DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/16/2026 has been entered.
Applicant’s amendments to the claims and arguments filed on January 16, 2026 have been received and entered. Claims 1, 38, 41, 42 have been amended, while claims 2-23, 25-27, 29-31, 33-37, 39-40, 43-49 , 52-53, 55, 57-59, 61, 63-64, 68-72 have been canceled. Claims 73-115 are newly added.
Claims 1, 24, 28, 32, 38, 41-42, 50-51, 54, 56, 60, 62, 65-67, 73-114 and 115 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 24, 28, 32, 38-41 (group I) in the reply filed on June 24, 2025 was acknowledged. Applicant’s election of (i) a muscle specific promoter: SEQ ID NO: 2402; (ii) a sequence encoding micro dystrophin: SEQ ID NO: 2407; (iii) a first and a second DRG de-targeting miRNA binding site: SEQ ID NO: 2399; (iv) a recombinant nucleic acid: SEQ ID NO: 2430; and (v) an amino acid sequence of formula (I): SEQ ID NO: 215 was also acknowledged. Upon further consideration restriction between invention of group I and IV are hereby withdrawn and therefore, claims 50-51, 54, 56, 60, 62, 88-98 are rejoined with the elected invention. Claims 1-3, 7, 9, 13-15, 21-23, 42 link inventions of group I and therefore Claims 1, 24, 28, 32, 38, 41-42, 73-98, 105-115 read on elected species.
Claims 65-67 remain and claims 99-104 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 June 24, 2025.
Priority
This application claims priority from US provisional application no 63/688,024 filed on 08/28/2024, US provisional application no 63/676,780 filed on 07/29/2024, US provisional application no 63/666,899 filed on 07/02/2024 and US provisional application no 63/561,130 filed on 03/04/2024.
Claims 1, 24, 28, 32, 38, 41-42, 50-51, 54, 56, 60, 62, 73-98, 105-115 are under consideration.
Allowable Subject Matter
Claims 83-87 are free of prior art and allowed
Claim Objections
Claims 1, 41-42 are objected to continue to recite withdrawn combination of species of (i) muscle specific promoter: (ii) a sequence encoding micro dystrophin; (iii) a first and a second DRG de-targeting miRNA binding site: (iv) a recombinant nucleic acid. Appropriate correction is required.
Claims 1 and 42 are objected because they do not recite proper Markush groups. When the recombinant nucleic acid is selected from recited in a claim are so related as to constitute a proper Markush groups, they may be recited in the conventional manner, or alternatively. For example, if “wherein the recombinant nucleic acid is selected from the group consisting of A, B, C and D” is a proper limitation, then “wherein the recombinant nucleic is A, B, C or D” shall also be considered proper. Appropriate correction is required.
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Withdrawn -Claim Rejections - 35 USC § 103
Claims 1-2, 7, 9, 15, 24, 28, 32 and 38 were rejected under 35 U.S.C. 103 as being unpatentable over Rodino-Klapac et al (WO/2017/181015, dated 10/19/20217)/ Dickson (US20180346533, dated 06/122019) and Hordeaux (Sci. Transl. Med. 12, eaba9188 (2020), 1-14) and in view of Chakraborty (USP 9597380, dated 3/21/2017)/Wen et al (Neural Regeneration Res. 2023, 18(3), 671-682). In view of Applicants’ amendment of base claims introducing the limitation “ from claim 23”, that was included in the rejection, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 3, 21-22, 38-40, 42 are rejected under 35 U.S.C. 103 as being unpatentable over Rodino-Klapac et al (WO/2017/181015, dated 10/19/20217)/ Dickson (US20180346533, dated 12/6/2018) and Hordeaux (Sci. Transl. Med. 12, eaba9188 (2020), 1-14), Chakraborty (USP 9597380, dated 3/21/2017)/Wen et al (Neural Regeneration Res. 2023, 18(3), 671-682) as applied to claim 1 above and further in view of Takeshita (International J of Molecular Med, 2007, 19, 309-315) as evidenced by Pan (,USP 9453241 6/27/2016) and Genbank accession number AH001878, 8/26/2016), Minshull (USP 11713468, dated 8/1/2023)/Constable (US9943573), Kennedy (US20220380735, dated 12/1/22) and Fontayne (US9551009, 1/24/17). The rejection is withdrawn for the reasons discussed above.
