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 .
Priority
This application is a national stage entry (371) of PCT/JP2020/037986 filed on 10/07/2020. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in JAPAN (2019-189091) on 10/16/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s amendment filed on July 24, 2025, amending claims 13, 18 and 22 has been entered. Claims 14 and 18-24 are withdrawn. Claims 1-12 were previously canceled. Claims 13 and 15-17 are being examined as they read on the elected species.
Response to Arguments
Applicant's arguments filed July 24, 2025 have been fully considered but they are not persuasive.
Applicant argues that in contrast to the assertion in the Office Action, neither the Guan et al. Patent Application nor the Kaneda et al. Patent Application disclose using a topical application for treating epilepsy. Applicant argues that Guan et al. does not teach that topical administration is a suitable route of administration for the mTOR inhibitor for the treatment of epilepsy and nowhere in Guan et al. is topical administration of rapamycin taught. Applicant argues that the Examples in Guan et al. only disclose using oral composition of mTOR inhibitor and thus Applicant argues that one skilled in the art would NOT use a topical application to treat epilepsy.
These arguments are found not persuasive because it has been well established that consideration of a reference is not limited to the preferred embodiments or working examples, but extends to the entire disclosure for what it fairly teaches, when viewed in light of the admitted knowledge in the art, to a person of ordinary skill in the art. In re Boe, 355 F.2d 961,148 USPQ 507, 510 (CCPA 1966); In re Lambedi, 545 F.2d 747, 750, 192 USPQ 279,280 (CCPA 1976): In re FracalossL 681 F.2d 792,794, 215 USPQ 569, 570 (CCPA 1982)4 In re Kaslow, 707 F.2d 1366, 13:4,217 USPQ 1089, 1095 (Fed. Cir. 1983). Furthermore, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In the instant case, Guan et al. is specifically directed to the treatment of epilepsy and reducing seizures comprising the administration of an mTOR inhibitor such as rapamycin. Guan et al. further teaches that suitable alternatives for oral administration of the mTOR inhibitor include topical administration [0152]-[0153]. Accordingly, prior to the effective filing date of the claimed invention it would have been obvious to a person of ordinary skill in the art to select topical administration as a suitable alternative to oral administration. Thus selecting topical administration as an alternative to oral administration would have been within the purview of an artisan practicing the invention and seen as an obvious substitution of one known element for another to obtain predictable results.
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Applicant further argues that Kaneda et al. is directed to treating skin disease not epilepsy. Applicant argues that Kaneda et al. teaches that the external medicine does not increase blood level of sirolimus and its derivatives, and their effects remain local and do not cause systemic effects. Thus Applicant argues that those skilled in the art would have understood that the external application as described in Kaneda et al. retains the active ingredient in the skin and are not adsorbed systemically and one skilled in the art would not expect topical application of sirolimus to have any effect on epilepsy as it would not reach the blood stream to effect the central nervous system of a subject. Applicant argues that it is surprising and unexpected that epilepsy can be treated via a topical administration of sirolimus or a derivative thereof by affecting the nerve cells at the site of application, which then directly or indirectly affects the brain.
These arguments are found not persuasive because Kaneda et al. specifically teaches treating the same patient population having TSC (tuberous sclerosis complex) comprising the same topical formulation of rapamycin as claimed, and therefore the treatment of Kaneda et al. will necessarily treat the same symptoms of TSC including epilepsy. Moreover, Guan et al. further specifically teaches that suitable alternatives for oral administration of the mTOR inhibitor for the treatment of epilepsy include topical administration such as a gel form [0152]-[0153]. Thus Guan et al. teaches the use of the same topical form as claimed in the instant claims and does not teach or suggest that the topical administration must result in increases of drug concentration in the blood of a subject in order to treat epilepsy as argued by Applicant. All Applicant presents is Attorney arguments which is not the type of factual evidence necessary to rebut a prima facie case of obviousness. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Thus since Guan et al. teaches that topical administration of mTOR inhibitors such as rapamycin can be used to treat epilepsy associated with TSC, and Kaneda et al. specifically teaches the use of a topical formulation comprising the mTOR inhibitor rapamycin, for the treatment of subjects with TSC, a person of ordinary skill in the art would have been motivated to treat a subject with TSC with the topical formulation of Kaneda et al. with a reasonable expectation of treating epilepsy in said subject with TSC. Thus for these reasons, the previous rejection under 35 USC 103 is hereby maintained and reproduced below. This action is FINAL.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 13 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Guan et al. U.S. Publication No. 2008/0188461 A1 in view of Kaneda et al. U.S. Publication No. 2013/0317053 A1.
Claims 13 and 15-17 of the instant application claim a method for treating epilepsy in a subject in need thereof wherein the epilepsy is accompanying tuberous sclerosis complex, comprising topically applying a therapeutically effective amount of a topical composition comprising an active ingredient selected from the group consisting of sirolimus (also known as rapamycin), a sirolimus derivative, and a combination thereof.
Guan et al. teaches compositions and methods for the detecting, preventing, treating, and empirically investigating seizures and seizure related disorders (e.g., West syndrome, TSC, childhood absence epilepsy, benign focal epilepsies of childhood, juvenile myoclonic epilepsy (JME), temporal lobe epilepsy, frontal lobe epilepsy, Lennox-Gastaut syndrome, occipital lobe epilepsy). In particular, Guan et al. provides compositions and methods for detecting, treating, preventing and empirical investigating seizures and seizure related disorders through inhibition of mTOR function (e.g., mTOR activity, mTOR expression). In addition, Guan et al. provides methods and compositions that utilize mTOR inhibiting agents (e.g., rapamycin) in the detecting, preventing, treating, and empirical investigating of seizures and seizure related disorders (see abstract, [0002] and [0008]).
