OPHTHALMIC CREAM FORMULATIONS AND THEIR USES

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 claims the benefit of U.S. Provisional Application No. 63/452,633 filed March 16, 2023, U.S. Provisional Application No. 63/605,955 filed December 4, 2023, and U.S. Provisional Application No. 63/549,789 filed February 5, 2024. Information Disclosure Statement The information disclosure statement (IDS) submitted on 10/02/2025 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Status of claims Claims 4-16, 18, 20-21, 24, 31, 36, 41, and 43 are currently pending and under examination. Claims 4, 15, 16, 24, 31, and 43 have been amended. Claims 1-3, 17, 19, 22-23, 25-30, 32-35, 37-40, 42, 44-45 have been cancelled by applicant without prejudice or disclaimer. Applicant’s arguments, filed 08/10/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application. The obviousness rejection below is repeated from the 05/19/2026 Office Action and modified in order to address the most recent amendments. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. Claims 4-15, 18, 20-21, 24, 31, 36, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Ostrow (US 2018/0042911 Al) in view of Nanduri (WO2011053792) and further in view of Avramoff (US 2020/0237651 Al). The instant claims are directed to a pharmaceutical composition of a gel, ointment, lotion, or cream formulation of a 50% w/w tropanyl group compound, a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; and a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of a polyalcohol; and a polynucleotide base compound in a gel, ointment, lotion, or cream formulation is an oil-in-water emulsion cream formulation that includes at least 50 % w/w water in a pH range of about 4.0 to about 5.5. Ostrow et al. teach an aqueous ophthalmic pharmaceutical formulation in example 1, table 6 wherein the cellulose gel is formulated with 0.001-0.05% w/w of the tropane alkaloid atropine sulfate and up to 100% w/w deuterated water [0281]. Ostrow teaches "As described herein, the ophthalmic agent includes optically pure stereoisomers, optically enriched stereoisomers, and a racemic mixture of stereoisomers. For example, some ophthalmic compositions disclosed herein includes atropine or atropine sulfate in which the atropine is a racemic mixture of D- and L-isomers; and some ophthalmic compositions disclosed herein includes atropine or atropine sulfate in which the atropine is a optically enriched in favor of the more ophthalmically active L-isomer." (sic) [0082]. Ostrow discloses In some embodiments, the presence of deuterated water shifts the pKa of the buffer and that the ophthalmic composition formulated with deuterated water allows for a lower tear production, or less tear reflex in the eye, in comparison with an ophthalmic composition formulated with H2O [0111]. Ostrow discloses some single phase gels are prepared from synthetic macromolecules (e.g., carbomer) single-phase gels are generally aqueous but will also be made using alcohols and oils. [0210]. Ostow teaches allyl ethers of a polyalcohol in an embodiment wherein polyethylene glycols are used in amounts from 1-10% w/w [0243]. Ostrow also teaches in some embodiments that other gel formulations are useful depending upon the particular ophthalmic agent, pharmaceutical agent or excipients/additives used, including crosslinked gels and are expected to be useful in the ophthalmic agent formulations [0220]. Ostrow also discloses the ophthalmic composition is formulated as an ophthalmic solution for the treatment of an ophthalmic disorder including myopia, or progression of myopia [0372]. However, Ostrow et al. fail to disclose a compound of the formula of instant claim 11 or a polycyclic nucleobase in an ophthalmic pharmaceutical composition. Nanduri et al. teach an aspect of the invention as treatment of an eye disease or condition such as glaucoma [0014]. Nanduri also teaches that administration of an ophthalmic composition results in about 1-5% delivery of the topically administered therapeutic agent [0048]. Nanduri teaches methods and compositions for the topical sustained delivery of therapeutic agents containing a muscle fasciculating agent resulting in the sustained release of any therapeutic agent contained within the composition and that the topical application of such compositions to the outer surface of the eyelid of a patient results in increased absorption and sustained release of the therapeutic agent into the eyes or systemically (Abstract). Nanduri teaches atropine, scopolamine and up to about 50% of a micro fasciculating agent, such as caffeine in pharmaceutically effective amounts as a general ophthalmic composition [0065]. Nanduri teaches an embodiment wherein the muscle fasciculating agent is caffeine, which may be included in the topical composition in an amount of up to about 1% [0069]. Examiner notes Nanduri's disclosure of caffeine in a topical composition satisfies the structural