Maintained & New-Claim Rejections - 35 USC § 112-in modified form
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.
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.
Claims 1, 24, 28, 32, 38, 41-42, 50-51, 54, 56, 60, 62, 73-82, 88-98, 105-114 and 115 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims embrace a genus of:
capsid protein comprises an amino acid sequence of formula (I): X1NX2X3X4RG DRXsX6L wherein each of X₁-X₆ is any amino acid (claim 54 and dependent therefrom ).
muscle specific promoter comprising of the nucleic acid sequence of SEQ ID NO: 2402, 2403, or 2404,
a sequence encoding micro dystrophin comprising of the nucleic acid sequence of SEQ ID NO: 2405, 2406 or 2407,
at least one dorsal root ganglia (DRG) de-targeting miRNA binding site comprises a binding site for miR- 338-3p, miR-138-5p, or miR-9-5p that comprises the nucleic acid sequence of any one of SEQ ID NOs: 2399, 2400, or 2401
The claims recite transitional phrase muscle specific promoter, micro dystrophin coding sequence and miR sequence each comprising additional nucleotide sequence. The transitional term “comprising", which is synonymous with "including," "that is inclusive or open-ended and does not exclude additional, unrecited nucleotide sequence (see MPEP211.03).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that ''applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1 117. The specification does not ''clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.'' Vas-cath Inc. v. Mahurkar, 19USPQ2d at 1116.
Regarding genus of AAV particle comprising capsid protein comprising X1NX2X3X4RGDRXsX6L, wherein each of X1-X6 is any amino acid, prior art teaches that change in even a single amino acid could result in loss of a functional virus. For instance, Choi et al (Curr Gene Ther. 2005 June ; 5(3): 299–310.) teach engineering adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types that are non-permissive to wild type (wt) viruses and to improve efficacy in infecting only the cell type of interest (see abstract). However, Choi reported “Mutants generated in capsid mutation studies can be used to identify important domains of the capsid that are critical for viral assembly. Choi cite study from Wu that shows that alanine substitution at specific capsid positions carrying charged amino acids generated mutant viruses that were not able to assemble, In addition, a mutation at R-432 to A-432 alone can generate empty capsid (see page 12, para. 4). Michelfelder et al (PLoS ONE 2009;4:e 5122,pages 1-13, the abstract) teaches cell type-directed vector capsids can be selected from random peptide libraries displayed on viral capsids in vitro but so far this system could not easily be translated to in vivo applications (abstract).Xing ((PLoS Pathog 2025, 21(9): e1013533, pages 1-16) in a post filing publication support these assertions by stating “a diverse panel of AAV capsid variants previously identified from human clinical samples to discover candidates with enhanced liver tropism. In a high-throughput comparative analysis, although no capsid variant outperformed the parental AAV8 capsid in targeting the mouse liver, one variant exhibited markedly reduced liver tropism despite differing from AAV8 by only a single amino acid in the capsid protein. Further investigation demonstrated that introducing this single amino acid change into other AAV capsids similarly reduced their liver targeting (emphasis added). Notably, this amino acid resides in a structural region previously implicated in modulating liver tropism. (see page summary, page 2). Likewise, Varadi et al (Gene Ther. 2012 Aug;19(8):800-9) teach random peptide libraries can be displayed on AAV9 and can be utilized to select for AAV9 capsids redirected to the cell type of interest. Varadi et al generated an AAV9 peptide display library, which ensures that the displayed peptides correspond to the packaged genomes and performed four consecutive selection rounds on human coronary artery endothelial cells in vitro. This is screening yielded AAV9 library capsids with distinct peptide motifs enabling up to 40- fold improved transduction efficiencies compared with wild-type (wt) AAV9 vectors. Incorporating sequences selected from AAV9 libraries into AAV2 capsids could not increase transduction as efficiently as in the AAV9 context (see abstract). In view of foregoing, it is apparent that the state of the art pertinent to searches for the desired rAAV vectors having the desired function among a library of random peptides had been carried out, were within the knowledge of the skilled, but the results were unpredictable.
