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 October 2, 2025 are acknowledged.
Claims 1-56, 58, 61, 68, 69, and 73 have been canceled. Claims 57, 59, 60, 62, and 77 were amended. Claims 57, 59, 60, 62-67, 70-72, and 74-78 are pending. Claims 70-72 and 74-76 are withdrawn.
Claims 57, 59, 60, 62-67, 77, and 78 are examined on the merits herein.
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Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b), 35 U.S.C 112(d), and 35 U.S.C 101 rejections are withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on October 2, 2025 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 June 11, 2021.
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers
must be preceded by the abbreviation "FIG."”. In the current case, the view numbers for Figures 1A, 1B, 2-5, 6A, 6B, 7A, 7B, 8A, 8B, 9A, 9B, 10A, 10B, 11A, 11B, 11C, 12, 13, 14, 15, 16A, and 16B are preceded by the word "Figure" instead of the abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology ("e.g." stands for "exempli gratia", and should be removed or replaced with a non-Latin version, such as "for example"). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112
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.
Claim 65 is 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.
Claim 65 recites in part the synthetic particle of claim 57 wherein (vi) the intracellular polypeptide or intracellular nucleic acid comprises an IDH1 inhibitor, an IDH2 inhibitor, an EGFR inhibitor, an LRP5 inhibitor, a DKK2 inhibitor, a DPP-4 inhibitor, a KRAS inhibitor, a neutrophil elastase inhibitor, a FGFR3 activator, or a HTT activator. The claim is drawn to the genus of IDH1, IDH2, EGFR, LRP5, DKK2, DPP-4, KRAS, and neutrophil elastase inhibitors and genus of FGFR3 and HTT activators and as instantly presented encompasses any inhibitor from those inhibitors recited and any activator from those activators recited without limitation on the structure of the inhibitor or activator.
Applicant is referred to MPEP 2163(II)(A)(3)(a)(i and ii), which indicates that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
The instant specification does not provide the structural requirements of the inhibitor and/or activator that are required for the inhibitor and/or activator to be able to organize into a proteinaceous exterior around a genetic element. The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of inhibitors and/or activators which must function to provide a proteinaceous exterior around a genetic element.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claim 65.
Response to Arguments
Applicant's arguments filed October 2, 2025 have been fully considered but they are not persuasive.
In view of Applicant’s amendments and response, the 35 U.S.C 112(a) written description rejection in reference to claim 57 and its dependents are withdrawn. However, Applicant asserts that the instant specification provides extensive disclosure of effectors, including inhibitors and activators thus providing sufficient written description in the specification. Applicant refers to page 338, line 8 to page 351, line 24; however, the specification filed on March 10, 2025 does not have line numbers. Nonetheless, the instant specification does not provide the structural requirements of the inhibitor and/or activator that are required for the inhibitor and/or activator to be able to organize into a proteinaceous exterior around a genetic element. Therefore, the Examiner is maintaining the 35 U.S.C 112(a) written description rejection in reference to claim 65.
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, 62-67, 77, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Leary et al. (US 6,395,472; reference cited by Applicant), Wang et al. (Molecular Genetics and Metabolism 2012), Bostan et al. (J. Vaccines Vaccin 2013; reference cited by Applicant), Peng et al. (Archives of Virology 2002), Galmes et al. (Eur Respir J 2013; reference cited by Applicant), and GenBank Accession No. JX134045 (2013) as evidenced by Modha et al. (Virus Evolution 2025).
Regarding claims 57, 59, 60, 62-67, 77, and 78, 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]. 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 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 is an intracellular polypeptide or an intracellular nucleic acid, 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. 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. Leary et al. does not teach that the ORF1 molecule comprises the sequence of SEQ ID NO: 58. 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. Leary et al. also does not teach a pharmaceutical composition comprising at least 103, 104, 105, 106, 107, 108, or 109 synthetic particles and a pharmaceutically acceptable carrier or excipient.
Wang et al. teaches that ornithine transcarbamylase deficiency (OTCD), the most common and severe urea cycle disorder, is an excellent model for developing liver-directed gene therapy. Wang et al. generated a vector for a proposed OTC gene therapy trial in humans based on a self-complementary AAV8 vector expressing codon-optimized human OTC under the control of a liver-specific promoter. Functional expression of hOTC in 40% of liver areas was found in mice treated with a low vector dose of 1 x 109 GC. Furthermore, the vector has the potential to achieve therapeutic effects in OTCD patients [abstract].
Bostan et al. teaches the structure and genomic organization of TTV as shown below.
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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 promoter element and a nucleic acid sequence encoding an exogenous effector wherein the nucleic acid sequence is operably linked to the promoter element and wherein the exogenous effector is an intracellular polypeptide or an intracellular nucleic acid, and (II) a proteinaceous exterior comprising an Anellovirus ORF1 molecule, wherein the genetic element is enclosed within the proteinaceous exterior, because Wang et al. generated a vector for ornithine transcarbamylase deficiency 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 1.0 x 109 GC (genome copy) of engineered TTV-based or TTMV-based virions for treating a subject with ornithine transcarbamylase deficiency.
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.
Response to Arguments
Applicant's arguments filed October 2, 2025 have been fully considered but they are not persuasive.
Applicant provides the following assertions:
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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 is an intracellular polypeptide or an intracellular nucleic acid, 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 Wang 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, Wang et al. was cited because it teaches ornithine transcarbamylase which is an intracellular polypeptide. 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:
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It is noted that an opinion has been made; however, no evidentiary support has been provided for the opinion. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP 2145(I) and 716.01(c)(II). Nonetheless, before the effective filing date of the instant application, Bostan et al. already reviewed the structure and genomic organization of TTV [Figure 1] and disclosed that ORF1 encodes a capsid protein and contains hyper variable regions [page 2, left column, last paragraph]. 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, right column, first paragraph].
Applicant provides the following assertions:
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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). 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. Wang et al. teaches ornithine transcarbamylase which is an intracellular polypeptide. 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. One of ordinary skill in the art would have been motivated to construct a TTV-based or TTMV-based vector based on the teachings of Leary et al., Wang et al., Bostan et al., Galmes et al., and GenBank Accession No. JX134045 with a reasonable expectation of success because it would have amounted to combining prior art elements according to known methods to yield predictable results.
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, and 66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 97-100 and 102 of copending Application No. 17/413,392 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims overlap in scope.
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57, 59, 60, and 62-67 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). 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.
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57, 59, 60, and 62-67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-58, 60-67 and 71 of copending Application No. 17/413,207 (reference application). 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.
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 57, 59, 60, and 62-67 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.
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Response to Arguments
Applicant's arguments filed October 2, 2025 have been fully considered but they are not persuasive.
Applicant requests that the nonstatutory double patenting rejections be held in abeyance until the outstanding rejections are overcome, and if appropriate, Applicant will consider the filing of terminal disclaimers. Thus, the nonstatutory double patenting rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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
/CELINE X QIAN/Primary Examiner, Art Unit 1637
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