limitations of the compound of instant claim 11 wherein R2 and R6 are 0, R1, R3 and R7 are CH3, R8 is H (R9)z is 0, elements g, p, x, y, n, m and w, are 1, element z is 0, elements a, b, c are single bonds, and elements e, f, and d, are double bonds. PNG media_image1.png 128 207 media_image1.png Greyscale PNG media_image2.png 192 246 media_image2.png Greyscale However, neither Ostrow nor Nanduri et al. disclose the constituents of a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80 in an ophthalmic pharmaceutical composition. Avramoff et.al teach "A topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis" (Abstract). Avramoff also discloses, “[i]n one embodiment, a gel may be prepared by providing a gelling agent and adding an excipient such as water in case of a hydrous gel. The gel may include a variety of additional components such as, but not limited to solvents, emulsifiers, thickeners, stabilisers, gelling agents, chelating agents, surfactants, emollients, permeation enhancers, preservatives, antioxidants, lubricants, pH adjusters” (sic) [0031]. Avramoff et al teach a topical gel formulation in the table of formula 4 wherein Sepineo© 600 (Acrylamide/ Sodium Acryloyldimethyl Taurate copolymer/isohexadecane and Polysorbate 80) is disclosed as an emulsifier/thickener/stabilizer, 3.0% w/w glycerin in formula 2, preservatives 0.30% w/w methyl paraben and 0.105 w/w propyl paraben, 0.105 w/w butylated hydroxytoluene (BHT) antioxidant and that the gel formulation may also comprise pH adjusting agents and occlusive agents wherein the concentration of ingredient or ingredients may be determined based on knowledge by a person skilled in the art. [0050-0052], [0054] and [0056]. Avramoff also discloses an oil in water emulsion, “[t]o protect montelukast from light and increase its stability particulate drug carriers can be formulated ( e.g. oil in water or water in oil emulsions, liposomes, microparticles and nanoparticles of polymers (synthetic or natural), solid lipid nanoparticles in which sodium montelukast is encapsulated (dissolved or suspended)) [0086]. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to use the L or S isomer of the tropanyl compound atropine, in a topical pharmaceutical composition in a gel, ointment, lotion, or cream formulation because Ostrow showed the L/S isomer version of atropine is a more opthalmically active isomer. A skilled artisan, seeking to improve the delivery of the active agent in a formulation would have looked to Nanduri's use of caffeine in an ophthalmic formulation because Nanduri disclosed the polycyclic nucleobase caffeine improved delivery of a therapeutic agent by acting as a micro fasciculating agent in a topical formulation and thereby solving the problem of low therapeutical agent delivery with eye drop administration. Furthermore, a skilled artisan would have improved the stability and aided the emulsification of a pharmaceutical composition using an oil-in water emulsion administration form by using Avramoff’s disclosure of Sepineo© 600 (Acrylamide/Sodium Acryloyldimethyl Taurate copolymer/ isohexadecane and Polysorbate 80) with the polymer of acrylic acid crosslinked with one or more allyl ether of a polyalcohol to the composition and regulate the ratio of the polymers, R/S or D/L isomers of atropine and regulate the pKa of the buffer to find the most effective combination of ingredients for the composition based on intended method of administration. See MPEP 2144.05(I) and (II). A person of ordinary skill in the art would have been motivated to combine the atropine and caffeine in a topical ophthalmic pharmaceutical composition with a tropanyl group of the opthalmically active agent L-atropine as disclosed by Ostrow with the improved the delivery of active agent by using Nanduri’s caffeine and Avramoff’s contribution of stability and emulsifier agents in Sepineo© 600 to give a skilled artisan a reasonable expectation of success in improving therapeutic agent delivery using caffeine as a micro fasciculating and stability agent and selecting the optimal pharmaceutically acceptable carriers to formulate the most effective composition. Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Kano (WO 2013/031935 Al) in view of Avramoff (US 2020/0237651 Al). The instant claims are directed to a composition, comprising: one or more of a purified tropane alkaloid or a pharmaceutically acceptable salt thereof; one or more of a purified polycyclic nucleobase or a pharmaceutically acceptable salt thereof; and a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80. Kano et al. teach a stable pharmaceutical composition containing ibuprofen and scopolamine butyl bromide. A pharmaceutical composition comprising the following components (A), (B) and (C): (A) ibuprofen; (B) scopolamine butyl bromide; and (C) at least one compound selected from the group consisting of a basic compound having an acid-neutralizing ability, a xanthine derivative, tranexamic