DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the first Office action on the merits of the claims.
All citations to the Manual of Patent Examining Procedure (MPEP) refer to Revision 01.2024, which was released in November 2024.
Status of the Claims
In the Preliminary Amendment filed 10 January 2025, Applicant amended claims 3, 5, and 7-10. Additionally, Applicant cancelled claims 11-20 and added five new claims, i.e., claims 21-25. Claims 1-10 and 21-25 are pending and under consideration.
Claim Rejections - 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-10 and 21-25 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter that the inventor regards as the invention.
Regarding claim 1, the patient population — i.e., the “subject” — is too poorly defined to satisfy 35 U.S.C. 112(b). Is it any subject, regardless of medical status? For example, persons having ordinary skill in the art can reasonably disagree over who is in need of prevention of trigeminal nerve pain and, conversely, who is not. MPEP § 2173.04 (“a genus claim that could be interpreted in such a way that it is not clear which species are covered would be indefinite (e.g., because there is more than one reasonable interpretation of what species are included in the claim)”). This is due primarily to the fact that even relatively healthy people could potentially benefit from such an act of prevention. After all, isn’t everyone potentially in need of pain prevention? If not, then what is the threshold or patient risk level required to trigger the administration of the “modulator of oxidative stress or a composition thereof” pursuant to claim 1? The specification does not answer this question. This ambiguity renders claim 1 and all claims depending thereon indefinite.
Claim Rejections - 35 U.S.C. 102(a)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102(a) that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless
(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; or
(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 1-3, 5, 7-8, 10, and 23-25 are rejected under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2) as being anticipated by Trevisan (“TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.” Brain 139.5 (2016): 1361-1377), as evidenced by Fayez (“Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.” Biomedicine & Pharmacotherapy 105 (2018): 428-433).
Trevisan is a study directed to the relationship between the transient receptor potential ankyrin 1 channel (encoded by TRPA1) and trigeminal neuropathic pain. Title/Abstract.
Trevisan discloses: “Trigeminal neuropathic pain arises in a variety of orofacial painful conditions, which include typical (type 1) trigeminal neuralgia, characterized by excruciating and sudden pain generated by subthreshold mechanical stimuli or cold exposure, and atypical (type 2) trigeminal neuralgia, associated with background pain of lower intensity between sharp painful poussées. Insult of the nerve trunk caused by degeneration or mechanical compression produced by various aetiologies (immunological, metabolic, viral, vascular, cancerous, traumatic or surgical) is the most plausible cause of trigeminal neuropathic pain.” Page 1362, left column (internal citations omitted).
Trevisan discloses: “The present findings show for the first time that TRPA1 is essential in generating pain-like behaviours in a model of mechanical injury of the trigeminal nerve, as genetic ablation of this channel totally prevented non-evoked nociceptive behaviour, mechanical allodynia and cold and chemical hypersensitivity produced by constriction of the infraorbital nerve.” Page 1362, right column.
Trevisan discloses: “The key role of TRPA1 in the maintenance of nociception evoked by constriction of the infraorbital nerve and mechanical or cold hypersensitivity is further corroborated by pharmacological findings. At Day 10, when nociception and hypersensitivity robustly persisted, systemic administration of the selective TRPA1 antagonists HC-030031 and A-967079 completely reverted all pain-like behaviours, indicating that some hitherto undefined endogenous mechanisms promote the ongoing channel activation that maintains the altered condition.” Page 1370, right column (emphasis added); see also page 1362 at top (defining both HC-030031 and A-967079 by their chemical names). Effective amounts of the foregoing TRPA1 antagonists are disclosed in the caption of Figure 2 (page 1368) and on page 1363 (left column).
