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 06/08/2026. Claims 1-2 and 4-28 are currently pending. The restriction requirement mailed 02/02/2026 is still deemed proper. Applicant elected the invention of Group I (claims 1-22) and species A1 (claims 24-25) without traverse in the reply filed 02/25/2026. Claims 23 and 26-27 are generic. Claim 28 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Accordingly, claims 1-2 and 4-27 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.
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 1-2, 4, and 6-27 are rejected under 35 U.S.C. 103 as being unpatentable over Bestas (Nucleic Acid Therapeutics. Volume 24, Number 1, 2014.; of record, applicant’s submission) in view of U.S. Patent Publication 2008/0118487 A1 to Ferenc (hereinafter ‘Ferenc’) and NCBI reference sequence NM_005259.3 (hereinafter ‘NM_005259.3’; of record, cited in a previous office action).
Claim interpretation: the term “splice variant of myostatin” is interpreted as encompassing any variant of myostatin that differs from full-length myostatin (wild type or mutant) as a result of alternative splicing.
Bestas teaches AONs which are complementary to exon 2 of the myostatin gene and allow expression of a myostatin splice variant by inducing exon skipping (Abstract and p. 14 in the final two paragraphs of the Introduction). The AONs were 25 nt long (p. 16, §Evaluation of SSOs for myostatin corruptive exon skipping), and all effectively spliced exon 2 from the mature transcript (Id.) by targeting either splice sites or exon internal sites (FIG. 2). Bestas further notes that previous studies have demonstrated that allowing expression of myostatin splice variants via exon-skipping PMOs (antisense oligonucleotides) was known effective at increasing muscle size in muscle wasting conditions such as Duchenne muscular dystrophy (DMD)(Abstract, p. 21).
Bestas does not teach that the AONs target exon 3 of the myostatin gene.
Ferenc teaches “splice variants of myostatin that promote muscle growth” (Abstract) that are antagonists of mature myostatin and able to promote myoblast proliferation and reduce cancer muscle cachexia in vivo (para [0196]).
Ferenc further teaches that the splice variants have cryptic splice sites in exon 3 (donor site SD3 and acceptor site SA3). As seen in Figure 1, these splice sites can induce the partial excision of the 5’ region of exon 3, producing two types of truncated variants comprising exons 1 and 2 and only the 3’ UTR region of exon 3:
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[0140] The presently disclosed myostatin splice variant (MSV) is believed to be the result of an alternative splicing event. As shown in FIG. 1, the precursor canonical myostatin mRNA may be transcribed so as to include polynucleotide sequences of all three exons of the myostatin gene. The three exons are bounded by splice donor and acceptor sites, SD1 and SA1, and SD2 and SA2 respectively. Removal of the two introns, one between SD1 and SA1, and the other between SD2 and SA2, produces the canonical myostatin mRNA. The translation start site is located in exon 1, and the stop codon is located about one third of the 5 way into exon 3, meaning that normally there is a large 3′ untranslated region within exon 3.
[0141] As disclosed herein for the first time, an alternative splicing event may also take place in the course of myostatin gene expression by a process in which an extra splicing event occurs between SD3 and SA3 or between SD2 and SA3 (FIG. 1), causing the majority of the normally translated portion of the canonical exon 3 to be excised and replaced with the normally 3′ untranslated section of exon 3. This unexpected splicing event creates a new open reading frame from which the MSV protein may be translated.
Ferenc and Bestas do not teach wherein the nucleotide sequence of the antisense oligonucleotide comprises a sequence consisting of at least 15 consecutive nucleotides of the sequence as shown in SEQ ID NO: 24.
However, NM_005259.3 teaches the nucleotide sequence for the human myostatin mRNA transcript, which comprises a sequence at positions 890-907 which is a 100% reverse complement to SEQ ID NO: 24,
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Please note that Ferenc teaches that the cryptic splice site, SD3, is located 21 nucleotides into exon 3. Per NM_005259.3, exon 3 spans positions 881-2819, which would place SD3 at nucleotide 901. The ordinary artisan would have recognized, based on Bestas’s teachings, that this would make the region comprising the SD3 site a target for a splice-switching AON.