In view of foregoing, it is apparent that the state of the art pertinent to searches for the desired rAAV vectors having the desired function among a library of random peptides had been carried out, were within the knowledge of the skilled, but the results were unpredictable. One cannot extrapolate the teachings of the specification to the scope of the claims because the skilled artisan cannot envision the structural function of the rAAV capsid variants encompassed by these claims except the rAAV comprising a capsid protein consisting of the amino acid sequence set forth in MyoAAV-LD A and MyoAAV-LD B (see example 1 and page 186 of the specification).
The DNA sequences of all the muscle specific promoter comprising SEQ ID NO 2402, 2403 or 2404, coding sequence of micro dystrophin comprising 2405, 2406 or 2407 and DRG de-targeting miRNA binding site comprising 2399, 2400, or 2401 other than muscle specific promoter consisting of SEQ ID NO 2402-2403 or 2404, coding sequence of micro dystrophin consisting of 2405, 2406 or 2407 and de-targeting miRNA binding site consisting of 2399, 2400, or 2401 respectively, encompassed within the genus of muscle specific promoter, micro dystrophin and de-targeting miRNA binding site have not been disclosed. Further, the claims encompass a genus of AAVs comprising a peptide-modified capsid protein, wherein the peptide-modified capsid protein comprises an amino acid sequence of formula X1NX2X3X4RGDRXsX6L wherein each of X₁-X₆ is any combination of amino acid selected from group of 20 amino acid. As such, insertion and/or substitution of up to 6 amino acid that may be any one of the 20 amino acids at different positions and additionally there are numerous substitution positions on each capsid protein, and all of the aforementioned variables would bring the sum to a genus of modified rAAVs capsid variants, whose function of enhanced expression in one or more of muscle cells are unknown and unpredictable in terms of their expression in muscle cells.
Based upon the prior art there is expected to be sequence variation a muscle specific promoter comprising SEQ ID NO 2402, 2403 or 2404. The specification has provided the description of muscle specificity of promoter consisting of SEQ ID NO 2402, 2403 or 2404. The specification however has not disclosed the sequences of any other sequences that could be included by SEQ ID NO 2402, 2403 or 2404 as embraced by the claims. The art teaches addition of heterologous enhancer element or other cis regulatory element could broaden the expression beyond muscle specific pattern. Grayson et al (Molecular & Cellular Biology, 1995, 1870-1878) teaches adding upstream activation element changes the behavior of muscle specific promoter and the specificity of the promoter depends on the exact combination of promoter and upstream regulatory element and not the promoter sequence alone (abstract, page 1876, col. 1, para. 1 and page 1877, col. 1, para. 2-4). Grayson teaches that the two elements are not only necessary but sufficient, in conjunction with a minimal promoter containing only a TATA box, to constitute a potent muscle-specific transcription unit. There is no evidence on the record of a relationship between the structures of the DNA molecules of any of the embraced muscle specific promoter consisting of 2402, 2403 or 2404 that would provide any reliable information about the structure of DNA molecules containing additional heterologous elements within the genus. There is no evidence on the record that embraced broader sequence had known structural relationships to each other; the art indicated that there is variation between DNA sequences of various elements that could positively or negatively affect the muscle specific promoter activity.
