Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Application, Amendments and/or Claims
2. Applicant’s response dated 3/10/2026 is considered and entered into record. Claims 8 and 15 have been amended. Claims 9-14 and 20 are canceled. Claims 1-8 and 15-19 are pending.
3. Claims 1-7 and 16-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 21 April 2025.
4. Claims 8 and 15, drawn to a method of treating traumatic brain injury (TBI) in a subject, are considered for examination in the instant application.
Withdrawn Objections/Rejections
5. Upon consideration of cancellation of claims 11 and 20, the objection is withdrawn.
6. Upon consideration of cancellation and amendment of claims, the rejection under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
7. Upon consideration of claim 8 amendment, and cancellation of claims 9, 10 and 20, the rejections under AIA 35 U.S.C. 102(a)(1), are withdrawn.
8. Upon consideration of amendment of claim 8, the rejections under AIA 35 U.S.C. 103, are withdrawn.
New Rejections – as necessitated by amendment
Claim Rejections - 35 USC § 112
9. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
10. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
11. Claims 8 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
12. Claim 8 is directed to a method of treating TBI: wherein “a dosage of salsalate and/or diflunisal is escalated to a second therapeutically effective amount over time”.
13. The specification as originally filed does not provide adequate written description for the escalation of salsalate dosage to a second therapeutically effective amount over time, because the specification does not contemplate the narrowed limitation, that also includes the escalated dosage of salsalate. The instant specification teaches salsalate or diflunisal administration starting 24 hours after TBI (page 52, line 15; para 1; page 44, lines 6-12), followed by daily “escalating doses of diflunisal” (page 44, lines 9-10; Figs 7E, 7F). However, that the escalated dosage to a second therapeutically effective amount over time also applies to salsalate, is not expressly asserted, nor does this flow naturally from the specification. Applicant is required to cancel the new matter in the response to this Office Action. Alternatively, applicant is invited to provide sufficient written support for the “limitation” indicated above. See MPEP 714.02 and 2163.06.
14. Claim 15 is rejected as depending from claim 8 not providing adequate written description for reasons explained above.
Claim Rejections - 35 USC § 103
15. 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.
16. Claim 8 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Gan et al (US 20170368080, 12/28/2017), in view of Ross et al WO 2019/165240, 8/29/2019 (both listed in IDS), in further view of Edwards et al (J Neurotrauma 37: 80-92, January 2020) and Mohamadpour et al (Front Neurosc 13: 1-10, 2019).
17. Claim 8 is directed to a method of treating TBI in a subject comprising administering a first therapeutically effective amount of about 10-25 mg/kg/day of salsalate and/or diflunisal starting 24 hours after TBI, and escalating the dosage to a second therapeutically effective amount over time.
18. Gan et al teach methods of treating tauopathy by reducing the level of acetylated Tau (ac-tau) in a neuron of an individual comprising administering an effective (therapeutically effective) amount of a prodrug to the individual (Abstract; para 0002, 0087, 0088, 0129, 0017), wherein the prodrug is salsalate (para 0105, 0107). The reference teaches that salsalate inhibits p300 activity and reduces Tau acetylation in PS19 mice (model for neurodegenerative tauopathy) (para 0235). Gan et al teach that administration in repeated doses could be higher "to maintain a therapeutic concentration" (page 13, para 139), indicating an escalated second therapeutically effective dose over time.
19. Gan et al do not mention TBI as one of the tauopathies.
20. Ross et al teach a method of treating diseases having neuroinflammation and tauopathy such as TBI resulting in neurodegeneration (page 7, para 2; page 38, para 4; para spanning pages 38 and 39), comprising administering to a subject in need, a therapeutically effective amount of salsalate (page 6, lines 5-7). Ross et al also teach that the effective amounts of salsalate used in the inventive method can be determined empirically, which will depend upon the desired therapeutic effect, route of administration, duration of treatment, body weight of the subject/patient, etc. (page 32, para 1, 2). The reference teaches a daily dose of salsalate that is less than the typical dose, wherein the daily dose can range from about 100 mg to about 2000 mg (understandably total daily dose) (page 32, para 3). Even though Ross et al do not mention the “per kg” dose, the said daily dose range overlaps with the instantly claimed doses. Note that instant claim 8 recites about 10-25 mg/kg/day. That is a total daily dose range administered to a human subject for example, having an average weight of about 60 kg will be about 600-1500 mg (which falls within the reference total dose range of about 100 to about 2000 mg).