acid or a salt thereof, acetaminophen and an isovaleryl urea derivative (Abstract). Kano also teaches, “However, because ibuprofen is a type of NSAID, it can cause gastrointestinal disorders and other side effects. Therefore, even if one intends to increase the dose of ibuprofen to obtain a sufficient antipyretic and analgesic effect, it is actually not possible to increase the dose.” [0003] Kano teaches “As xanthine derivatives used in the pharmaceutical composition of the present invention, caffeines are preferred from the viewpoint of using the pharmaceutical composition of the present invention as an antipyretic analgesic or a combination cold medicine. Suitable specific examples of caffeines include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, anhydrous caffeine, and sodium benzoate caffeine are mere preferred” [0025]. However, Kano et al. fail to disclose the specific pharmaceutically acceptable carrier, of a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80. Avramoff et al. teaches a topical formulation comprising Montelukast or a pharmaceutically acceptable salt thereof, a gelling agent and water for the treatment of atopic dermatitis (Abstract). Avramoff also discloses, “[i]n one embodiment, a gel may be prepared by providing a gelling agent and adding an excipient such as water in case of a hydrous gel. The gel may include a variety of additional components such as, but not limited to solvents, emulsifiers, thickeners, stabilisers, gelling agents, chelating agents, surfactants, emollients, permeation enhancers, preservatives, antioxidants, lubricants, pH adjusters” (sic) [0031]. Avramoff discloses a combination of an Emulsifier/Thickener/Stabilizer in the product of Sepineo© 600 (Acrylamide/ Sodium Acryloyldimethyl Taurate copolymer/ isohexadecane and Polysorbate 80) in a gel formulation named Formula 4 (sic) [0051]-[0056]. Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to combine Kano’s disclosure of a stable pharmaceutical composition containing ibuprofen and scopolamine (a tropane compound) butyl bromide, xanthine derivative (caffeine), tranexamic acid and an isovalerylurea derivative with Avramoff’s disclosure of an atopic gel formulation using Sepineo© 600 because a topical administration of a pharmaceutical composition would avoid the problems of causing gastrointestinal disorders with the use of NSAIDs. A person of ordinary skill in the art would have been motivated to formulate a topically administered pharmaceutical composition with a tropane alkaloid (scopolamine), a polycyclic nucleobase (caffeine) and Sepineo© 600 (Acrylamide/ Sodium Acryloyl dimethyl Taurate copolymer/ isohexadecane and Polysorbate 80) to avoid causing gastrointestinal disorders with the administration of NSAIDs by topically administering a gel form of a pharmaceutical composition by with a reasonable expectation of success. Response to Arguments Applicant's arguments filed 08/10/2026 have been fully considered but they are not persuasive. Applicant argues that Avramoff does not teach or suggest any oil-in-water emulsion cream formulation. Furthermore, as the Office admits, Avramoff does not teach or suggest the elements of the second pharmaceutically acceptable carrier of amended claims 4 and 24. Regarding the applicant’s assertion that Ostrow nor Nanduri teach or suggest the use of the first and second pharmaceutically acceptable carriers of the amended claim elements therefore, the present claims are not obvious over Ostrow in view of Nanduri. Examiner notes the amended instant claims required revision to the 35 U.S.C. § 103 rejection of claims 4-15, 18, 20-21, 24, 31, 36, and 41 in regard to the prior art of Ostrow in view of Nanduri (WO2011053792), and of Avramoff (US 2020/0237651 A1), Church (WO 2017/212422 A1) has been removed. Avramoff teaches “[t]o protect montelukast from light and increase its stability particulate drug carriers can be formulated ( e.g. oil in water or water in oil emulsions, liposomes, microparticles and nanoparticles of polymers (synthetic or natural), solid lipid nanoparticles in which sodium montelukast is encapsulated (dissolved or suspended)) [0086]. The examiner notes that the second pharmaceutically acceptable carrier of amended claims 4 and 24 is satisfied by a carbomer compound which is disclosed by Ostrow who discloses some single phase gels are prepared from synthetic macromolecules (e.g., carbomer) single-phase gels are generally aqueous but will also be made using alcohols and oils. [0210]. Ostow also teaches allyl ethers of a polyalcohol in an embodiment wherein polyethylene glycols are used in amounts from 1-10% w/w [0243]. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Conclusion All claims are rejected, no claims are 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. Correspondence Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /E.V./Examiner, Art Unit 1623 /SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623