ANELLOSOMES FOR DELIVERING INTRACELLULAR THERAPEUTIC MODALITIES

§103 §DOUBLEPATENT

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 . DETAILED ACTION Applicant’s amendments and remarks filed on May 22, 2026 are acknowledged. Claims 1-56, 58, 61-65, 68, 69, and 73 have been canceled. Claims 57 and 67 were amended. Claims 57, 59, 60, 66, 67, 70-72, and 74-83 are pending. Claims 70-72 and 74-76 are withdrawn. Claims 57, 59, 60, 66, 67, and 77-83 are examined on the merits herein. Continued Examination Under 37 CFR 1.114 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 22, 2026 has been entered. Priority This application claims priority to PCT/US2019/065874 filed on December 12, 2019 which claims priority to U.S. provisional application 62/778,851, filed on December 12, 2018 and U.S. provisional application 62/778,866, filed on December 12, 2018. Withdrawn Objections In view of Applicant’s amendments and response, the objections to the drawings and abstract are withdrawn. Withdrawn Rejections In view of Applicant’s amendments and response, the 35 U.S.C 112(a) written description rejection is withdrawn. In view of Applicant’s amendments, the nonstatutory double patenting rejections in reference to copending Application No. 17/413,392 and 17/413,207 are withdrawn. Information Disclosure Statement The information disclosure statement (IDS) submitted on May 22, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Drawings The drawings were received on May 22, 2026. These drawings are found acceptable by the examiner. Claim Objections Claims 57 and 82 are objected to because of the following informalities: Claim 57 part (I) recites in part “comprises an miRNA and decreases expression of a host gene” and should recite “comprises an miRNA capable of decreasing expression of a host gene” because the claim is clearly drawn to a product with the recited functional capability. Claim 82 recites in part “wherein delivery of the genetic element results in modulation of expression of a nucleic acid or protein in the human cell” and should recite “wherein the genetic element is capable of modulating expression of a nucleic acid or protein when delivered to the human cell” because the claim is clearly drawn to a product with the recited functional capability. Appropriate correction is required. 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. Claims 57, 59, 60, 66, 67, 77-79, 82, and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Leary et al. (US 6,395,472; reference cited by Applicant) in view of Bostan et al. (Bostan, N., N. E. Amen, and H. Bokhari. "Current and future prospects of torque teno virus." J Vaccines Vaccin S 1.2 (2013); reference cited by Applicant), Peng et al. (Peng, Y. H., et al. "Analysis of the entire genomes of thirteen TT virus variants classifiable into the fourth and fifth genetic groups, isolated from viremic infants." Archives of virology 147.1 (2002): 21-41; reference previously cited by the Examiner), Galmes et al. (Galmès, Johanna, et al. "Potential implication of new torque teno mini viruses in parapneumonic empyema in children." European Respiratory Journal 42.2 (2013): 470-479; reference cited by Applicant), GenBank Accession No. JX134045 (2013) as evidenced by Modha et al. (Modha, S., Hughes, J., Orton, R. J., & Lytras, S. (2025). Expanding the genomic diversity of human anelloviruses. Virus Evolution, 11(1), veaf002; reference previously cited by the Examiner), and Heller et al. (Heller, Kristin N., et al. "MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin." JCI insight 2.9 (2017): e93309; reference cited by Applicant). Regarding claims 57, 59, 60, 66, 67, 77-79, 82, and 83, Leary et al. teaches a TTV-based vector (genetic element of the claims) comprising: 1) a promoter; 2) a heterologous DNA sequence encoding a protein; and 3) a nucleotide sequence encoding TTV, a fragment of the nucleotide sequence or a complement of the nucleotide sequence or the fragment, wherein the heterologous DNA sequence is operably linked to the promoter derived from TTV or from a heterologous source. The vector may be capable of being packaged into TTV particles for stable maintenance or expression of said heterologous DNA sequence [column 5, first full