21. As Ross et al teach that the effective amounts of salsalate can be determined empirically implies that the differences between the claimed method and the prior art method appears to be one of optimization of conditions of administration. It would therefore, have been obvious to one of ordinary skill in the art at the time the invention was made to have optimized the administration conditions of salsalate to arrive at the administration conditions recited in the claims. See MPEP 2144.05: A. Optimization Within Prior Art Conditions or Through Routine Experimentation. Generally, differences in dosage will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such dose is critical. Dosages are results-effective variables which can be optimized. In the case of administering salsalate, one of skill in the art would clearly recognize that doses could easily be optimized by a treating physician based on the needs and physiology of the individual patient. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."
22. Gan et al or Ross et al do not teach the starting time of treatment after TBI.
23. Edwards et al teach detection of pathological tau “as early as one day” (24 hours) after TBI induction in the transgenic TBI mice as compared to sham mice (Abstract; Methods: Animals; page 82, col 2, para 3, 5; page 86, Discussion: para 2; Figs. 1A, B, D, E). The reference teaches tau presence and AT8 burden levels over time using AT8 antibody, and demonstrates significantly increased tau pathology in TBI mice as compared to sham controls after 1 week of induction (page 82, col 2, para 2, 5; Fig. 2B), with a higher AT8 burden at 1-2 months after TBI induction (page 84, col 1; Figs 3A, B), and at 6 months (Fig. 5B). Edwards et al conclude that TBI results in “an increasing progression of tau aggregation…. in a time- and spatial-dependent manner” (page 90, last para).
24. Gan et al, Ross et al or Edwards et al do not teach starting administration 24 hours after TBI.
25. Mohamadpour et al teach the significance of therapeutic time window for TBI, which is the “time interval between TBI onset and the initiation of treatment”, and provides a list including drugs with long therapeutic window (24 hours) (Abstract; Table 1). The reference teaches that improved outcomes of neurological symptoms/function such as motor function, neuroprotection, mitochondrial protection etc. were seen when the first dose was provided at 24 hours post TBI (page 3, col 2, para 1; Table 1; page 7, col 1, para 1, 2). The reference even states that it might not always be feasible or possible to administer therapy earlier in the case of mild TBI, because subjects may delay treatment or wait longer to seek medical attention (Abstract; page 2, col 1, last para).
26. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to try modifying treating TBI by administration of a therapeutically effective amount (first) of salsalate of about 10-25 mg/kg/day, and providing repeated doses in view of the combined teachings of Gan et al and Ross et al, by considering administering the therapeutic starting 24 hours post TBI, in view of the teachings of Edwards et al. and Mohamadpour et al. The person of ordinary skill would have been motivated to start administration at 24 hours, as several drugs have shown improved neurological outcomes at the therapeutic time window of 24 hours post TBI (Mohamadpour et al). The person of ordinary skill would have also been motivated to use an escalated second dose of salsalate over time as there is a significant increase in acetylated tau with time (days, weeks), and repeated doses could be higher to “maintain a therapeutic concentration” (Edwards et al, Gan et al). The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of the prior art references, before the effective filing date of the instant invention.
27. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
28. Claims 8 and 15 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Gan et al (2017)/Ross et al (2019)/Edwards et al (1/2020)/Mohamadpour et al (2019), in view of Jesus-Cortes HJ (Ph.D. Thesis, 118 pages, 2015).
29. Claim 15 recites further administration of 3,6-dibromo-β-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine.
30. The teachings of Gan et al, Ross et al, Edwards et al, and Mohamadpour et al are set forth above.
31. Gan et al, Ross et al, Edwards et al, or Mohamadpour et al do not teach further administration of the compound in claim 15.
