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 .
Application Status
This action is written in response to applicant’s correspondence received 07/13/2026 Claims 1, 5 and 7-15 are currently pending. Claims 2-4, 6 and 16-20 were cancelled by Applicant in the amendments received 07/07/2026. A supplemental amendment was filed and received 07/13/2026 to correct the status identifier of claim 1. Claims 1, 5 and 7-15 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Regarding the previous rejections of claims 1-20 under 35 USC 112(a) for failing to enable the full scope of the claimed invention: Applicant’s argument that one could make and use the claimed invention, as recited in the currently amended claims, from the disclosures in the specification coupled with information known in the art without undue experimentation, have been fully considered and are persuasive. Applicant has noted that the examples in the specification show effects relevant to the treatment of the limited myopathies (of claim 1) in mdx mice, including increased muscle mass cross-sectional area, suppression of muscle fibrosis, increase of quiescent cells, and increased expression of utrophin (pp. 9-10 of the remarks of 07/07/2026). Applicant has further provided evidenced, with citations to references, to support the argument that these effects were known in the art as therapeutic or potentially therapeutic in muscular dystrophy, ALS, and sarcopenia (p. 9 of the remarks of 07/07/2026). In light of the amendments to the claims and the arguments set forth by Applicant, the rejections of the claims under 35 U.S.C. 112(a) for lack of enablement are withdrawn.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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.
Claims 1 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ljubicic (Ljubicic et al. AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy. Trends in Molecular Medicine, 2013; 19, 614-624.; of record, cited in a previous office action) in view of Dávalos (Dávalos et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci U S A. 2011 May 16;108(22):9232–9237.; of record, cited in a previous office action)
Regarding claim 1, Ljubicic teaches that “AMP-activated protein kinase” is “at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy” (Title). Specifically, “Pharmacological AMPK activation remodels skeletal muscle towards a slower, more oxidative phenotype, which is more pathologically resistant to the lack of dystrophin. Moreover, recent studies suggest that AMPK-activated autophagy may be beneficial for myofiber structure and function in mice with muscular dystrophy. Thus, AMPK may represent an ideal target for intervention because clinically approved pharmacological agonists exist, and because benefits can be derived via two independent yet, complementary biological pathways.” (Abstract).
Ljubicic does not teach a method of treating muscular dystrophy comprising administering an effective amount of a miR-33b inhibitor to a subject in need thereof.
Dávalos teaches that miR-33b inhibits AMPK expression, and that inhibition of miR-33b using an anti-miR-33b oligonucleotide (i.e., an antisense oligonucleotide for reducing the level of miR-33b):
Transfection of Huh7 cells with miR-33b (32-fold increase expression) significantly inhibited the mRNA levels of CROT, CPT1a, HADHB, AMPKα, and IRS2 (Fig. 1A). Notably, inhibition of endogenous miR-33b using anti–miR-33b oligonucleotides (threefold decrease expression) increased the mRNA expression of CROT, CPT1a, AMPKα, and IRS2 in Huh7 cells (Fig. 1B), consistent with a physiological role for miR-33b in regulating the expression of these genes. Similar regulation of these genes by miR-33b was also seen at the protein level (pp. 9233-9234)
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating muscular dystrophy by enhancing AMPK expression/activation, as taught by Ljubicic, by administering a miR-33b inhibitor to enhance AMPH expression, as taught by Dávalos.As taught by Dávalos, miR-33b was a known inhibitor of AMPK, and inhibition of miR-33b increased expression and activity of AMPK. Based on that, the ordinary artisan would have expected that inhibition of miR-33b would be an effective therapeutic approach to diseases which can be treated with AMPK agonists. Ljubicic teaches that DMD was known to be a disease for which AMPK agonists are therapeutic, further providing a reasonable expectation that administration of a miR-33b inhibitor to inhibit miR-33b and increase AMPK expression would have presented an alternative method of activating AMPK and thus treating DMD.
Regarding claims 14 and 15, the limitations regarding the effect of the method are not given patentable weight because they simply express the intended result of a process step (administration of the inhibitor) positively recited (MPEP 2111.04).
Claims 5 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Ljubicic and Dávalos, as applied to claims 1 and 14-15, further in view of Koyama (Koyama et al. Identification of Differential Roles of MicroRNA-33a and -33b During Atherosclerosis Progression With Genetically Modified Mice. J Am Heart Assoc. 2019; 8:e012609.; of record, cited in a previous office action) and Lima (Lima et al. Anti-miRNA oligonucleotides: A comprehensive guide for design. RNA Biology, 2018. Vol. .15, No. 3, 338-352.; of record, cited in a previous office action).
Ljubicic and Dávalos render obvious the method of treating muscular dystrophy via administration of a miR-33b inhibitor (reducing substance) of claim 1, from which instantly rejected claims 5 and 7-10 respectively depend, as described above.
Ljubicic and Dávalos do not explicitly teach that the miR-33b-level-reducing substance has a miR-33b-level- reducing rate that is higher than the miR-33a-level-reducing rate, or the specific characteristics of the inhibitor as recited in claims 7-10.
Koyama teaches that the sequences of miR-33a and miR-33b are almost the same except at the 9th and 10th position immediately after the seed sequences (Figure 1B). While Koyama does not provide any particular guidance regarding how to design anti-miRs, Lima teaches that anti-miRs are typically designed to be a perfect match to the miRNA target, especially to the seed region (p. 342).