paragraph]. Therefore, Leary et al. teaches a synthetic particle capable of delivering a genetic element into a mammalian cell because Leary et al. teaches that the host cell may be eukaryotic [column 5, lines 24-25]. Leary et al. also teaches that potential applications of a TTV-based vector are the same for vectors already in use and includes cell culture production of useful proteins such as antigens for vaccines, enzymes of clinical or research value, and gene therapy for replacement of defective genes [column 21, third full paragraph]. Further, Leary et al. teaches that administration of the vectors to animals or humans could be accomplished [column 21, second full paragraph]. Further, Leary et al. teaches that a DNA fragment of interest (e.g. containing a protein binding site or encoding a RNA or protein) is inserted into the TTV vector cloning site and the ligated product is amplified in bacteria and then introduced into cell culture. The effect that the cloned insert has on the cells is studied, or the expressed product (e.g. any protein of interest such as an enzyme, antigen or recombinant vaccine protein) is isolated [column 48, first full paragraph]. Leary et al. also teaches a host cell comprising the vector wherein the host cell may be eukaryotic [column 5, second full paragraph]. Leary et al. also teaches that the vector can consist of parts of the genome such as the replication origin, specific genes, promoters, or other control elements and can be used for expression of cloned genes in culture or in gene therapy treatment [column 7, fourth full paragraph]. Leary et al. teaches that the entire TTV genome could be used, either in its wild type form or modified to alter specific properties such as vector capacity, efficiency of replication, host cell range, transmission and the like [column 20, last paragraph]. Leary et al. also teaches that TTV sequences, non-essential to vector function, can be eliminated in order to increase the amount of foreign DNA the vector can accommodate [column 48, first paragraph]. Leary et al. teaches that gene therapy can alternatively be performed using virions (e.g., proteinaceous exterior already encoded/synthesized) isolated from cell culture and used to infect the host [column 48, second full paragraph]. Leary et al. teaches that similar to the Circoviridae, TTV is a non-enveloped virus which contains a single-stranded circular DNA genome [column 9, second full paragraph]. However, Leary et al. does not specifically teach (I) the genetic element where the exogenous effector comprises an miRNA and decreases expression of a host gene, and (II) a proteinaceous exterior comprising an Anellovirus ORF1 molecule wherein the ORF1 molecule comprises a jelly-roll domain, a hypervariable domain, and an N22 domain; wherein the genetic element is enclosed within the proteinaceous exterior (claim 57). While Leary et al. does not teach the proteinaceous exterior comprising an Anellovirus ORF1 molecule, the instant specification discloses that a wild-type Anellovirus includes e.g., a wild-type Torque Teno virus, Torque Teno mini virus, or TTMDV [page 3, last paragraph]. Leary et al. does not teach that the ORF1 molecule has been proteolytically processed (claim 59). Leary et al. does not teach that the ORF1 molecule comprises the sequence of SEQ ID NO: 58 (claim 60). Leary et al. also does not teach a pharmaceutical composition comprising at least 103 synthetic particles and a pharmaceutically acceptable carrier or excipient (claims 66 and 67). Leary et al. does not teach the genetic element comprises a sequence having at least 75% sequence identity to a 5’ UTR conserved domain of a wild-type Anellovirus (claim 77) or wherein the ORF1 molecule comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 216 (claim 78). Leary et al. also does not teach wherein the host gene comprises KRAS, EGFR, IDH1, or IDH2 and is associated with cancer (claims 79-81). Leary et al. does not teach wherein the genetic element is capable of modulating expression of a nucleic acid or protein when delivered to the human cell (claim 82). Heller et al. teaches that the levels of miR-29c, a known regulator of collagen, are reduced in DMD. Heller et al. also teaches that the