Trevisan additionally discloses: “At Day 10 after constriction of the infraorbital nerve, changes in non-evoked nociceptive behaviour, mechanical allodynia and cold hypersensitivity were abrogated 1 h after the systemic (intragastric) administration of the antioxidant agent, α-lipoic acid (Fig. 4 A). A similar complete attenuation was obtained after local treatment (subcutaneous) with α-lipoic acid into the left upper lip, ipsilateral to the surgery (Fig. 4 B).” Page 1367, right column (emphasis added); see also page 1371 at Figure 4. “The observation that α-lipoic acid reverted CION-evoked spontaneous nociception and mechanical and cold hypersensitivity indicates that oxidative stress byproducts, generated by nerve injury, promote pain-like behaviours.” Page 1373, left column. Effective amounts of α-lipoic acid are disclosed in the caption of Figure 4 (page 1371) and on page 1363 (left column). As evidenced by Fayez, α-lipoic acid is an activator of the Nrf2 pathway. Page 430 at Section 3.6; page 1432 at Table 4.
Trevisan further discloses: “Thus, as both TRPA1 blockade and oxidative stress inhibition diminished non-evoked nociceptive behaviours and mechanical or cold hypersensitivity, it can be proposed that oxidative stress by-products mediate CION-evoked pain-like behaviours through TRPA1.” Page 1373, left column.
Trevisan concludes: “Trigeminal neuropathic pain affects a substantial proportion of the general population and patient treatment remains unsatisfactory. Present findings that CCL2-dependent monocyte/macrophage accumulation and the ensuing oxidative stress by-products that engage TRPA1 are key factors for the development and maintenance of pain-like behaviours in a mouse model of trigeminal neuropathic pain offer a new interpretation of the pathophysiology of this condition. In this novel paradigm, different mechanisms identified in the present study emerge as new pharmacological targets for drug development. However, while predictable pharmacodynamic or pharmacokinetic hurdles may limit interventions directed to inhibit monocyte/macrophage accumulation or oxidative stress, TRPA1 blockade appears to be a feasible endeavor, fostered by the current clinical development of channel antagonists.” Page 1375, right column (internal citations omitted).
On the basis of the foregoing disclosure, the examiner concludes that Trevisan anticipates treating trigeminal pain by administering an effective amount of a TRPA1 antagonist or α-lipoic acid. Therefore, claims 1-3, 5, and 10 are anticipated by Trevisan.
Regarding claim 7, Applicant is referred to the abstract of Trevisan, which discloses that “pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, α-lipoic acid or the anti-CCL2 antibody (all P < 0.001).” Emphasis added; see also page 1368 at Figure 2 at caption (disclosing the intraperitoneal (i.p.) route of systemic administration, which involves injecting medication directly into the peritoneal cavity).
Regarding claim 8, Trevisan discloses: “To identify the site of TRPA1 engagement, HC-030031 was administered locally. At Day 10 after surgery, local (subcutaneous) injection of HC-030031 in the left upper lip, ipsilateral to the surgery, reverted the non-evoked nociceptive behaviour, mechanical allodynia and cold hypersensitivity (Fig. 2 D). Importantly, HC-030031 injection in the right upper lip, contralateral to the surgery side, did not affect any pain-like behaviours measured in the ipsilateral upper lip (Fig. 2 D). HC-030031 (subcutaneous) did not change any pain-like parameters in sham-operated mice (Fig. 2 D). However, due to the vicinity of the injection site to both the ligature site and the skin area where Von Frey hairs are applied, it is possible that HC-030031 diffuses to both of them. Accordingly, these experiments cannot distinguish if only one or both of the two areas along the nerve fibre are targeted by the channel antagonist.” Page 1367, left column (emphasis added).
Regarding claims 23 and 24, Applicant is referred to page 1362 of Trevisan, which discloses that typical (type 1) trigeminal neuralgia is characterized by excruciating and sudden pain, while atypical (type 2) trigeminal neuralgia is associated with background pain of lower intensity.
