DETAILED ACTION
Formal Matters
Claims 1-50 are cancelled. Claims 51-72 are pending and under examination.
Priority
The instant application is a continuation of PCT/US2022/023130 filed on 4/1/2022, which claims priority from US provisional application 63/169,768 filed on 4/1/2021.
Information Disclosure Statements
The information disclosure statement (IDS) filed on 12/12/2025 has been considered by the examiner.
Objections/Rejections Withdrawn
The objections over claim 58 are withdrawn per applicant’s amendments.
The objection over claim 60 is withdrawn per applicant’s amendments.
The objection over claim 65 is withdrawn per applicant’s amendments.
The objection over claim 66 is withdrawn per applicant’s amendments.
The objection over claim 67 is withdrawn per applicant’s amendments.
The objection over claim 72 is withdrawn per applicant’s amendments.
The rejection under USC 112(b) over claim 58 is withdrawn per applicant’s amendment to the claim.
The rejection under USC 112(b) over claim 61 is withdrawn per applicant’s amendment to the claim.
The rejections under USC 112(b) over claim 63 are withdrawn per applicant’s amendments.
The rejection under USC 112(b) over claim 64 is withdrawn per applicant’s amendment.
The rejection under USC 112(b) over claim 66 is withdrawn per applicant’s amendment.
The rejection under USC 103 over Lozinsky and Whiteblaze over claim 72 is withdrawn as applicant deleted the drying step from the claim. Claim 72 is now taught by the teachings of Lozinsky.
As these objections and rejections are withdrawn, applicant’s arguments toward these objections and rejections are moot.
Modified Rejections Over Original Prior Art- As Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 51-64, 66-72 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lozinsky US 2018/0344743.
Lozinsky teaches a topical anorectal or genital composition with anesthetic agent that can be lidocaine and in an amount of 0.15 w/w% to 25 w/w% and a muscle relaxant that is nifedipine and in an amount of 0.1 w/w% to 15 w/w% (paragraphs 55, 155, and 159). Lozinsky teaches nifedipine in an amount of 0.1% to 5% w/w (paragraph 68). Lozinsky teaches that the formed film remain intact for more than 12 hours giving release of pharmaceutical agent for an extended period of time (abstract and paragraph 31). Lozinsky teaches “The sustained or extended release of the pharmaceutical agent(s) from the compositions of the present invention enables methods of treatment including less frequent administration (such as once daily, once every other day or twice weekly) than existing commercially available products, while achieving similar or better therapeutic results” (paragraph 32). Lozinsky teaches application to mucosal surfaces (paragraphs 73, 93 and 112-119). Lozinsky teaches the compositions are stored in a container and the topical water-based compositions are in the form of a pre-packaged towelette/wipe (paragraphs 229-231). Lozinsky teaches a sealed package or pocket with single use wipe impregnated with the topical liquid composition (paragraphs 231 and 266). Lozinsky teaches wipes that are woven or non-woven fabric or cloth (paragraph 231). Fabric and cloth are a materials made of fibers, and thus, fibrous. Lozinsky teaches additive/excipient (paragraphs 62 and 154). Lozinsky teaches antioxidant (paragraphs 61 and 154). Lozinsky teaches antioxidative compounds including plant extracts and catechins (paragraph 166). Lozinsky teaches preservatives (paragraph 168). Lozinsky teaches a volatile solvent and water (paragraphs 172-176) for formulations. Lozinsky teaches glycerin (aka glycerol) as a protectant active ingredient which is construed as an alcohol solvent (paragraph 167). Lozinsky teaches various ingredients including penetration enhancers, preservatives, moisturizers, humectants, emollients, emulsifiers, and others (paragraph 168). Lozinsky teaches polysorbate (paragraphs 170-171). Lozinsky teaches benzyl alcohol (paragraph 55). Lozinsky teaches aloe vera as a plant extract (paragraph 166). Lozinsky teaches poloxamers, carbomers, carbomer copolymers, cellulose and other gelling agents (paragraph 65). Lozinsky teaches Tweens (paragraph 50) as nonionic organic surfactant. Lozinsky teaches sorbitans (paragraph 137). Lozinsky teaches perianal abscess adjacent to the anus (paragraph 252). Lozinsky teaches pemulen (paragraph 307). Lozinsky teaches “The composition is applied to areas of the anal canal or rectum affected by hemorrhoids, fissures, fistulae, cracks, warts or pruritus, under conditions suitable for film formation of the composition so as to form a protective coating and typically under non-sterile conditions. In general, sufficient amounts of topical composition are employed to cover the entire affected mucosal surface area. In an embodiment, the coating is extended by at least about 1 centimeter and by at least about 5 centimeters beyond the affected surface area.” (paragraph 253). It is indicated that a cause of non-healing chronic anal fissures is spasm of the internal anal sphincter muscle that can become infected by fecal bacteria (paragraphs 250-251). Lozinsky teaches anal fissures are cracks in the skin of the anal canal (paragraph 250). Thus, the anal sphincter and anal canal are a target for topical treatment and such a wipe of Lozinsky would target the proximal and external portions. Therefore, Lozinsky’s treatment is seen as useful for application to treat anal fissures through application to various perianal areas that are in proximity to the affected areas. Lozinsky provides for multiple use devices (paragraph 242).