gastrocnemius muscle was injected with self-complementary AAV.CMV.miR-29c or single stranded AAV.MCK.micro-dystrophin alone or in combination in the mdx/utrn+/– mouse, a DMD mouse model. Treatment of 3-month-old mdx/utrn+/– mice with AAV.miR-29c showed a reduction in collagen and combinatorial gene delivery in 3-month-old mdx/utrn+/– mice further decreased fibrosis [abstract]. Heller et al. also teaches that 5 × 1011 vg of scAAVrh.74.CMV.miR-29c, 5 × 1011 vg of scAAVrh.74.MCK.micro-dystrophin, or both are diluted in saline and delivered intramuscularly [page 10, “Gene delivery” paragraph]. Bostan et al. teaches the structure and genomic organization of TTV as shown below: PNG media_image1.png 380 542 media_image1.png Greyscale Bostan et al. teaches that the TTV genome is single stranded, circular, and 3.8 kb in length which contains both coding and non-coding regions with sizes 2.6 kb and 1.2 kb, respectively. Further, the genome contains conserved regions in the non-coding area of the genome (UTRs) that include GC rich region, a poly A sequence downstream, and a TATA box upstream of the coding region [page 2, left column, first full paragraph]. Bostan et al. also teaches that ORF1 (predicted length of 719-770 amino acids) encodes a capsid protein and contains hyper variable regions where the occurrence of mutations in ORF1 is much higher than any other proteins of TTV in which change in nucleotides leads to amino acid changes and occurs more frequently than in other protein parts. Further, the protein encoded by ORF1 has an Arginine-rich N-terminus that may function in binding of DNA during the process of packaging of viral DNA into capsid [page 2, left column, last paragraph bridging to right column]. Bostan et al. also teaches that other types of TTV-like viruses have been discovered such as torque teno mini virus (TTMV), small anellovirus (SAV), and torque teno midi virus (TTMDV). Further, TTMV’s genome has a great resemblance with TTV such as a GC-rich region, a coding region, CAV like motif in ORF 2 region and an Arginine-rich N-terminus [page 3, third and fifth full paragraph]. Modha et al. teaches that ORF1 is used for species and genus delineation and has recently been confirmed to function as the capsid protein of the virion, containing a jellyroll-like domain and forming a capsid of 60 ORF1 monomers in an icosahedral (T = 1) conformation [page 2, left column, first full paragraph]. Thus, although post-filing, as evidenced by Modha et al., the ORF1 of Bostan et al. will inherently comprise a jelly-roll domain. Peng et al. teaches that the nucleotide sequence of the untranslated region (UTR) of TTV is more conserved than that of the coding regions, and some blocks in the UTR are well conserved even among the four distinct genetic groups of TTV [page 22, second paragraph]. As shown in Figure 6, two specific regions downstream of the polyadenylation signal and just downstream of the TATA box were well preserved among the TTVs of the five distinct groups. The point mutations and deletion/insertion of nucleotide observed in the inverted repeat sequences downstream of the polyadenylation signal were covariant (Figure 6b) thus suggesting the strict conservation of the putative stem-loop structures maintained by all TTV groups as previously described for TTVs of groups 1 and 3 [page 34, first full paragraph]. Galmes et al. identified three new isolates of TTMV (TTMV-LY) and demonstrated the in vitro replication of TTMV-LY in alveolar epithelial cells and effective release of infectious viral particles [abstract]. Galmes et al. teaches that one other feature of the viruses is the highly conserved 5’-UTR as shown in Figure 2. Further, Figure 2a shows that TTMV-LY2 possess a significant insertion in the 5’UTR forming a predictive secondary structure of RNA sequence and appears to be capable of forming a stable loop-and-dimer structure [page 473, last paragraph]. Galmes et al. also teaches that for the first time, TTMV, like TTV, was able to replicate in cell lines after transfection of its genome and thus lead to the production of infectious virions [page 477, last paragraph]. GenBank Accession No. JX134045 shows the complete genome of TTV-like mini virus isolate TTMV-LY2 which is 2979 