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 Amendment
The amendments received 07/28/2025 have been entered. Claims 1-4 and 6-19 are pending. Applicant’s amendments to the claims and specification have overcome each and every objection and rejection under 35 U.S.C. 112(a) and 112(b) previously set forth in the Office Action mailed 01/27/2025.
Examiner has reviewed the declaration under 37 CFR 1.130(a) filed 07/28/2025 and finds it sufficient to disqualify Lai et al. as prior art. The rejection under 35 U.S.C. 102 over Lai et al. is withdrawn.
Specification
Examiner notes that multiple references have been set forth in the specification (p. 20-25). If Applicant wishes for the Examiner to consider these references, Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6 and 11-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites “wherein the ROCK inhibitor is Y27632 or a pharmaceutically acceptable salt, the CDK inhibitor is SU9516 or a pharmaceutically acceptable salt, and the cAMP activator is forskolin or a pharmaceutically acceptable salt”. However, the scope of claim 1 does not include pharmaceutically acceptable salts of Y27632, SU9516, or forskolin. These limitations therefore lack antecedent basis. Claims 11-14 require the limitation at issue and are similarly rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4 and 6-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (WO 2019/241620 A1; 2019) in view of Veremeyko et al. (Frontiers in Immunology; 2018), Gao et al. (Neuroimmunomodulation; 2013), and Ueda (Molecular Pain; 2008).
Huang et al. discloses a method of inducing oligodendrocyte formation and inducing myelination in neurons, comprising administering a chemical cocktail comprising Y27632, SU9516, and forskolin to fibroblasts to convert the fibroblasts into induced oligodendrocytes and co-culturing the induced oligodendrocytes with mouse neurons, which resulted in myelination of the neurons (pars. [000115]-[000119]). Huang et al. additionally discloses that the induced oligodendrocytes can be used to treat demyelinating diseases or disorders, including multiple sclerosis (pars. [00087]-[00088]). Huang et al. further describes Y27632, SU9516, and forskolin as small molecules (par. [00038]). Huang et al. discloses that multiple sclerosis is an inflammatory demyelinating disease (par. [0006]). Huang et al. additionally suggests injecting the induced oligodendrocytes into the central nervous system, such as the corpus callosum or cerebellum, to promote neuron myelination (par. [00089]) and points to successful studies wherein oligodendrocytes have been injected into demyelinated regions to promote myelination (par. [0007]).
Huang et al. does not disclose specifically treating multiple sclerosis in a subject comprising administering the Y27632, SU9516, and forskolin. Huang et al. does not teach injecting the composition into the brain or into the demyelinating lesion of the subject. However, these limitations are obvious over Veremeyko et al., Gao et al., and Ueda.
Veremeyko et al. teaches that in mice with experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) forskolin attenuates neuroinflammation and reduces demyelination compared to vehicle-treated mice (p. 2, col. 2, par. 2; p. 4, col. 2, par. 4). Veremeyko et al. teaches that forskolin was administered via intraperitoneal injection (p. 3, col. 2, par. 1). Veremeyko et al. additionally teaches that forskolin may promote oligodendrocyte maturation and differentiation (p. 19, col. 1, par. 2).
Gao et al. discloses the treatment of experimental autoimmune encephalomyelitis (EAE, an animal model of human multiple sclerosis) in mice comprising administering to the mice Rho-associated kinase (ROCK) inhibitor Y-39983 via intraperitoneal injection (Abstract; p. 335, col. 2, par. 1). Gao et al. teaches that Y-39983 attenuated EAE, reduced inflammatory lesions, and inhibited demyelination in the cerebra (p. 336, col. 1-2 bridging paragraph; col. 2 par. 2). Gao et al. also teaches that another ROCK inhibitor, Y-27632, has been shown to reverse lysophosphatidic acid-induced demyelination (p. 339, col. 2, par. 2).