One of ordinary skill in the art before the time of filing would have combined ingredients including functional excipients suitable for making a wipe along with an anesthetic agent such as lidocaine and a muscle relaxant such as nifedipine to make an effective treatment for anal fissures based on the teachings of Lozinsky with the reasonable expectation of numbing pain and relaxing spasming muscles that are associated with anal fissures as provided in Lozinsky. Lozinsky provides for overlapping amounts of nifedipine and lidocaine, and thus, one of ordinary skill in the art would have sought to work within such ranges to make new formulations for treating anal fissures and conditions thereof (see MPEP 2144.05). Ingredients would be routinely adjusted based on the muscle relaxant and anesthetic effects that are desired for the patients.
Claim 65 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lozinsky US 2018/0344743 and Dreher US 20140315995.
Lozinsky teaches the claims as discussed above.
Lozinsky does not teach antioxidants in claim 65, but it does allow for antioxidants.
Dreher teaches non-irritating, stable topical compositions including at least Vitamin C (ascorbic acid), Vitamin E (tocopherol) and a polyphenol antioxidant and such compositions can be used to facilitate the prevention or treatment of free oxygen, nitrogen, and/or other free radical related skin damage (abstract and paragraph 8). Dreher teaches lidocaine as an anesthetic (paragraph 224) and muscle relaxant (paragraph 169). Dreher teaches the form of wipes (paragraphs 155 and 156) as a type of product.
Therefore, one of ordinary skill in the art before the time of filing would have included antioxidants such as tocopherol and ascorbic acid in Dreher as they have the benefit of topically treating free radical damage on the subject. Note that Lozinsky provides for the addition of antioxidants and Dreher provides other known antioxidants that have benefits to the user. There was a reasonable expectation of success in adding antioxidants of Dreher into the topical formulations of Lozinsky and obtaining a topical wipe that has the benefits of such antioxidants against free radical damage.
Response to Applicant’s Arguments over the Rejections under USC 103
Applicant argues that Lozinsky does not teach a wipe with both nifedipine and lidocaine. In this rejection under USC 103, it is the full teachings of reference that teach a wipe containing pharmaceutical active ingredients for topical use. Lozinsky does contain nifedipine and lidocaine within small groups in its teachings where lidocaine has the purpose of anesthetic and nifedipine has the purpose of muscle relaxant in Lozinsky. Thus, there is motivation to use such drugs in the topical wipes that Lozinsky teaches. Beyond the examples or preferred embodiments, the full teachings of the references including alternative and non-preferred embodiments have to be considered (see MPEP 2123). As now noted after applicant’s recent amendment, Lozinsky does recognize the ability of its compositions to remain intact for over 12 hours after application, and thus, Lozinsky would recognize that the drugs present would be capable of being present for transmucosal permeation in periods over 12 hours when applied to a mucosal surface. Lozinsky also teaches permeation enhancers as an ingredient, and so, keeping drugs taught in Lozinsky at a site for times greater than 12 hours and inclusion of permeation enhancers for permeation of the drugs is in the scope of Lozinsky and would be accomplished with a reasonable expectation of success.
Applicant also argues the concentrations of lidocaine and nifedipine provided in the claims are narrow and that the examiner depends on overlapping ranges of the prior art. Applicant argues that there is no obviousness when there is no motivation to work within the sub-range or without desirability of the claimed range. It remains that Lozinsky teaches overlapping ranges for one of ordinary skill in the art to work within and applicant has not provided where the references teach away from applicant’s range, a criticality of these narrow ranges in the claims nor unexpected results for the drug combination in these ranges.
Applicant argues that routinely optimized is unsupported in light of the API’s having sustained release transmucosal permeation. As noted in response to applicant’s amendment, Lozinsky does recognize the ability to have drugs at a site for over 12 hours and allows addition of penetration enhancers. Thus, there is a reasonable expectation of success in obtaining a product that provides such capabilities in applicant’s claims.
Applicant argues that there are conclusory statements toward the optimization, however, Lozinsky does teach its wipes to be able to treat anal fissures and conditions thereof. Lozinsky also recognizes the anesthetic (pain numbing) quality of lidocaine and the muscle relaxant effect of nifedipine which would be important to treat pain and muscle spasms that occur with anal fissures. Lozinsky was used to teach “It is indicated that a cause of non-healing chronic anal fissures is spasm of the internal anal sphincter muscle that can become infected by fecal bacteria (paragraphs 250-251). Lozinsky teaches anal fissures are cracks in the skin of the anal canal (paragraph 250).” Thus, the motivations to use drugs such as lidocaine and nifedipine exist in the prior art along with motivations to optimize amounts to obtain desired effectiveness for treating symptoms of anal fissures.
