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 April 20, 2026, in response to the Office Action of January 20, 2026, are acknowledged.
Response to Arguments
Applicant has amended the claims to require decreasing cerebral infarction volume in a subject. The examiner has applied prior art to directly address this limitation. The examiner has also considered Applicant’s allegations of unexpected results.
The art cited below teaches topical menthol on the hands and feet will agonize TRPM8 because they have a high density of TRPM8 receptors. Further, such agonizing will decrease TNFalpha, which has been shown to reduce infarct size and swelling when decreased following a stroke. As such, it is not clear that the claimed method is unexpected in view of the cited prior art.
Barone teaches the following with regard to TNFalpha and cerebral ischemia/stroke.
TNF-α increased the percent hemispheric infarct induced by permanent MCAO in a dose-related manner from 13.1±1.3% (vehicle) to 18.9±1.7% at 2.5 pmol (P<.05) and 27.1±1.3% at 25 pmol (P<.0001). The high dose of TNF-α increased ischemia-induced forelimb deficits from 1.6±0.2 to 2.3±0.2 (P<.01). TNF-α (2.5 pmol) also increased the infarction induced by 80 or 160 minutes of transient MCAO from 1.9±0.9% to 4.3±0.4% (P<.01) and from 14.2±1.3% to 21.6±2.2% (P<.05), respectively. The exacerbation of infarct size, swelling, and neurological deficit after exogenous TNF-α was reversed by preinjection of 60 pmol mAb. Blocking endogenous TNF-α also significantly reduced focal ischemic brain injury. Treatment with 60 pmol mAb before and after permanent MCAO significantly reduced infarct size compared with control (nonimmune) antibody treatment by 20.2% (P<.05). It appear that blocking and/or downregulating TNFalpha after a stroke will have a neuroprotective effective that includes reducing infarct size, swelling, and neurologic deficit after an increase in TNFalpha is reversed.
Also see: Dimitriadis et al., “Does Pretreatment with a Tumor Necrosis Factor Alpha-inhibitor Improve the Outcome After Ischemic Cerebral Infarction? A Case Report,” 2019 Dimitriadis et al. Cureus 11(2): e4089. This is an additional state of the art reference that is not applied below as the examiner sees the relevant teachings herein as duplicative.
Wang teaches TRPM8 expression is upregulated when TNFalpha is downregulated. Stimulating the expression of TRPM8 leads to the inhibition of TNFalpha gene transcription and provides for an anti-inflammatory role of TRPM8. See Abstract. Menthol is noted as an agonist of TRPM8 that can activate both TRPM8 mRNA and protein expression while downregulating TNFalpha. See p4, 1st par. Wang notes a cooling brain from TRPM8 upregulation and TNF downregulation. See p4, last par.
Barone and Wang do not teach topical menthol to the hands or feet will activate/agonize TRPM8.
Aronhalt teaches menthol for topical administration to an area such a hand or foot that has a high density of TRPM8 receptors and that those in the skin are especially available for TRPM8 activation by agonists, such as menthol. See par. 41.
Tupone teaches that “TRPM8, activated by menthol and cooling is the primary candidate for the cutaneous cold receptor TRP channel.” See p2, 1st full par.
Status of the Claims
Claims 1-7 are pending and examined.
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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Barone et al., “Tumor Necrosis Factor-α A Mediator of Focal Ischemic Brain Injury,” Volume 28, Issue 6, June 1997; Pages 1233-1244, in view of Wang et al., “TRPM8 in the negative regulation of TNFα expression during cold stress,” March 23, 2017, in view of Aronhalt et al., (US2015/0119849), and in view of Paschke et al., “Activation of the cold-receptor TRPM8 by low levels of menthol in tobacco products,” Toxicology Letters 271 (2017) 50-57.
Barone teaches the following with regard to TNFalpha and cerebral ischemia/stroke.
TNF-α increased the percent hemispheric infarct induced by permanent MCAO in a dose-related manner from 13.1±1.3% (vehicle) to 18.9±1.7% at 2.5 pmol (P<.05) and 27.1±1.3% at 25 pmol (P<.0001). The high dose of TNF-α increased ischemia-induced forelimb deficits from 1.6±0.2 to 2.3±0.2 (P<.01). TNF-α (2.5 pmol) also increased the infarction induced by 80 or 160 minutes of transient MCAO from 1.9±0.9% to 4.3±0.4% (P<.01) and from 14.2±1.3% to 21.6±2.2% (P<.05), respectively. The exacerbation of infarct size, swelling, and neurological deficit after exogenous TNF-α was reversed by preinjection of 60 pmol mAb. Blocking endogenous TNF-α also significantly reduced focal ischemic brain injury. Treatment with 60 pmol mAb before and after permanent MCAO significantly reduced infarct size compared with control (nonimmune) antibody treatment by 20.2% (P<.05). As such, blocking and/or downregulating TNFalpha after a stroke will reduce infarct size, swelling, and neurologic deficit after an increase in TNFalpha caused by a stroke is reversed.
Barone does not teach TRPM8 upregulation by menthol.
Wang teaches TRPM8 expression is upregulated when TNFalpha is downregulated. Stimulating the expression of (i.e., agonizing) TRPM8 leads to the inhibition of TNFalpha gene transcription and provides for an anti-inflammatory role of TRPM8. See Abstract. Menthol is noted as an agonist of TRPM8 that can activate both TRPM8 mRNA and protein expression while downregulating TNFalpha. See p4, 1st par. Wang notes a cooling brain from TRPM8 upregulation and TNF downregulation. See p4, last par.
Wang does not teach topical menthol on the hands and/or feet will do so.
Aronhalt teaches menthol for topical administration to an area such a hand or foot that has a high density of TRPM8 receptors and that those in the skin are especially available for TRPM8 activation by agonists, such as menthol. See par. 41.
The route or method of application to the skin through a sock or glove, e.g., does not appear to alter the purpose of administration of the claimed agent to a part of a subject’s body that has a high density of TRPM8 receptors.
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of Barone, Wang, and Aronhalt. One would be motivated to do so because downregulating TNFalpha is taught to decrease infarct volume after a stroke and upregulating TRPM8 is taught to do so. Further, menthol is taught as a TRPM8 agonist when it is topically applied to a hand or foot because it is a location that is known to have a high density of TRPM8 receptors. As such, there is a reasonable and predictable expectation of success in decreasing infarct volume after a stroke by administering a known TRPM8, including menthol, to a hand or foot of a subject in a sufficient concentration and for a sufficient time to downregulate TNFalpha. Such would appear to have a reasonable and predictable expectation of success in doing so when applied to an area of the body that has a high density of TRPM8 receptors.
Paschke teaches that 50 micrograms of menthol can activate TRPM8 receptors. Of those agonists investigated, menthol was the strongest. See Abstract. 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). In light of the known mechanism of action by which menthol is taught to treat stroke, a POSA would be able to optimize a dose to arrive at a percentage or amount to effectuate the desired mode of action through nothing more than routine experimentation.
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.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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