Regarding claim 25, Trevisan discloses pain mitigation. See, e.g., page 1370 (right column) and page 1375 (left column). Alternatively, the intended results recited in claim 25 are not afforded patentable weight because they do not result in a manipulative difference over the prior art reference (Trevisan), as applied above. MPEP § 2111.04(I) (a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited’”), quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003)).
Claim Rejections - 35 U.S.C. 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 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(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.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Trevisan (“TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.” Brain 139.5 (2016): 1361-1377), as evidenced by Fayez (“Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.” Biomedicine & Pharmacotherapy 105 (2018): 428-433).
Trevisan, as evidenced by Fayez, is discussed above in the rejection under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2). That discussion is incorporated by reference into this §103 rejection.
Regarding claim 21, although Trevisan discloses that “both TRPA1 blockade and oxidative stress inhibition diminished non-evoked nociceptive behaviours and mechanical or cold hypersensitivity” (page 1373), Trevisan is silent to whether the TRPA1 antagonist and the α-lipoic acid (antioxidant/Nrf2 activator) can be co-administered. Consequently, Trevisan does not anticipate claim 21. Nevertheless, before the effective filing date of the claimed invention, the foregoing teachings of Trevisan would have motivated a person having ordinary skill in the art to co-administer the TRPA1 antagonist and α-lipoic acid, in an effort to treat trigeminal neuropathic pain more effectively. MPEP § 2144.06(I) (“‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’”), quoting In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). Therefore, claim 21 is rendered prima facie obvious by Trevisan.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Trevisan (“TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.” Brain 139.5 (2016): 1361-1377) in view of Souza (“TRPA1 as a therapeutic target for nociceptive pain.” Expert opinion on therapeutic targets 24.10 (2020): 997-1008), as evidenced by Fayez (“Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.” Biomedicine & Pharmacotherapy 105 (2018): 428-433).
Trevisan, as evidenced by Fayez, is discussed above in the rejection under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2). That discussion is incorporated by reference into this §103 rejection.
Although Trevisan discloses that the TRPA1 antagonists HC-030031 or A-967079 can be administered to treat trigeminal neuropathic pain, Trevisan is silent as to whether ruthenium red can be administered instead for that purpose. Consequently, Trevisan does not satisfy claim 4. As explained below, Souza compensates for this deficiency.
Souza teaches that ruthenium red is a TRPA1 antagonist. Page 999 at Section 2.4.
Souza teaches: “Several lines of evidence support TRPA1 implication in models of neuropathic pain, with the first report obtained by spinal nerve ligation in mice. Downregulation of TRPA1 expression in L5/DRG, and upregulation in L4/DRG, suggested that a compensatory mechanism could occur after nerve injury. Subsequent studies showed a similar expression pattern using other nerve injury models, such as sciatic nerve injury by chronic constriction or transection. All these data revealed a possible analgesic strategy by blocking/inhibiting TRPA1.” Page 1001, right column (emphasis added).
Before the effective filing date of the claimed invention, the foregoing teachings of Souza would have motivated a person having ordinary skill in the art to modify Trevisan by selecting and administering ruthenium red as the TRPA1 antagonist in the course of routine experimentation, as part of an effort to develop a more effective treatment for trigeminal neuropathic pain. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination); see also MPEP § 2144.06(II) (substituting equivalents known for the same purpose). Therefore, claim 4 is prima facie obvious.
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Trevisan (“TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.” Brain 139.5 (2016): 1361-1377) in view of Wang (“Anti-nociceptive and anti-inflammatory actions of sulforaphane in chronic constriction injury-induced neuropathic pain mice.” Inflammopharmacology 25.1 (2017): 99-106) and optionally Landers (US 2005/0137146 A1), as evidenced by Fayez (“Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.” Biomedicine & Pharmacotherapy 105 (2018): 428-433).
Trevisan, as evidenced by Fayez, is discussed above in the rejection under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2). That discussion is incorporated by reference into this §103 rejection.