Ueda teaches that Y27632 reverses demyelination caused by lysophosphatidic acid administered to sciatic nerves of mice (p. 5, col. 2, par. 3)
It would have been prima facie obvious to one of ordinary skill in the art to administer the composition of Huang et al. for the treatment of multiple sclerosis in a subject in need thereof. One would have been motivated to do so, with reasonable expectation of success, as forskolin has been shown to effectively treat multiple sclerosis in mice models with EAE by reducing neuroinflammation and demyelination, as well as promoting oligodendrocyte differentiation, in vivo. Additionally, ROCK inhibitors have also successfully attenuated multiple sclerosis in mice models with EAE with similar effect, and Gao et al. additionally suggests that Y-39983 and Y-27632 have been shown to have similar effects in their ability to reverse or inhibit demyelination (as shown by Ueda). In considering this combination of references, the art strongly suggests that the combination taught by Huang et al. would be effective in treating multiple sclerosis when administered directly to a subject, and would still be effective in promoting oligodendrocyte differentiation and maturation.
Moreover, it would have been prima facie obvious for one of ordinary skill in the art to inject the composition directly into the brain and/or lesioned area of the subject. One would have been motivated to do so, with reasonable expectation of success, as Huang et al. suggests that oligodendrocytes can be directly injected to the site of demyelination in the central nervous system, such as the brain. One would be apprised that the promotion of oligodendrocyte differentiation and maturation, and subsequent inhibition of demyelination, would be more effective when administered directly to the affected area, while as argued above, the cocktail comprising Y27632, SU9516, and forskolin would still be expected to be effective when administered directly.
Response to Arguments
Applicant's arguments filed 07/28/2025 have been fully considered but they are not persuasive.
Applicant argues that the claimed invention would not be obvious in view of the prior art, as cited in the above 35 U.S.C. 103 rejection, because Huang et al. does not disclose in vivo treatment and that compounds that demonstrate efficacy in vitro would not necessarily have the same efficacy in vivo due to diffusion in the body. This is not persuasive.
While Applicant argues that “Indeed, in this art, it is generally understood that compounds that can induce cellular reprograming in vitro would not necessarily lead to the same efficacy in vivo since it may diffuse in the body” (p. 8 of Remarks, second paragraph), no evidence has been set forth to substantiate this statement. Moreover, despite Applicant’s claim that in vivo efficacy would not be expected, the prior art does not agree with such an assertion. As above, Veremeyko et al. and Ueda demonstrate the in vivo efficacy of forskolin and Y27632 in reversing demyelination. As such, one of ordinary skill in the art would expect some degree of efficacy in vivo in view of the prior art, which as such would not be considered a surprising effect (p. 8 of Remarks, first paragraph). Applicant additionally argues that Veremeyko et al., Gao et al., and Ueda et al. only disclose treatment with a single agent and does not suggest in vivo administration of Y27632, SU9516, and forskolin together (p. 8 of Remarks, third paragraph). However, in view of Huang et al., which teaches the in vitro application of Y27632, SU9516, and forskolin to treat demyelination, one of ordinary skill in the art would be apprised that this combination could be applied in vivo with a reasonable expectation of success.
Additionally, regarding Applicant’s argument that “[t]he inventors unexpectedly found that a combination comprising a ROCK inhibitor, a CDK inhibitor and a cAMP activator can effectively rescue demyelination in vivo by administration to a demyelination lesion of a subject in need thereof” (p. 8 of Remarks, first paragraph), the only compounds that were tested in vivo were Y27632, forskolin, and SU9517 (Example 2.3 in specification). The claims are drawn to a much broader scope of ROCK inhibitors, CDK inhibitors and cAMP activators. Yet, Applicant additionally argues that in vivo efficacy is unpredictable as the compounds may diffuse in the body. If this were accepted to be true, how can Applicant assert that the additional ROCK inhibitors, CDK inhibitors and cAMP activators of claim 1 (that are not Y27632, forskolin, and SU9517) would yield the same “unexpected” results?
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this 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).
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/M.E.B./Examiner, Art Unit 1624 09/15/2025
/BRENDA L COLEMAN/Primary Examiner, Art Unit 1624