Further, the region comprising the SD3 splice site includes a sequence complementary to SEQ ID NO: 27:
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SEQ ID NO: 28:
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SEQ ID NO: 30:
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SEQ ID NO: 31:
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SEQ ID NO: 32:
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SEQ ID NO: 33:
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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, absent objective evidence of nonobviousness ( to have tried substituting the antisense oligonucleotide targeting splice sites of exon 2 of myostatin for exon skipping to produce a myostatin splice variant, as taught by Bestas, with an antisense oligonucleotide comprising any sequence that is complementary to the region of exon 3 of the human myostatin gene which comprises the cryptic splice site, SD3, as taught by Ferenc. Bestas teaches that exon skipping to knock down or inhibit myostatin was an effective way to promote muscle growth in muscle-wasting diseases such as DMD. Bestas teaches one possible set of splice sites that could be targeted to skip exon 2, and demonstrates methods of making AONs capable of targeting the splice sites in the myostatin gene to induce exon skipping. Ferenc provides alternative splice sites which allow expression of alternative myostatin variants also capable of promoting muscle growth. Therefore, Ferenc provides the ordinary artisan with additional variants and the motivation to express those variants using known methods in the art, including those taught by Bestas. Based on Bestas’s teachings, the ordinary artisan would have a reasonable expectation that AONs could successfully be designed to target the particular splice sites taught by Ferenc as an alternative to those disclosed by Bestas. As taught by NM_00529.3, the target region comprising Ferenc’s cryptic splice site comprises sequences complementary to SEQ ID NOs: 24, 27, 28, 30, 31, 32 and 33.
Regarding claim 2, NM_00529.3 teaches the nucleotide sequence of human myostatin, including the recited target regions, as shown above.
Regarding claim 4, please note that the claim recites wherein the antisense oligonucleotide “has” 18 bases. The word “has” is open-ended, and is interpreted as meaning that the oligonucleotide must have at least 18 bases, but may have additional bases beyond that. Therefore, insofar as Bestas teaches 25-mer AONs, Bestas teaches the limitations of claim 4.
Regarding claims 6-8, Bestas teaches 2’-O-methyl-modified AONs (p. 14 § Synthesis of oligonucleotides).
Regarding claim 9, Bestas teaches pharmaceutical compositions comprising the AONs and, “In-Vivo jetPEI…at an N/P ratio of 10 in 10% glucose” (p. 15 §Animal Experiments).
Regarding claim 10, it is relevant to note that the claim merely recites an intended use for the product, i.e., “for preventing and/or treating a pathological condition and/or a disease in which myostatin is involved”. This recitation of intended use does not result in a structural difference between the claimed invention and the prior art. Therefore, it does not serve to limit the claim. Please see MPEP 2111.02. Even if the recitation of intended use were limiting, the use of the pharmaceutical condition to treat diseases involving myostatin is already taught by Bestas and Ference, as discussed above.
Regarding claims 11-15, Ferenc teaches that myostatin is involved in diseases involving muscular atrophy, such as muscular dystrophy, cachexia, etc., as well as the muscle wasting associated with cancer (paras [0077-0078]). In combination, Ferenc and Bestas both teach myostatin splice variants caused by exon skipping which promote muscle growth. Regarding claim 15, and for clarity, cardiac failure is interpreted as encompassing heart attacks.
Regarding claims 16-17, Ferenc teaches that the ASO composition may be administered orally (para [0147]), and further that the myostatin variants are present in various livestock animals such as pigs, sheep, cattle, etc., (para [0142]) for which including the ASO composition in a food would be an obvious mode of administration.
