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 Amendments
Applicant’s amendments to the claims of October 7, 2025, in response to the Office Action of July 7, 2025, are acknowledged.
Response to Arguments
Applicant’s arguments and allegations of unexpected results have been considered by the examiner in their entirety. Those allegations are addressed below.
Applicant argues that the claims are not anticipated by Bajic in view of the amendments.
The examiner acknowledges that while Bajic teaches using propylene glycol and PEG, it does not teach PEG400 or PEG600 for topical application in form of a cream, lotion, solution, hydrogel, or lotion. However, solutions taught by Bajic include propylene glycol. See par. 57. As such, claim 1 remains rejected under Bajic. The remaining rejections under Bajic for anticipation are withdrawn.
With regard to Applicant’s traversal of the § 103 rejection, Applicant argues that there are no specific formulations taught. Further, Applicant argues that there is no motivation to combine references. Finally, Applicant argues that data provided on pages 29-30 and the Figures demonstrate superior results.
The examiner notes that the prior art is cited as a combination. Teachings of prior art are proper even if they do not recite specific formulations or examples that teach each of the claimed limitation in a single embodiment, e.g. Each claimed limitation is taught by the prior art as a whole. Applicant has not indicated a specific limitation that is not taught and/or rendered obvious by the prior art.
The examiner notes that Gant teaches the claimed API formulated for topical administration in the form of a solution, cream, lotion, or hydrogel and comprising water-miscible vehicles include PEG for treating any condition ameliorated by inhibiting TLR4 cytokine production. Blohm-Mangone teaches topical application of TLR4 antagonist TAK-242 has been shown to block acute UV-induced AP-1 and NF-ĸB signaling. It was evaluated as a topical agent to the skin and was shown to provide potent photochemopreventive activity and suppress tumor area multiplicity. See Abstract. It is a novel target for nonmelanoma skin cancer (NMSC). Moreover, UV exposure leads to DNA damage, oxidative stress, and dysregulation of cell signaling. See p266, 1st full par. TLR4 is identified as a major driver of cutaneous inflammation. See p266, 2nd full par. Resatorvid demonstrates that topical application effectively inhibited UV-induced stress signaling and tumorigenesis with no observable toxicity. Kaushik teaches that PEG400 is a commonly used solvent in dermal formulations and a good penetration modifier. Similarly, Kochling also teaches PEG-400 solubilizes many poorly water-soluble compounds and it is a water-miscible solvent and routinely employed as a solubilizing agent.
Thus, inhibiting TLR4 when applied topically is a nexus that motivates combining Gant and Blohm-Mangone, while Kaushik and Kochling are linked by their teaching of an ability of a claimed carrier to solubilize poorly water soluble drugs for dermal application.
With respect to Applicant’s allegations of unexpected results, the examiner notes that unexpected results means unexpectedly superior as compared to the closest prior art and such superiority must be commensurate in scope with the breadth of the claims. There does not appear to be any showing or comparison showing the claimed composition as compared to those taught by Gant. As such, unexpected results are not shown.
A prima facie showing is established because the claimed API is usable in a topical dermal composition in a claimed form comprising a carrier to include PEGs of varying molecular weights. Such composition can treat conditions by inhibiting TLR4, which is a novel target for nonmelanoma skin cancer (NMSC), DNA damage, oxidative stress, and dysregulation of cell signaling, among others skin conditions.
Status of the Claims
Claims 1, 3, 4, 6, 9-18, 21, and 32 are pending and examined.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Bajic et al., (US2015/0164858) (cited in ISR).
Bajic teaches a composition comprising the TLR4 suppressor TAK-242. See par. 48. The formulation can be a cream comprising PEG, lanolin, and/or petrolatum, e.g. See par. 62. Further, it can be in the form of a skin or dermal patch. See par. 62. Petrolatum and lanolin are hydrophobic. A composition comprising a substantial proportion of hydrophobic components would have hydrophobic properties.
Claim 1 is anticipated by the prior art.
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 1, 3, 4, 6, 9-18, 21, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Gant et al., (US2009/0022706), in view of Blohm-Mangone et al., “Pharmacological TLR4 Antagonism Using Topical Resatorvid Blocks Solar UV-Induced Skin Tumorigenesis in SKH-1 Mice,” Cancer Prev Res; 11(5) May, and in view of Kaushik et al., “Percutaneous Penetration Modifiers and Formulation Effects: Thermal and Spectral Analyses,” AAPS PharmSciTech, 2010 Jun 26;11(3):1068-1083, and in view of Kochling et al., “Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400,” Journal of Pharmaceutical and Biomedical Analysis,” Vol. 43, Issue 5, April 11, 2007.