The art teaches further teaches adding nucleotide sequence with the open reading frame of micro dystrophin gene comprising the stated SEQ ID NO could introduce a frameshift if the insertion is not in a multiple of three nucleotide or it could create a premature stop codon or may alter folding, stability and localization or function through changes in mRNA structure. Larsen et al (Neuromuscular Disorders 24 (2014) 693–706 ) teaches “several factors may affect the efficiency of translation initiation, including the presence of upstream open reading frames or secondary structures that can limit the number of scanning pre-initiation ribosomes that access the initiation codon” (see page 694, col. 1, para. 2). It is noted that use of transitional phrase comprising could also include additional nucleotide sequence in untranslated region upstream or downstream of the codon optimized micro dystrophin sequence. It is further noted that adding a sequence upstream or downstream of the coding sequence in untranslated region could also alter the mRNA stability, translation efficiency and polyadenylation (see abstract, page 3, para. 4, to page 4 Steri et al Wiley Interdiscip Rev RNA. 2018 Jul;9(4):e1474, 1-36). The specification has provided the description of codon optimized sequence consisting of SEQ ID NO: 2505, 2406 or 2407. The specification however has not disclosed the adding additional nucleotide sequences with micro dystrophin ORF, upstream or downstream of coding sequence other codon optimized sequence consisting of SEQ ID NO: 2505, 2406 or 2407 embraced by the claims. There is no evidence on the record of a relationship between the structures of the DNA molecules of any of the embraced codon optimized sequence comprising the SEQ ID NO: 2505, 2406 or 2407 that would provide any reliable information about the structure of other sequences within the genus.
The claimed genus of at least one dorsal root ganglia (DRG) de-targeting miRNA binding site comprises a binding site for miR- 338-3p, miR-138-5p, or miR-9-5p that comprises the nucleic acid sequence of any one of SEQ ID NOs: 2399, 2400, or 2401 other than de-targeting miRNA binding site consisting of nucleotide sequence of any one of SEQ ID NOs: 2399, 2400, or 2401 have not been disclosed. It is emphasized that adding nucleotide sequence to miRNA binding site could alter the transcript and miRNA mediated regulation. Liu et al (Nucleic Acids Res . 2014 Jul 31;42(15):9543–9552) teaches genetic variants within flanking regions of miRNA binding sites may also alter local target structure, affecting the potential of miRNA: target hybridization (see page 6, col. 1, para. 2). The specification however has not disclosed the sequences of any of the other sequence consisting of the recited SEQ ID NO embraced by the claims. There is no evidence on the record of a relationship between at least one of miR- 338-3p, miR-138-5p, or miR-9-5p consisting of the nucleic acid sequence structures of the DNA molecules of any DRG de-targeting miRNA binding site comprising additional sequences upstream or downstream of the DRG de-targeting miRNA binding site that would provide any reliable information about the structure of DNA molecules within the genus. The specification has not provided the description of all the different muscle specific promoter, codon optimized micro dystrophin sequence or at least one dorsal root ganglia (DRG) de-targeting miRNA binding site embraced by the genus discussed above.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements or motifs which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
The skilled artisan cannot envision the detailed chemical structure of the encompassed genus of muscle specific promoter, micro dystrophin gene, DRG de-targeting miRNA binding site, AAV particle comprising variant capsid protein and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the muscle specific promoter consisting of SEQ ID NO: 2402-2403 or 2404 (MSP), coding sequence consisting of SEQ ID NO: 2405-2406 or 2407 (micro dystrophin gene) and DRG de-targeting miRNA binding site consisting of SEQ ID NO 2399-2400 or 2401 (DRG de-targeting miRNA binding site ) and capsid protein consisting of amino acid sequence set forth in MyoAAV-LD A or MyoAAV-LD B meet the written description provision of 35 U.S.C. §112, first paragraph. In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus as embraced by the claims.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Sie et al , 2012, FEBS Lett. 586, 2313–2317 teaches nucleotide change at codon could alter translation rate or efficiency, which in turn might modify protein folding.
Agarwal et al eLife 2015;4:e05005, 1-38 teaches model identifying that canonical site, rather than non-canonical sites, drive the vast majority of functional miRNA targeting.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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