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 .
Status of the Application
This Office Action is in response to applicant’s arguments filed on 7/27/26. Claims 3, 6, 8, 15, 18, 20 have been cancelled. Claims 1-2, 4-5, 7, 9-14, 16-17, 19, 21-25 are pending. Claims 1-2, 13-14, 25 have been amended. Claims 5, 7, 9-12, 17, 19, 21-24 have been withdrawn. Claims 1-2, 4, 13-14, 16, 25 are examined herein.
Applicant’s arguments have been fully considered but found not persuasive. The rejection of the last Office Action is maintained for reasons of record and repeated below for Applicant’s convenience.
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 1-2, 4, 13-14, 16, 25 are rejected under 35 U.S.C. 103 as being unpatentable over Ratan et al. (US Patent Application 2018/0344678 A1, of record) in view of Wall et al. (US Patent Application 2019/0135741 A1, of record).
The instant claims are directed to a method of treating ferroptosis in a human subject by administering a composition consisting of (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA).
Ratan et al. teach methods of treating central nervous system conditions associated with oxidative stress by administering a 5-lipoxigenase activating protein (FLAP) inhibitor (abstract and claim 17). A preferred CNS condition is amyotrophic lateral sclerosis (paragraph 0051) as well as ferroptosis (paragraphs 0114, 0135, 0167). A preferred FLAP inhibitor is N-acetylcysteine (NAC) (abstract) or NAC amide (same as the instantly claimed NACA) (paragraph 0057, embodiment 4 on paragraph 0190, and claim 4) and derivatives thereof (paragraph 0090). Diagnostic tools for the conditions taught by Ratan et al. are discussed (paragraphs 0095, 0107). Oral, topical, intravenous administration (paragraph 0061), pharmaceutically acceptable carriers (paragraph 0065), and tablets, powders, capsules, and liquids are taught (paragraph 0066). Therapeutically effective amounts are about 1-50 mg/kg or 1, 5, 10, 20, 50, 100, or 500 mg doses (paragraphs 0092-0094). Single daily dose or multi-doses are taught (paragraphs 0073, 0088, 0091). Suitable excipients, such as sorbitol, may be administered (paragraph 0083). Alpha-tocopherol is taught (paragraphs 0028, 0162).
It is noted that the limitation regarding “wherein the therapeutically effective amount decreases a loss of cognition or any physical ability by at least 10%...” is considered inherent because this decrease in loss of cognition or physical ability will necessarily occur since in Ratan et al. the same claimed patient population is being administered the same claimed active agent at the same claimed dosage amount.
However, Ratan et al. fail to disclose a composition consisting of diNACA.
Wall et al. teach that diNACA and derivatives thereof are useful for treating diseases associated with oxidative stress or damage (title, abstract, paragraphs 0003 and 0008). Wall et al. also teach NACA for the same methods (paragraphs 0033-0034, claims 21-37).
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 claimed invention, to have substituted diNACA, as taught by Wall et al., for NACA in the method of treating the ALS, as taught by Ratan et al.
A person of ordinary skill in the art would have been motivated to substitute diNACA for NACA because of the functionally equivalency of these two active agents. Since Wall et al. teaches that both diNACA and NACA are individually useful for treating diseases associated oxidative stress or damage, one of ordinary skill in the art would have had a reasonable expectation of success in using diNACA in place of NACA, absent a showing of unexpected results or criticality.
Response to Arguments
Applicant argues that the claims have been amended to a dose of 40 mg or greater and up to 1000 mg, which is significantly lower than the dose of Ratan, which is at a minimum around 2500 mg for a 70 kg human. Moreover, Applicant argues that Ratan teaches that in a rat model, 40 mg/kg was the highest dose tolerated without toxicity. Higher doses that were effective in mice (300 mg/kg) cause significant toxicity in rats. Thus, Ratan teaches that the dose should be less than 40 mg/kg.
This is not persuasive because, at the outset, Ratan teaches dosages of 1, 5, 10, 20, 50, 100, or 500 mg (paragraphs 0092-0094), which reads on the amended claims. Regardless, Ratan teaches the effectiveness of the active agent even in doses from 40 to 300 mg/kg. Toxicity is another issue and can vary from subject to subject. For example, data regarding mice and other rodents does not necessarily translate 1 to 1 in humans. One of ordinary skill in the art would know how to optimize the dosage to maximize therapeutic effectiveness and minimize toxicity.
Applicant argues that the poor in vitro results would have led the skilled artisan away from trying the compound in vivo. However, it was surprisingly found that diNACA showed remarkable and unexpected results, with diNACA outperforming all known drugs tested in a ferroptosis animal model system.
This is not persuasive because these results are not surprising or unexpected. Paragraph 0039 of the instant specification clearly teach that diNACA has some anti-ferroptotic properties. Therefore, the in vivo anti-ferroptotic properties of diNACA cannot be viewed as unexpected since its anti-ferroptotic properties have already been established. Furthermore, just because a particular result may be better than another result, it does not rise to the level of unexpected results.
Regarding the establishment of unexpected results or synergism, a few notable principles are well settled. The Applicant has the initial burden to explain any proffered data and establish how any results therein should be taken to be unexpected and significant. See MPEP 716.02 (b). It is applicant’s burden to present clear and convincing factual evidence of nonobviousness or unexpected results, i.e., side-by-side comparison with the closest prior art in support of nonobviousness for the instant claimed invention over the prior art. The claims must be commensurate in the scope with any evidence of unexpected results. See MPEP 716.02 (d). With regard to synergism, a prima facie case of synergism has not been established if the data or result is not obvious. The synergism should be sufficient to overcome the obviousness, but must also be commensurate with the scope of the claims. Further, if the Applicant provides a DECLARATION UNDER 37 CFR 1.132, it must compare the claimed subject matter with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See MPEP 716.02 (e).
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 Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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