Applicant argues that routinely optimized is a conclusory statement, but does not address the motivations that were outlined to use the drugs for their anesthetic and muscle relaxant properties on anal fissures and other conditions taught by the Lozinsky. The motivation is to work within the ranges to optimize for obtaining effective and desired treatment for the subject with anal fissures.
Applicant argues that it is not guided to make the wipe that contains both lidocaine and nifedipine due to instability of nifedipine. It remains that Lozinsky teaches these drugs and motivates the use of wipes for application of the composition. Thus, it is expected that the use of these drugs on such a wipe would be recognized as acceptable for administration to sites such as anal fissures. It appears in data of applicant’s specification that the solution form (F1) is better for permeation, average flux, and retention time than the wipe form (F2) (figures 7-10) and F1 and F2 or at most similar for solution form and wipe form when examining tissue retention of lidocaine and nifedipine (figure 11A and figure 12A). Thus, the wipe form does not appear to offer more superior results for application when comparing against application of solutions, which are both acceptable forms for drug application in the prior art.
Applicant argues that Lozinsky focuses on formulations of pramoxine HCl and Phenylephrine HCl as actives. It remains that Lozinsky teaches lidocaine and nifedipine as alternatives along with their respective functions for the formulation (lidocaine as anesthetic and nifedipine as muscle relaxant). Further, the reference recognizes the making and use of wipes as well as the ability of the applied formulation to retain on the surface for over 12 hours and to have permeation enhancers as an ingredient. The results that applicant argues, are therefore, expected based on the teachings of Lozinsky and would be expected for the drugs that it teaches.
Applicant argues that there is robust experimental data for the use of lidocaine and nifedipine within its claimed ranges. The examiner appreciates applicant’s results toward its tested formulation, but Lozinsky teaches that high retention time (over 12 hours) and that permeation enhancers may be used. Lozinsky teaches treating anal fissures and the anesthetic and muscle relaxant properties of lidocaine and nifedipine, and so, it is also expected that treatment can be afforded to the subject. Thus, the effect can be reasonably expected by teachings of Lozinsky. Applicant may consider presenting information toward the criticality of the drug ranges if suboptimal effects occur when lower and higher than (i.e. outside of) the claimed range. If applicant used a particular formulation of ingredients or formulation ingredient that is not in Lozinsky’s formulation and can show how that would provide improvement over a formulation of Lozinsky, then this may also be another way forward. Such additional ingredients that provide any unexpected benefit would have to be added to the claim.
Applicant argues that the loading of the formulation was precise and reproducible. The only claim toward a method of making the wipe is claim 72 and Lozinsky and Whiteblaze provided for the claimed steps. Since applicant deleted the drying step in claim 72, Lozinsky now teaches the steps on its own. As Lozinsky provides the teachings that can be used to make a drug containing wipe and teaches use of lidocaine and nifedipine as alternative drugs, there is a reasonable expectation of success in making the wipe formulations as applicant has claimed in the manner applicant claims.
Applicant argues that Lozinsky does not provide data, however, it does teach the ability to remain intact as a film for over 12 hours and can contain permeability enhancers. Example 2 of Lozinsky teaches a wipe with the composition H1 of example 1 for wiping the anal region that has Tween 80 and drugs in an oil-in-water emulsion (paragraph 263), Although this one example contains different drugs (pramoxine, an anesthetic, and phenylephrine, a vasoconstrictor), there remains motivation to utilize the other drugs such as lidocaine (another anesthetic) and nifedipine (muscle relaxant) that Lozinsky teaches as alternatives (see MPEP 2123) with the expectation of obtaining a wipe formulation that functions as applicant argues.
Applicant argues that claim 65 is toward antioxidant excipients that have stabilizing effects on nifedipine and lidocaine in wipe form, but Lozinsky or Dreher do not teach these effects on lidocaine and nifedipine. Lozinsky also promotes the use of antioxidants in paragraphs 61, 154 and 166. Dreher teaches antioxidants of claim 65 that would be used in stable topical formulations. Thus, one of ordinary skill in the art would look to teachings of Dreher (combined with Lozinsky in this 103 rejection) for the antioxidants that it teaches when making a topically applied formulation of drugs. In response to applicant's argument that antioxidants provide stability to the drugs in the claim, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). There is also no objective indication that antioxidants of claim 65 provide unexpectedly better stability than antioxidants presented in Lozinsky’s teachings.
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). As discussed above, the teachings of the actives, additives, wipe form and functionality come from the teachings of the references with motivations from the references.
For these reasons, the rejections are maintained. Modifications were made to address applicant’s amendments to the claims.
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 MARK V STEVENS whose telephone number is (571)270-7080. The examiner can normally be reached on M-F 9:00 am to 6:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached on (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARK V STEVENS/
Examiner, Art Unit 1613