Although Trevisan discloses that antioxidant α-lipoic acid can be administered to treat trigeminal neuropathic pain, Trevisan is silent as to whether sulforaphane, exemestane, or JQ-1 can be administered instead for that purpose. Consequently, Trevisan does not satisfy claim 6. As explained below, Wang compensates for this deficiency.
Wang is directed to the “[a]nti-nociceptive and anti-inflammatory actions of sulforaphane [(SFN)] in chronic constriction injury-induced neuropathic pain mice.” Title.
Wang teaches: “Evidence also shows that SFN is effective to alleviate oxidative stress and inflammation in various diseases.” Page 100, left column.
Wang teaches: “In the present study, we provided evidence supporting that daily treatment with SFN for consecutive 7 days reduced the severity of pain behaviors in CCI neuropathic pain mice. Specifically, chronic administration of SFN through systematic delivery was effective in blunting mechanical allodynia and thermal hyperalgesia in CCI mice (Fig. 1), suggesting that SFN attenuated behavioral hypersensitivity in CCI mice.” Pages 103, 105 (bridging paragraph).
Wang teaches: “Therefore, SFN can be a good candidate for neuropathic pain due to its anti-nociceptive and anti-inflammatory properties.” Page 105, right column.
Before the effective filing date of the claimed invention, the foregoing teachings of Wang would have motivated a person having ordinary skill in the art to modify Trevisan by selecting and administering sulforaphane (SFN) as the antioxidant in the course of routine experimentation, as part of an effort to develop a more effective treatment for trigeminal neuropathic pain. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination); see also MPEP § 2144.06(II) (substituting equivalents known for the same purpose). Therefore, claim 6 is prima facie obvious.
Regarding claim 9, the optional reference (Landers) teaches that sulforaphane can be administered nasally. Paras. [0023] and [0050]; see also page 5 at claims 6 and 11. Nasal administration, since before the effective filing date of the present application, has been recognized among persons having ordinary skill in the art of pharmaceutical formulations as an especially convenient route of administration. MPEP § 2144.01 (“[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.”).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Trevisan (“TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.” Brain 139.5 (2016): 1361-1377) in view of Souza (“TRPA1 as a therapeutic target for nociceptive pain.” Expert opinion on therapeutic targets 24.10 (2020): 997-1008) and Wang (“Anti-nociceptive and anti-inflammatory actions of sulforaphane in chronic constriction injury-induced neuropathic pain mice.” Inflammopharmacology 25.1 (2017): 99-106), as evidenced by Fayez (“Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats.” Biomedicine & Pharmacotherapy 105 (2018): 428-433).
Trevisan, as evidenced by Fayez, is discussed above in the rejection under 35 U.S.C. 102(a)(1) and/or 35 U.S.C. 102(a)(2). That discussion is incorporated by reference into this §103 rejection.
Souza is discussed above in the rejection of claim 4 under 35 U.S.C. 103. That discussion is incorporated by reference into this §103 rejection.
Wang is discussed above in the rejection of claim 6 under 35 U.S.C. 103. That discussion is incorporated by reference into this §103 rejection.
Before the effective filing date of the claimed invention, the respective teachings of Souza and Wang would have motivated a person having ordinary skill in the art to modify Trevisan by selecting and co-administering ruthenium red (as the TRPA1 antagonist) and sulforaphane (as the antioxidant) in the course of routine experimentation, as part of an effort to develop a more effective treatment for trigeminal neuropathic pain. MPEP § 2144.07 (the selection of a known material based on its suitability for its intended use can support a prima facie obviousness determination); see also MPEP § 2144.06(I) (combining equivalents known for the same purpose). Therefore, claim 22 is prima facie obvious.
Conclusion
Claims 1-10 and 21-25 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER ANTHOPOLOS whose telephone number is 571-270-5989. The examiner can normally be reached on Monday – Friday (9:00 am – 5:00 pm). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany P. Barham, can be reached on Monday – Friday (9:00 am – 5:00 pm) at 571-272-6175. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.A./
30 May 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
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