Regarding claim 7, Koyama teaches the hsa-miR-33b-5p target sequence is 5’-GUGCAUUGCUGUUGCAUUGC-3’ and differs from miR-33a at the 9th and 10th positions, while Lima teaches that anti-miRs should be a perfect match (i.e., not less than 90% complementary to the target). Lima also teaches that anti-miRs should be fully complementary to the 5’ end of the mature miRNA, and that the designed sequence can have the same length, be shorter, or be longer than the target (§ 4), although Lima notes that shorter sequence had shown lower toxicity and are more likely to improve mismatch discrimination (p. 344). It is relevant to note that the full mature sequence of miR-33b-5p is 20 nucleotides long, while the seed sequence is 6 nucleotides long, which encompasses the recited range of 7-20 nucleotides.
Regarding claim 8, Koyama teaches that miR-33b has a seed sequence of 5’-UGCAUU-3’ and differs from the miR-33a sequence at the 9th and 10th positions. Positions 1-10 of miR-33b are 5’-GUGCAUUGCU-3’. It is relevant to note that the recited antisense oligonucleotide has the sequence of AACAGCAATGCA, which is a perfect reverse complement to all but the terminal nucleotide of the 5’ end of miR-33b (5’-UGCAUUGCUGUU-3’), as suggested by Lima.
Regarding claim 9, Lima teaches that, “chemical modifications should be employed into the design of AMOs” (§ 4).
Regarding claim 10, Lima teaches that, “Chemical modifications are mainly introduced in the sugar ring” (§ 3.1).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have designed an antisense oligonucleotide for inhibiting miR-33b, as taught by Ljubicic and Dávalos, to be specific to the miR-33b sequence and not to miR-33a. Based on the combination of Koyama’s teachings of the sequences of miR-33a and -33b and the differences between them, and Lima’s teachings that anti-miRs should be a perfect match to their target (including the seed sequence) and should be chemically modified, the ordinary artisan would have predicted, with a reasonable expectation of success, that a chemically modified anti-miR designed to be a perfect match to the 5’ end and seed sequence of the miR-33b sequence, but not the miR-33a sequence, would have effectively reduced miR-33b more than miR-33a. It would further have been obvious to try optimizing the length of the anti-miR to reduce toxicity and improve specificity. Given the requirement for a perfect match at the 5’ end and the limited size of the target microRNA, there would have been a finite number of possible anti-miR sequences to try.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Ljubicic, Dávalos, Koyama and Lima (all cited above), as applied to claims 5 and 7-10, further in view of Yahara (Yahara et al. Amido-Bridged Nucleic Acids (AmNAs): Synthesis, Duplex Stability, Nuclease Resistance, and in Vitro Antisense Potency. ChemBioChem 2012, 13, 2513 – 2516.; of record, cited in a previous office action).
Ljubicic, Dávalos, Koyama and Lima render obvious the method of claim 10, from which instantly rejected claim 11 depends, as described above.
Ljubicic, Dávalos, Koyama and Lima also teach the antisense oligonucleotide having the nucleobase sequence recited in claim 8, as described above.
Ljubicic, Dávalos, Koyama and Limarender do not teach wherein the modified sugar is an AmNA, as depicted in the claim.
Yahara teaches that amido-bridged nucleic acids (AmNAs) are LNA analogues with improved properties (compared to LNAs), including high nuclease resistance along with high RNA selectivity when incorporated into antisense oligonucleotides (p. 2513).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the nucleobase sequence of the anti-miR as taught by Ljubicic, Dávalos, Koyama and Limarender to incorporate amido-bridged nucleic acids, as taught by Yahara, because Yahara teaches that AmNAs had superior properties to LNAs.
Response to Arguments
Applicant's arguments filed 07/07/2026 have been fully considered but they are not persuasive for the reasons that follow.
Applicant argues that, “Davalos teaches that not only miR-33b, but miR-33a also suppresses an expression of AMPKa and the inhibition of miR-33 upregulates the AMPKa expression.” and that, “On the other hand, Examples of the present application show that inhibition of miR-33a did not produce the therapeutic effects observed with inhibition of miR-33b, such as an increase in muscle cross-sectional area. Therefore, based on the disclosure of Davalos and the results of the Examples in the present application, it is considered that miR-33a is not effective for treating muscular dystrophy, despite activating AMPK expression. Accordingly, since not all agents that activate AMPK expression can be said to be effective for treating muscular dystrophy, the mere fact that miR-33b inhibition activates AMPK expression does not render it obvious that miR-33b inhibition is effective for treating muscular dystrophy.”. This argument, which may be summarized as indicating that inhibition of miR-33a showed an absence of the expected property of having the therapeutic effects of miR-33b inhibition despite upregulation of AMPK expression (see MPEP 716.02(a)(IV)), is acknowledged. However, the argument is not commensurate in scope with the claimed invention (MPEP 716.02(d)). Instead, claim 1 more broadly encompasses any antisense oligonucleotides which reduce miR-33b. Given the similarity between the miR-33a and miR-33b sequences disclosed by Koyama (see the above rejection of claims 7-8 under 35 USC 103), this also encompasses antisense oligonucleotides capable of reducing miR-33a.
Conversely, claims 12 and 13 have been excluded from the modified rejection of the claims under 35 USC 103 because those claims recite specific nucleotide sequences and modifications which are commensurate in scope with the specific miR-33b inhibitors which yielded the unexpected results.
Conclusion
Claims 12 and 13 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claim is allowed at this time.
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 AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/AMANDA M ZAHORIK/ Examiner, Art Unit 1636 /BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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