Regarding claims 18-22, these claims merely recite various agents followed by intended uses. The intended uses do not further limit the structure of the ASO of claim 1, and an agent is interpreted as encompassing merely the ASO of claim 1 itself. Nonetheless, insofar as Ferenc and Bestas teach that splice-skipping ASOs targeting myostatin are capable of promoting myocyte proliferation (see above); increasing muscle mass (see above); switching splicing of the myostatin gene (see above); decreasing myostatin signaling (i.e., knocking it down or antagonizing it; see above); or treating cancer cachexia (see above); they also teach those limitations.
Regarding claims 23-27, these claims merely recite methods for achieving the same outcomes recited in claims 18-22, and are taught by the prior art for the same reasons discussed above.
Response to Arguments
Applicant's arguments filed 06/08/2026 have been fully considered but they are not persuasive because one of ordinary skill in the art could have reasonably expected that myostatin isoforms could be produced by transfecting cells with antisense oligonucleotides comprising the specific sequences recited in claim 1 because the combination of references teaches using splice-switching antisense oligonucleotides targeting splice sites to induce myostatin splice variants, and various myostatin splice variants with their associated splice sites, and the sequence of various alternative target sites comprising those splice sites.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ferenc, Bestas, and NM_005259.3, as applied to claims 1-2, 4, and 6-27 above, further in view of Maruyama (Toshifumi Yokota and Rika Maruyama (eds.). “Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion”. In: Exon Skipping and Inclusion Therapies: Methods and Protocols, Methods in Molecular Biology, vol. 1828, 2018.; of record, cited in a previous office action).
Ferenc, Bestas and NM_005259.3 render obvious the antisense oligonucleotide of claim 4, from which the instantly rejected claim depends, as described above.
Ferenc, Bestas and NM_005259.3 also render obvious an antisense oligonucleotide comprising a sequence consisting of at least 15 consecutive nucleotides of SEQ ID NOs: 24, 27, 28, 30, 31, 32, or 33, as described above.
Ferenc, Bestas and NM_005259.3 do not render obvious an antisense oligonucleotide wherein the nucleotide sequence of the antisense oligonucleotide is the recited 18-mer sequences. The prior art differs from the instant claims in that Bestas teaches 25-mer ASOs, not 18-mer ASOs.
Maruyama teaches that the length of SSOs is an important factor that appears to depend on the chemical modification (p. 85). Maruyama notes that, “longer oligos lead to secondary structures and off-target effects” (p. 81), thus motivating the ordinary artisan to select shorter SSOs when possible.
Maruyama further teaches that the typical length of 2’-O-methyl RNA AONs, such as those taught by Bestas, is 9-25 nt.
Lastly, in the Methods section, Maruyama teaches various routine methods and publicly available software tools for the optimization of SSOs.
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 25-mer oligonucleotide as taught by Ferenc, Bestas and NM_00529.3 by optimizing its length, as taught by Maruyama. Maruyama teaches a range of possible lengths, optimization methods and tools, and encourages the design of shorter SSOs where possible to reduce off-target effects. Thus in regards to the limitations of the claims, where the prior art teaches the optimization of SSO length within a range of 9-25 and provides the tools to do so, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the SSO. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Response to Arguments
Applicant's arguments filed 06/08/2026 have been fully considered but they are not persuasive.
In response to applicant’s arguments that the combination of cited art fails to teach or suggest the specific sequences now recited in claim 1 and the Examiner has inherently recognized this fact due to the absence of claim 3 from the base rejection of claim 1 discussed above, the argument is not found persuasive because, as discussed in the previous office action and above, the specific sequences now recited in amended claim 1 were previously recited in claim 3, and rejected both in the previous office action and current office because splice-switching antisense oligonucleotides for inducing myostatin splice variants, various myostatin splice variants and their associated splice sites, and target sequences comprising those splice sites, are taught by the combination of references, as discussed above.
Conclusion
No claims are 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636
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