral application of P-gp efflux inhibitors significantly increases the brain concentration of oxime. ([0407]). Valdez discloses the MDR1 efflux assay, which measures whether a drug compound is pumped out of the brain by MDR1 (P-gp). ([0403]-[[0408]).
Valdez does not explicitly disclose wherein the P-gp inhibitor is metformin.
Abbasi discloses that metformin, gliclazide and pioglitazone are inhibitors of P-gp expression. It discloses that P-gp is a trans-membrane drug efflux pump. (Abstract). Abbasi further discloses that P-glycoprotein (P-gp; MDR1; ABCB1) is a 170 kDa trans-membrane ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. P-gp is expressed in tissues such as intestinal epithelium, hepatocytes, renal proximal tubular cells, and the blood–brain and blood–testis barriers. (p. 177, col. 1).
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Taylor, Valdez and Abbasi in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been motivated to do guided by the desire to obtain a therapeutic composition with an enhanced effect of treating, ameliorating or protecting (preventing) an organophosphate toxicity or poisoning or toxic exposure with a combination of compounds known to do so, such as RS 194B, as disclosed in Taylor, and various P-gp inhibitors, to include metformin, as disclosed in Valdez and Abbasi.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627