nucleotides in length. The sequence of nucleotides 612-2612 (designated as Db) encodes an ORF1 molecule that is 100% identical to SEQ ID NO: 58 (designated as Qy) of the present application. LOCUS JX134045 2979 bp DNA circular VRL 16-MAR-2013 DEFINITION TTV-like mini virus isolate TTMV_LY2, complete genome. ACCESSION JX134045 VERSION JX134045.1 KEYWORDS . SOURCE TTV-like mini virus (TTMV) ORGANISM TTV-like mini virus Viruses; Viruses incertae sedis; Anelloviridae; Betatorquevirus. REFERENCE 1 (bases 1 to 2979) AUTHORS Galmes,J., Li,Y., Rajoharison,A., Ren,L., Dollet,S., Richard,N., Vernet,G., Javouhey,E., Wang,J., Telles,J.N. and Paranhos-Baccala,G. TITLE Potential implication of new torque teno mini viruses in parapneumonic empyema in children JOURNAL Eur. Respir. J. (2012) In press PUBMED 23060626 REMARK Publication Status: Available-Online prior to print REFERENCE 2 (bases 1 to 2979) AUTHORS Galmes,J., Li,S., Rajoharison,A., Telles,J.-N. and Baccala,G. TITLE Direct Submission JOURNAL Submitted (05-JUN-2012) Laboratoire des Pathogenes Emergents, Fondation Merieux, 21 Avenue Tony Garnier, Lyon Cedex 07 69365, France FEATURES Location/Qualifiers source 1..2979 /organism="TTV-like mini virus" /mol_type="genomic DNA" /isolate="TTMV_LY2" /host="Homo sapiens" /db_xref="taxon:93678" /geo_loc_name="France" /collection_date="14-Feb-2008" CDS 424..723 /note="ORF2" /codon_start=1 /product="hypothetical protein" /protein_id="AGG91485.1" /translation="MSDCFKPTCYNNKTKQTHWINNLHLTHDLICFCPTPTRHLLLAL AEQQETIEVSKQEKEKITRCLITTEEDGTTTDVLDGMDEVGLDALFAEDFEEKEG" CDS 612..2612 /note="ORF1" /codon_start=1 /product="hypothetical protein" /protein_id="AGG91484.1" /translation="MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRVRPTYTTI PLKQWQPPYKRTCYIKGQDCLIYYSNLRLGMNSTMYEKSIVPVHWPGGGSFSVSMLTL DALYDIHKLCRNWWTSTNQDLPLVRYKGCKITFYQSTFTDYIVRIHTELPANSNKLTY PNTHPLMMMMSKYKHIIPSRQTRRKKKPYTKIFVKPPPQFENKWYFATDLYKIPLLQI HCTACNLQNPFVKPDKLSNNVTLWSLNTISIQNRNMSVDQGQSWPFKILGTQSFYFYF YTGANLPGDTTQIPVADLLPLTNPRINRPGQSLNEAKITDHITFTEYKNKFTNYWGNP FNKHIQEHLDMILYSLKSPEAIKNEWTTENMKWNQLNNAGTMALTPFNEPIFTQIQYN PDRDTGEDTQLYLLSNATGTGWDPPGIPELILEGFPLWLIYWGFADFQKNLKKVTNID TNYMLVAKTKFTQKPGTFYLVILNDTFVEGNSPYEKQPLPEDNIKWYPQVQYQLEAQN KLLQTGPFTPNIQGQLSDNISMFYKFYFKWGGSPPKAINVENPAHQIQYPIPRNEHET TSLQSPGEAPESILYSFDYRHGNYTTTALSRISQDWALKDTVSKITEPDRQQLLKQAL ECLQISEETQEKKEKEVQQLISNLRQQQQLYRERIISLLKDQ" RESULT 1 AASEQ2_05092025_133541 Query Match 100.0%; Score 3640; DB 1; Length 666; Best Local Similarity 100.0%; Matches 666; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRVRPTYTTIPLKQWQPPYKRTCYIK 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRVRPTYTTIPLKQWQPPYKRTCYIK 60 Qy 61 GQDCLIYYSNLRLGMNSTMYEKSIVPVHWPGGGSFSVSMLTLDALYDIHKLCRNWWTSTN 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 GQDCLIYYSNLRLGMNSTMYEKSIVPVHWPGGGSFSVSMLTLDALYDIHKLCRNWWTSTN 120 Qy 121 QDLPLVRYKGCKITFYQSTFTDYIVRIHTELPANSNKLTYPNTHPLMMMMSKYKHIIPSR 180 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 121 QDLPLVRYKGCKITFYQSTFTDYIVRIHTELPANSNKLTYPNTHPLMMMMSKYKHIIPSR 180 Qy 181 QTRRKKKPYTKIFVKPPPQFENKWYFATDLYKIPLLQIHCTACNLQNPFVKPDKLSNNVT 240 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 181 QTRRKKKPYTKIFVKPPPQFENKWYFATDLYKIPLLQIHCTACNLQNPFVKPDKLSNNVT 240 Qy 241 LWSLNTISIQNRNMSVDQGQSWPFKILGTQSFYFYFYTGANLPGDTTQIPVADLLPLTNP 300 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 241 LWSLNTISIQNRNMSVDQGQSWPFKILGTQSFYFYFYTGANLPGDTTQIPVADLLPLTNP 300 Qy 301 RINRPGQSLNEAKITDHITFTEYKNKFTNYWGNPFNKHIQEHLDMILYSLKSPEAIKNEW 360 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 301 RINRPGQSLNEAKITDHITFTEYKNKFTNYWGNPFNKHIQEHLDMILYSLKSPEAIKNEW 360 Qy 361 TTENMKWNQLNNAGTMALTPFNEPIFTQIQYNPDRDTGEDTQLYLLSNATGTGWDPPGIP 420 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 361 TTENMKWNQLNNAGTMALTPFNEPIFTQIQYNPDRDTGEDTQLYLLSNATGTGWDPPGIP 420 Qy 421 ELILEGFPLWLIYWGFADFQKNLKKVTNIDTNYMLVAKTKFTQKPGTFYLVILNDTFVEG 480 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 421 ELILEGFPLWLIYWGFADFQKNLKKVTNIDTNYMLVAKTKFTQKPGTFYLVILNDTFVEG 480 Qy 481 NSPYEKQPLPEDNIKWYPQVQYQLEAQNKLLQTGPFTPNIQGQLSDNISMFYKFYFKWGG 540 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 481 NSPYEKQPLPEDNIKWYPQVQYQLEAQNKLLQTGPFTPNIQGQLSDNISMFYKFYFKWGG 540 Qy 541 SPPKAINVENPAHQIQYPIPRNEHETTSLQSPGEAPESILYSFDYRHGNYTTTALSRISQ 