Guan et al. teaches in certain embodiments methods for preventing the onset of seizures in a subject having an increased risk for developing seizures (e.g., an individual suffering from TSC), comprising administering to the subject a composition configured to reduce mTOR function (e.g., mTOR activity, mTOR expression) within the subject [0012]. In some embodiments, the composition comprises an mTOR inhibiting agent (e.g., rapamycin, a rapamycin derivative), and in some embodiments, the subject suffers from TSC [0012].
Guan et al. teaches that tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a birth incidence of approximately 1 in 6,000 wherein affected individuals develop hamartomatous growths in multiple organs of the body that occur throughout their life span [0094] . Low-grade neoplastic lesions of the central nervous system (CNS), usually in the form of subependymal giant cell astrocytomas (SEGAs), are reported in 5 to 15% of such individuals wherein these lesions exhibit insidious slow growth, often remaining clinically asymptomatic until causing obstructive hydrocephalus [0094].
Guan et al. teaches agents capable of inhibiting mTOR function (e.g., mTOR activity, mTOR expression) wherein the mTOR inhibiting agent is rapamycin and rapamycin derivatives [0107]. Rapamycin (sirolimus [Rapamune]) is a commercially available immunosuppressant, that forms an inhibitory complex with the immunophilin FKBP12, which then binds to and inhibits the ability of mTOR to phosphorylate downstream substrates, such as the S6Ks and 4EBPs [0108]. It is marketed as an immunosuppressant, because of its propensity to inhibit T-cell proliferation, and has been approved for use in this therapeutic setting in the United States since 2001 [0108].
Guan et al. further provides pharmaceutical compositions comprising an inhibitor of mTOR function [0152]. The pharmaceutical compositions of the invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated [0152]. Guan et al. teaches that administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral [0152].
Guan et al. teaches that pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders [0153]. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable [0153].
Guan et al. teaches in one embodiment the pharmaceutical compositions may be formulated and used as foams [0159]. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes [0159]. While basically similar in nature these formulations vary in the components and the consistency of the final product [0159].
Claims 1-12 of Guan et al. claim a method of preventing seizures, comprising administering to a subject suffering from a seizure related disorder a composition comprising an agent, wherein said agent is designed to inhibit mTOR function, wherein said seizure related disorder is TSC, wherein said agent is rapamycin, wherein said treating results in a reduction of seizures experienced by said subject.
Guan et al. does not specifically exemplify treatment of epilepsy comprising topically applying sirolimus to the head of the subject.
However, Guan et al. teaches that mTOR inhibitors can be administered as pharmaceutical compositions and formulations for topical administration including transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders [0153]. Guan et al. further teaches in one embodiment the pharmaceutical compositions may be formulated and used as foams [0159]. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes [0159].
Accordingly, prior to the effective filing date of the claimed invention, it would have been prima facie obvious to a person of ordinary skill in the art to administer the mTOR inhibitor composition of Guan et al. for the treatment of epilepsy by routes of administration taught therein including by topical administration with a reasonable expectation of similar success. Since Guan et al. teaches that topical administration is a suitable route of administration for the mTOR inhibitor for the treatment of epilepsy, a person of ordinary skill in the art would have been motivated to formulate the mTOR inhibitor in a topical form known in the art with a reasonable expectation of success.
Kaneda et al. teaches there is known a genetic disease called tuberous sclerosis complex (TSC) which causes (i) systemic tumors such as a skin tumor, (ii) central nervous system damage (e.g., epilepsy, delayed psychological development, and autism disorder), and (iii) vitiligo [0003]. It is known that causative genes of this genetic disease are (i) TSC1 which encodes protein hamartin and (ii) TSC2 which encodes protein tuberin and a complex of the protein hamartin and the protein tuberin are upstream of mTOR, and suppresses a function of mTOR [0003]. Kaneda et al. teaches that inhibition of mTOR is effective for treating tuberous sclerosis complex and in view of this, use of sirolimus, which is an inhibitory agent of mTOR, has been tried for treating tuberous sclerosis complex [0003].
Kaneda et al. teaches a topical gel composition comprising sirolimus or a derivative thereof as an active ingredient for inhibiting mTOR dissolved in a solvent [0064]-[0066]. Examples of the solvent which dissolves the active ingredient include, isopropanol and ethanol [0100]. Kaneda et al. also teaches an ointment composition comprising sirolimus or a derivative thereof as an active ingredient for inhibiting mTOR [0076] [0097].
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to use the topical form of sirolimus known in the art as taught by Kaneda et al. in the method of Guan et al. which is a method of preventing seizures, comprising administering to a subject suffering from a seizure related disorder a composition comprising an agent, wherein said agent is designed to inhibit mTOR function, wherein said seizure related disorder is TSC, wherein said agent is rapamycin (sirolimus), wherein said treating results in a reduction of seizures experienced by said subject, and wherein the agent may be administered by topical administration with a reasonable expectation of success. Thus since Guan et al. teaches treating TSC seizure disorder by topically administering sirolimus, an ordinary skilled artisan would have been motivated to administer the topical sirolimus formulations of Kaneda et al. with a reasonable expectation of predictable results. Moreover, it would have been within the skill of an ordinary artisan practicing the invention of Guan et al. to administer the topical formulation directly at the site of action which would be on the head of the patient with seizures.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-12 are canceled. Claims 13 and 15-17 are rejected. Claims 14 and 18-24 are withdrawn. No claims are allowed.
THIS ACTION IS MADE FINAL. 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 KARA R. MCMILLIAN whose telephone number is (571)270-5236. The examiner can normally be reached Tuesday-Friday 12:00 PM-6:00 PM.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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