32. Jesus-Cortes teaches that P7C3-series of compounds are neuroprotective and can be used for developing treatments for neurodegenerative diseases (Sections vi, vii – pages 4, 5 of the document), wherein P7C3A20 (3,6-dibromo-β-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine – see instant specification page 20, lines 3-4) has good potency and efficacy in neuroprotection and neuronal survival (para 41-45 – pages 44-47 of the document). Jesus-Cortes also teaches that treatment with P7C3-A20 resulted in improved neuronal survival in a TBI animal model (para 8 - page 22 of the document).
33. Neither Gan et al/Ross et al/Edwards et al/Mohamadpour et al NOR Jesus-Cortes teach the administration of both salsalate and P7C3A20 to the subject having TBI. However, in the absence of unexpected results, it would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references and to have both salsalate and P7C3A20 for use in treating TBI. Each of these therapeutics had been taught by the prior art to be useful agents for treating TBI. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven,205 USPQ 1069 (CCPA 1980) wherein the court held that 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 for a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant method claims, given the teaching of the prior art of using salsalate and P7C3A20 individually for achieving neuroprotection and treating TBI, it would have been obvious to use salsalate and P7C3A20 for the same purpose, because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful for the same purpose. The person of ordinary skill would have been motivated to treat the agents in combination, as Gan et al teach administration of one or more additional therapeutic agents in combination therapy to inhibit tau acetylation and treat tauopathies (para 0130).
34. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Applicant’s Remarks:
35. Applicant argues the 102 rejections and asserts that none of the references (Gan, Ross or Sen) teach the method as recited in amended claim 8, and therefore, the rejections should be withdrawn.
36. Applicant repeats the argument in response to the 103 rejections, asserting that Lagraoui or Ross do not teach or suggest the method of amended claim 8 reciting a “regimen for treating TBI”. Applicant alleges that Ross generally teaches salsalate administration to “potentially treat hundreds of disorders and diseases”, with a “large range of possible doses”. Applicant also alleges that Ross “provides an infinite number of unpredictable solutions of dosages for an infinite number of disorders and diseases”, and combining the teachings with Lagraoui “would require substantial experimentation to make the combination actually work”. Applicant argues that Jesus-Cortes teachings do not cure the deficiencies of the primary references. Applicant concludes that the 103 rejection should therefore, be withdrawn.
37. Applicant’s arguments with regards to amended claim 8, asserting that none of the cited art teach or suggest administration starting 24 hours after TBI of a first therapeutically effective dose of about 10-25 mg/kg/day of salsalate and/or diflunisal, and escalating to a second dose over time, are fully considered and found to be persuasive. All rejections under 102 and 103 are therefore, withdrawn, and new 103 rejections are set forth above as necessitated by current amendment. Also, the present amendment of claims renders the Lagraoui teachings moot, hence, the reference is withdrawn from the current rejections. Applicant’s arguments against the combination of Ross and Lagraoui requiring substantial experimentation is therefore, also moot.
38. Applicant’s argument that Ross generally teaches treating “hundreds” of diseases using a large number of possible doses of salsalate is considered. Even though Ross teaches treating a wide range of diseases, Ross particularly limits TBI as one of a finite number of brain inflammatory conditions (page 38, para 4, 5).
39. With regards to Applicant’s argument about the infinite number of possible doses taught by Ross, it is reiterated that Ross particularly sets forth treating TBI as one of a very finite number (three) of brain inflammatory conditions or non-Alzheimer tauopathies. Ross et al provide daily dose ranges to be used in the treatment method, which includes a dose range of about 10-25 mg/kg/day, as stated in the rejection. Ross et al therefore, teaches treating TBI by administration of salsalate at about a dose range which can be optimized by a treating physician based on the needs and physiology of the individual patient to arrive at the administration conditions recited in amended claim 8. “Where the general condition of a claim is disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As such, the success for treating TBI would not require undue experimentation.
Conclusion
40. No claims are allowed.
41. Applicant’s amendment necessitated the new ground(s) of rejection presented in the 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).
42. 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, however, event will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
43. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm.
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/A. D./
Examiner, Art Unit 1675
4 May 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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