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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, 12-13, in the reply filed on 7/2/2025 is acknowledged.
Applicant’s election without traverse of:
(i) triacetin;
(ii) propylene glycol and polyethylene glycol;
(iii-b) an antioxidant is present in a lipophilic solvent, namely BHT (claim 7);
(iv) the surfactant combination of glyceryl monostearate and polyoxyethylene hydrogenated castor oil from claim 11,
in the reply filed on 7/2/2025 is acknowledged.
Claims 9,11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/2/2025.
Response to Arguments
Applicants' arguments, filed 10/29/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1-2, 4-6, 12, 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shenoy et al. (WO 2008/091855 A1; 2008; cited in a prior Office action), in view of LeGuyader et al. (“Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas”; Eur. J. Hosp. Pharm.; 2020;27:e48–e52.; 2018; doi:10.1136/ejhpharm-2018-001695; 2018).
Shenoy teaches pharmaceutical formulations comprising poorly water-soluble drugs (title). The compositions of the invention may also be potentially used for other routes of administration (relative to oral), and topical is clearly named [0013].
In some embodiments, the active pharmaceutical ingredient is, inter alia, sirolimus (a.k.a., rapamycin) [0014], [0074]; this compound is also clearly claimed (claim 21).
Solvents useful in the embodied pharmaceutical formulations include, inter alia Applicant elected polyethylene glycol, triacetin, propylene glycol or a mixture of any two or more thereof [0075]. A shorter (13) listing of solvents in claim 22 also includes polyethylene glycol, triacetin, propylene glycol or a mixture of any two or more thereof. As claim 22 directly follows claiming of sirolimus in claim 21, the Examiner construes the elected combination rapamycin, triacetin, propylene glycol and polyethylene glycol are taught in close proximity. This elected combination is clearly obvious, based on the teachings of these four compounds for the purposes set forth.
Regarding the elected antioxidant, the dosage forms embodied herein may also include pharmaceutically acceptable additives such as, but not limited to, an antioxidant; exemplary antioxidants include Applicant elected butylated hydroxytoluene (BHT) [0070], rendering obvious incorporation of this compound as antioxidant. The elected solvent triacetin, is construed to read on the lipophilic solvent, that BHT is to be delivered in. Addition of antioxidant in lipophilic solvent would not be structurally different from addition of BHT, where the formulation also contains a lipophilic solvent, rendering claims 2, 3 and 7 prima facie obvious.
Regarding the elected additional surfactants, claim 30 recites the pharmaceutical formulation where the stabilizer is selected from glycerin monostearate, polyoxyl hydrogenated castor oil, and mixture of any two thereof, construed to read on the HLB levels of claim 1, 2, 12, or close enough to be prima facie obvious over recited HLB levels. The listing also includes generic SPAN (SPAN 40 is known to have HLB, rendering obvious selection of surfactant/s with the HLB range of claim 1, 2, 12). Thus, the surfactant elected, or alternate surfactant/s within the claim 1, 2, 12 metes and bounds would have been obvious to include.
Regarding relative amounts of components a, b and c, recited in claims 4-6, solvent amounts are not explicitly taught. However, Shenoy does indicate that solubilized state includes solubilization of the API in a solvent or solubilization in one or more liquid components of an emulsion [0043]. Taken together with the solubility considerations of the API [0040], the skilled artisan would have been motivated to identify relative amounts of the components to satisfy these considerations, resulting in determining workable amounts via routine optimization. Consider solubility of less than about 10 mg/mL [0040] (in water); 10 mg/g corresponds to about a 1:100 weight ratio. A lower amount embraces 1:70 or lower ratios, to 1:20. 2:1 to 2:6 is a wide range (claim 5), and a combination of, say 1:1:1 of each solvent would give 2:4 ratio; optimization in this general range would have been obvious
Regarding the amendment to claims 1, 2, 12, the claims now require the topical formulation to be in the form of a gel. Shenoy teaches polymeric carriers include, inter alia, gelatin [0067], which is suggestive of, and renders obvious a gel form.
Thus, each of the rejected claims are prima facie obvious over the teachings of Shenoy.
LeGuyader teaches gel formulations of rapamycin, prepared with Carbapol-974P as gelling agent, with or without alpha-tocopherol (Table 1). Gels were physically and microbiologically stable after 1 year at 4°C abstract; Table 3.
LeGuyader establishes good stability of a gel formulation, with or without an antioxidant (comparable to BHT, taught by Shenoy), rendering obvious selection of a gel formulation, whether prepared with gelatin or the gel material taught by LeGuyader.
Applicant argues:
Applicant respectfully traverses the rejection of claim 1 over Shenoy at least because Shenoy does not teach or suggest a gel as presently claimed and because the claimed composition yields unexpected stability results not predictable from Shenoy.
In particular, paragraph [0013] cited by the Office at the bottom of page 4 of the action discloses a solid dosage form and a liquid dosage form, but it does not disclose a gel.
Further, Shenoy basically concerns oral dosage forms (see, e.g., the Abstract) and does not address stability issues in topical rapamycin systems as in the present invention. As can be seen from the Examples in the present application, the features recited for the presently claimed invention provide superior results which would not have been expected from Shenoy.
For instance, the results in Tables 4 and 5 on pages 20-21 of the present application, as well as the results in Example 4 vs. Comparative Example 2 at pages 23-25, show the effect on stability provided by the presence of BHT as recited in the presently claimed invention.
In addition, Example 3 at pages 22-23 describes that the HLB range of 5 to 7 in the presently claimed invention suppresses phase separation.
Accordingly, the claimed formulation exhibits criticality and properties that would not have been expected from Shenoy, thereby establishing non-obviousness under 35 U.S.C. § 103.
Withdrawal of the rejection is respectfully requested.
This is not persuasive. Shenoy clearly teaches the component gelatin, which is construed as suggestive of a gel formulated with this material. Additionally, LeGuyader clearly teaches a gel with or without an antioxidant, which is comparable to the elected BHT antioxidant material. This reference also makes clear good stability is associated with the gel rapamycin forms, with or without the antioxidant component. Thus, achieving stability and argued properties are not considered to be unexpected.
Regarding the HLB in the 5-7 range, the skilled artisan would have been motivated to modify the two surfactants in amounts suitable to achieve elegant formulations; absent to the contrary, the HLB range cited would have been obvious, or close amounts would have been obvious, rendering the claimed HLB range prima facie obvious. (MPEP 2144.05 (II)).
Even if there were considered some superior result, none of the claims correspond to the disclosed combinations of ingredients, at concentrations disclosed. Therefore, any argued properties are not commensurate in scope with evidence (MPEP 716.02(d)).
Conclusion
No claim is allowed.
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 TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614
/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614