Gant teaches substituted cyclohexene TLR4 modulators, including TAK-242. See par. 4. It can be used to treat any condition ameliorated by inhibiting TLR4 cytokine production. See par. 10. Compounds can be used in a dose of about 2 to 100 mg, including 5 mg, 10 mg, 20, mg, and others. See par. 163. Pharmaceutical compositions can be used with carriers and excipients, including hydrophilic or hydrophobic matrices. See par. 158. Compositions can be formulated for oral, topical, and other routes of administration. See par. 165. Dermal patches and bandages are contemplated and application by microneedle is also described. See par.’s 199 and 201, respectively. Topical administration includes intradermal and transdermal and administration to the skin. See par. 198. Further, administration can be in the form of a solution, cream, lotion, or hydrogel. See par. 199. Ointments, creams, and gels can include oils, white petrolatum, lanolin, PEGs of varying molecular weights. See par. 202. Petrolatum, lanolin, and oils are hydrophobic, which are taught by Gant. A composition comprising a substantial proportion of hydrophobic components would have hydrophobic properties. Water-miscible vehicles include PEG 300 and PEG 400. See par. 190. Further, gelling agents can include crosslinked acrylic acid polymers and poloxamers. See par. 204. Mixing, stirring, and trituration can be used disperse. See par. 204. Topical administration can be modified release. See par. 212. Further, topical administration can be for local and transdermal administration. See par. 259. Isomers and enantiomers of TLR4 modulators are also contemplated, including compositions with different ratios of enantiomeric excess. See par.’s 13 and 133. A POSA would immediately envisage USP grade carriers and excipients, absent evidence to the contrary as the components are being used for application to a subject. Mineral oil and PEG are taught as lubricants and while this is for not specifically for topical delivery, the concentration includes about 0.1 to 5%. See par. 174. This would be considered at least as a starting point for optimization.
Grant teaches an advantage of deuterium modified TAK-242 at any position on the compound. A POSA would immediately envisage TAK-242 as usable in such method as well as it is similarly structured and identical other than the at least a single deuterium attached. Moreover, deuterium enrichment can include merely 1%. See prior art claim 27. Such incorporation is to improve the API already known to be beneficial. See par. 93.
Gant does not explicitly teach claimed conditions. However, the examiner notes that prevention is interpreted as a subject population that is merely capable of having a described condition. Claims 16-18 and 20 are each dependent upon claim 16, which is directed to prevention or treatment. For purposes of expediting prosecution on the merits, the examiner applies art below that teaches treatment of a claimed condition.
Blohm-Mangone teaches topical application of TLR4 antagonist TAK-242 has been shown to block acute UV-induced AP-1 and NF-ĸB signaling. It was evaluated as a topical agent to the skin and was shown to provide potent photochemopreventive activity and suppress tumor area multiplicity. See Abstract. It is a novel target for nonmelanoma skin cancer (NMSC). UV exposure leads to DNA damage, oxidative stress, and dysregulation of cell signaling. See p266, 1st full par. TLR4 is identified as a major driver of cutaneous inflammation. See p266, 2nd full par. Resatorvid demonstrates that topical application effectively inhibited UV-induced stress signaling and tumorigenesis with no observable toxicity. See p266, 3rd full par. An amount of 13 mmol/L was applied. The ears of mice were also treated with 10 mmol resatorvid. See Figure 1. Resatorvid successfully penetrates that SC layer and remains in the skin at least 8 hours reaching a concentration of 47 μg/cm2. See p270, last par.
With regard to claim 21, NMSC includes impaired skin barrier function, among others.
While Gant teaches using PEGs including PEG400, Kaushik and Kochling further this point.
Kaushik teaches that PEG400 is a commonly used solvent in dermal formulations and a good penetration modifier. See Table 1, e.g.
Kochling also teaches PEG-400 solubilizes many poorly water-soluble compounds and it is a water-miscible solvent and routinely employed as a solubilizing agent. See p1639, 2nd par. A sample of PEG-400 and a poorly water soluble drug was mixed through sonication. A POSA understands that PEG400 can be used as a solvent to dissolve TAK-242 as it is a known solvent taught for use with TAK-242. This is especially the case in formulation a liquid or solution taught by the cited prior art. As evidenced by:
https://www.selleckchem.com/datasheet/resatorvid-S745501-DataSheet.html,
(date accessed July 2, 2025), Resatorvid is water insoluble.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed products and methods. One would be motivated to do so because the claimed API is taught to treat claimed conditions, including through the topical application of the claimed TLR4 antagonist, TAK-242, to the skin of a subject. Further, the claimed API is taught to be administered to a subject topically in the claimed forms of a liquid, solution, and cream, e.g., and with the claimed emollient and a PEG. Even further, PEGs including PEG400 are taught to be suitable vehicles for the claimed API and PEG400 is a commonly used solvent for dermal formulations including for solubilizing poorly water soluble drugs when mixed, e.g., with sonication. TAK-242 is a poorly water soluble drug. TAK-242 is taught by Blohm-Mangone to block acute UV-induced AP-1 and NF-ĸB signaling when applied to the skin and was shown to provide potent photochemopreventive activity and suppress tumor area multiplicity. Resatorvid (i.e., TAK-242) demonstrates that topical application effectively inhibits UV-induced stress signaling and tumorigenesis with no observable toxicity. Overall, there is a reasonable and predictable expectation of success in applying a known API that inhibits TLR4 to a subject’s skin to treat conditions including NMSC with excipients that are known to be used to deliver the claimed API to the skin of a subject. Further, using a known solvent, PEG400, with TAK-242 would be obvious because it is a known vehicle and solubilizer. It would have been further obvious to optimize the concentrations of API, PEG, and other components as they are known result-effective variables. According to M.P.E.P. § 2144.05, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Whether a composition is hydrophilic or hydrophobic would depend on the components included therein. Both hydrophilic and hydrophobic matrices are contemplated by the prior art. The hydrophobicity of a composition would depend on the proportions of components included in that composition. In this case, petrolatum, lanolin, and oils are each hydrophobic, which are taught by Gant as excipients for use with the claimed API. A composition comprising a substantial proportion of hydrophobic components would have hydrophobic properties.
As such, no claim is allowed.
Conclusion
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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JARED BARSKY/Primary Examiner, Art Unit 1628