600 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 541 SPPKAINVENPAHQIQYPIPRNEHETTSLQSPGEAPESILYSFDYRHGNYTTTALSRISQ 600 Qy 601 DWALKDTVSKITEPDRQQLLKQALECLQISEETQEKKEKEVQQLISNLRQQQQLYRERII 660 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 601 DWALKDTVSKITEPDRQQLLKQALECLQISEETQEKKEKEVQQLISNLRQQQQLYRERII 660 Qy 661 SLLKDQ 666 |||||| Db 661 SLLKDQ 666 Instant SEQ ID NO: 216 (designated as Db) matches to instant SEQ ID NO: 58 (designated as Qy) as shown in the alignment below. RESULT 1 AASEQ2_11262025_150336 Query Match 6.1%; Score 223; DB 1; Length 38; Best Local Similarity 100.0%; Matches 38; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRVR 38 |||||||||||||||||||||||||||||||||||||| Db 1 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRVR 38 It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Leary et al. by also constructing a TTV-based or TTMV-based vector comprising a modified TTV or TTMV genome comprising at least a conserved UTR region of a TTV genome or the highly conserved 5’-UTR of a TTMV-LY genome, respectively. Specifically, a vector comprising (I) a genetic element comprising a nucleic acid sequence encoding an exogenous effector wherein the exogenous effector comprises an miRNA and decreases expression of a host gene; and (II) a proteinaceous exterior comprising an Anellovirus ORF1 molecule, wherein the genetic element is enclosed within the proteinaceous exterior, because Heller et al. generated a vector for DMD gene therapy, Bostan et al. taught that the conserved regions in the TTV genome are present in the UTRs, ORF1 encodes a capsid protein having an Arginine-rich N-terminus that may function in binding of DNA during the process of packaging of viral DNA into capsid, and TTV-like viruses such as TTMV having a great resemblance with TTV, Peng et al. taught that the nucleotide sequence of the UTR of TTV is more conserved than that of the coding regions, and two specific regions downstream of the polyadenylation signal and just downstream of the TATA box are well preserved among the TTVs of the five distinct groups, and Galmes et al. taught that the 3 new isolates of TTMV-LY all share the highly conserved 5’-UTR and successfully demonstrated in vitro replication of TTMV-LY in aveolar epithelial cells and effective release of infectious viral particles. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Leary et al., Bostan et al., Peng et al., and GenBank Accession No. JX134045 by formulating a pharmaceutical composition comprising about 5 × 1011 vg of engineered TTV-based or TTMV-based virions for treating a subject with DMD. One of skill would have been motivated to do so because it would have amounted to combining prior art elements according to known methods to yield predictable results. Claims 80 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Leary et al. (US 6,395,472; reference cited by Applicant) in view of Bostan et al. (Bostan, N., N. E. Amen, and H. Bokhari. "Current and future prospects of torque teno virus." J Vaccines Vaccin S 1.2 (2013); reference cited by Applicant), Peng et al. (Peng, Y. H., et al. "Analysis of the entire genomes of thirteen TT virus variants classifiable into the fourth and fifth genetic groups, isolated from viremic infants." Archives of virology 147.1 (2002): 21-41; reference previously cited by the Examiner), Galmes et al. (Galmès, Johanna, et al. "Potential implication of new torque teno mini viruses in parapneumonic empyema in children." European Respiratory Journal 42.2 (2013): 470-479; reference cited by Applicant), GenBank Accession No. JX134045 (2013) as evidenced by Modha et al. (Modha, S., Hughes, J., Orton, R. J., & Lytras, S. (2025). Expanding the genomic diversity of human anelloviruses. Virus Evolution, 11(1), veaf002; reference previously cited by the Examiner), and Heller et al. (Heller, Kristin N., et al. "MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin." JCI insight 2.9 (2017): e93309; reference cited by Applicant) as applied to claims 57, 59, 60, 66, 67, 77-79, 82, and 83 above, and further in view of Anant et al. (US 2011/0283372). Regarding claims 80 and 81, the teachings of Leary et al., Bostan et al., Peng et al., Galmes et al., GenBank, and Heller et al. are discussed above. However, Leary et al., Bostan et al., Peng et al., Galmes et al., GenBank, and Heller et al. do not teach wherein the host gene is associated with cancer (claim 80) or wherein the host gene comprises KRAS (claim 81). Anant et al. teaches that KRAS is a critical gene that is mutated in many cancers including pancreatic cancer, and several studies have reported that up to 95% of pancreatic cancers contain KRAS mutations. KRAS is another key downstream target of let-7a miRNA [0340]. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the synthetic particle wherein the exogenous effector comprises an miRNA and decreases expression of a host gene wherein the host gene is associated with cancer and the host gene comprises KRAS because Leary et al., Heller et al., and Bostan et al. taught a synthetic particle comprising: (I) a genetic element comprising a nucleic acid encoding an exogenous effector wherein the exogenous effector comprises an miRNA and decreases expression of a host gene; and (II) a proteinaceous exterior comprising an Anellovirus ORF1 molecule, Anant et al. taught that KRAS is a critical gene that is mutated in many cancers including pancreatic cancer, and Anant et al. also taught that KRAS is another key downstream target of let-7a miRNA. One of ordinary skill in the art would have made such a modification because it would have amounted to a simple substitution of one known element (miRNA) for another to obtain predictable results. Response to Arguments Applicant's arguments filed May 22, 2026 have been fully considered but they are not persuasive. Applicant provides the following assertions: PNG media_image2.png 516 818 media_image2.png Greyscale These arguments are not found persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Leary et al. teaches a TTV-based vector comprising a promoter, a heterologous DNA sequence, and a nucleotide sequence encoding TTV, or a fragment of the nucleotide sequence wherein the heterologous sequence is operably linked to the promoter. However, Leary et al. does not specifically teach (I) the genetic element where the exogenous effector comprises an miRNA and decreases expression of a host gene, and (II) a proteinaceous exterior comprising an Anellovirus ORF1 molecule wherein the ORF1 molecule comprises a jelly-roll domain, a hypervariable domain, and an N22 domain; wherein the genetic element is enclosed within the proteinaceous exterior. Therefore, the Heller et al., Bostan et al., Peng et al., Galmes et al., and GenBank Accession No. JX134045 references were used to remedy the deficiencies as discussed in the rejection above. Specifically, Heller et al. was cited because it teaches miR-29c which is an miRNA. Bostan et al. already reviewed the structure and genomic organization of TTV wherein the ORF1 encodes a capsid protein and contains hyper variable regions. Galmes et al. teaches sequences isolated from children with parapneumonia empyema corresponding to Torque Teno mini viruses sequences wherein one of the sequences isolated has been submitted to GenBank under Accession No. JX134045 [page 471, TTMV isolation by pathogen discovery and genetic characterisation paragraph]. GenBank Accession No. JX134045 is the complete genome of TTV-like mini virus isolate TTMV_LY2 and the sequence of nucleotides 612-2612 encodes an ORF1 molecule that is 100% identical to instant SEQ ID NO: 58. Applicant provides the following assertions: PNG media_image3.png 216 804 media_image3.png Greyscale PNG media_image4.png 60 808 media_image4.png Greyscale These arguments are not found persuasive. Applicant’s arguments are directed to the method claims; however, the method claims are not under examination. The method claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Nonetheless, in an assertion of unexpected results, one must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). See MPEP 716.02(e). Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 57, 59, 60, 66, 67, and 79-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55, 57, 58, 60-67 and 71 of copending Application No. 17/413,297 (reference application) in view of Heller et al. (Heller, Kristin N., et al. "MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin." JCI insight 2.9 (2017): e93309; reference cited by Applicant). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims overlap in scope. Instant SEQ ID NO: 217 has a 100% match to SEQ ID NO: 217 of application ‘297. PNG media_image5.png 260 646 media_image5.png Greyscale PNG media_image6.png 256 650 media_image6.png Greyscale PNG media_image7.png 110 628 media_image7.png Greyscale PNG media_image8.png 586 650 media_image8.png Greyscale PNG media_image9.png 474 650 media_image9.png Greyscale PNG media_image10.png 308 616 media_image10.png Greyscale PNG media_image11.png 696 648 media_image11.png Greyscale PNG media_image12.png 88 636 media_image12.png Greyscale PNG media_image13.png 84 622 media_image13.png Greyscale Heller et al. teaches that the levels of miR-29c, a known regulator of collagen, are reduced in DMD. Heller et al. also teaches that the gastrocnemius muscle was injected with self-complementary AAV.CMV.miR-29c or single stranded AAV.MCK.micro-dystrophin alone or in combination in the mdx/utrn+/– mouse, a DMD mouse model. Treatment of 3-month-old mdx/utrn+/– mice with AAV.miR-29c showed a reduction in collagen and combinatorial gene delivery in 3-month-old mdx/utrn+/– mice further decreased fibrosis [abstract]. Heller et al. also teaches that 5 × 1011 vg of scAAVrh.74.CMV.miR-29c, 5 × 1011 vg of scAAVrh.74.MCK.micro-dystrophin, or both are diluted in saline and delivered intramuscularly [page 10, “Gene delivery” paragraph]. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the synthetic particle of '297 wherein the exogenous effector comprises an miRNA and decreases expression of a host gene because application '297 taught a synthetic particle comprising a proteinaceous exterior and a genetic element and Heller et al. generated a vector for DMD gene therapy. One of ordinary skill in the art would have made such a modification because it would have amounted to a simple substitution of one known element (polypeptide of ‘297 for the miRNA of Heller et al.) for another to obtain predictable results. This is a provisional nonstatutory double patenting rejection. Claims 57, 59, 60, 66, 67, and 79-83 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-66 of U.S. Patent No. 11,166,996. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims overlap in scope and encompass the same recombinant anellovirus. PNG media_image14.png 564 514 media_image14.png Greyscale PNG media_image15.png 714 504 media_image15.png Greyscale PNG media_image16.png 135 278 media_image16.png Greyscale Claims 57, 59, 60, 66, 67, and 79-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 14-18 of copending Application No. 19/240,368 in view of Heller et al. (Heller, Kristin N., et al. "MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin." JCI insight 2.9 (2017): e93309; reference cited by Applicant). PNG media_image17.png 750 628 media_image17.png Greyscale PNG media_image18.png 736 586 media_image18.png Greyscale PNG media_image19.png 648 600 media_image19.png Greyscale PNG media_image20.png 666 614 media_image20.png Greyscale Heller et al. teaches that the levels of miR-29c, a known regulator of collagen, are reduced in DMD. Heller et al. also teaches that the gastrocnemius muscle was injected with self-complementary AAV.CMV.miR-29c or single stranded AAV.MCK.micro-dystrophin alone or in combination in the mdx/utrn+/– mouse, a DMD mouse model. Treatment of 3-month-old mdx/utrn+/– mice with AAV.miR-29c showed a reduction in collagen and combinatorial gene delivery in 3-month-old mdx/utrn+/– mice further decreased fibrosis [abstract]. Heller et al. also teaches that 5 × 1011 vg of scAAVrh.74.CMV.miR-29c, 5 × 1011 vg of scAAVrh.74.MCK.micro-dystrophin, or both are diluted in saline and delivered intramuscularly [page 10, “Gene delivery” paragraph]. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the synthetic particle of ‘368 wherein the exogenous effector comprises an miRNA and decreases expression of a host gene because application ‘368 taught a synthetic particle comprising a proteinaceous exterior and a genetic element and Heller et al. generated a vector for DMD gene therapy. One of ordinary skill in the art would have made such a modification because it would have amounted to a simple substitution of one known element (polypeptide of ‘368 for the miRNA of Heller et al.) for another to obtain predictable results. This is a provisional nonstatutory double patenting rejection. Response to Arguments Applicant's arguments filed May 22, 2026 have been fully considered but they are not persuasive. Applicant asserts that copending Application No. 17/413,297 does not recite that the exogenous effector comprises an miRNA and decreases expression of a host gene. Applicant further asserts that copending application ‘297 claim 55 recites (in part) that the exogenous effector comprises a polypeptide that is endogenous to neurons or muscle cells thus differentiating the instant application from copending application ‘297. This argument is not found persuasive. Heller et al. teaches that the levels of miR-29c, a known regulator of collagen, are reduced in DMD. Heller et al. also teaches that the gastrocnemius muscle was injected with self-complementary AAV.CMV.miR-29c or single stranded AAV.MCK.micro-dystrophin alone or in combination in the mdx/utrn+/– mouse, a DMD mouse model. Treatment of 3-month-old mdx/utrn+/– mice with AAV.miR-29c showed a reduction in collagen and combinatorial gene delivery in 3-month-old mdx/utrn+/– mice further decreased fibrosis [abstract]. Heller et al. also teaches that 5 × 1011 vg of scAAVrh.74.CMV.miR-29c, 5 × 1011 vg of scAAVrh.74.MCK.micro-dystrophin, or both are diluted in saline and delivered intramuscularly [page 10, “Gene delivery” paragraph]. It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the synthetic particle of '297 wherein the exogenous effector comprises an miRNA and decreases expression of a host gene because application '297 taught a synthetic particle comprising a proteinaceous exterior and a genetic element and Heller et al. generated a vector for DMD gene therapy. One of ordinary skill in the art would have made such a modification because it would have amounted to a simple substitution of one known element for another to obtain predictable results. Applicant asserts that the instant claims are related to synthetic particles; whereas, the claims of U.S. Patent No. 11,166,996 are related to methods of delivering a therapeutic polypeptide or nucleic acid to a subject. Therefore, the instant application and patent ‘996 are directed to different statutory classes of inventions. Applicant points to MPEP 806.05(h) indicating that the process of using as claimed can be practiced with another materially different product. Specifically, the process as claimed in patent ‘996 can be performed with an anellosome comprising a proteinaceous exterior comprising an Anellovirus ORF1 polypeptide and a genetic element encapsulated by the proteinaceous exterior which comprises a promoter operably linked to a heterologous sequence encoding either a therapeutic polypeptide or a nucleic acid. Applicant asserts that the instant claims do not recite that the exogenous effector comprises a therapeutic polypeptide and as such are patentably distinct from the claims of patent ‘996. Applicant further asserts that the restriction requirement of the instant application distinguished between method and compositions generally as separate invention groups; therefore, the instant claims are patentably distinct from the method claims of patent ‘996. These arguments are not found persuasive. MPEP 806.05 pertains to rules used in the restriction of related inventions. The instant application claims priority as follows: PNG media_image21.png 68 466 media_image21.png Greyscale . In application 16/448,589 which was later allowed and became U.S. Patent No. 11,166,996, there was no restriction requirement. Further, application ‘589 only claimed priority to U.S. provisional application 62/778,841, filed on December 12, 2018. Therefore, the instant application and patent ‘996 have two different continuities and the rules applicable to a restriction requirement between applications that are dependent with a “parent-child” relationship do not apply. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached on (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /C.T./ Examiner, Art Unit 1637 /Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637