DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 11/18/2025 in response to the Non-Final Rejection mailed on 05/19/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 24-26, 28-30, 38, 40, 42, 70, and 74 are pending.
4. Claims 42, 70, and 74 stand withdrawn pursuant 37 CFR 1.142(b).
5. Applicant’s remarks filed on 11/18/2025 in response to the Non-Final Rejection mailed on 05/19/2025 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Claim Rejections - 35 USC § 112(b)
6. The rejections of claims 29 and 38 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for indefiniteness are withdrawn in view of applicants’ amendment to the claims.
Claim Rejections - 35 USC § 102
7. The rejection of claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 24-26, 28-31, 38, and 40 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Samulski (WO 2019/246544 A2, priority to 06/22/2018; cited on PTO-892 mailed on 05/19/2025) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendments to the claims.
8. As amended, claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 24-26, and 28-31 are drawn to a method of manufacturing circular nucleic acid vectors containing a transgene, the method comprising: a) contacting a host system with a template, wherein the template comprises at least one flanking cleavage sites and: i) at least one phage origin of replication (ORI); ii) a promoter sequence operatively linked to a transgene; iii) at least one Inverted Terminal Repeat (ITR) flanking both ends of the promoter sequence operatively linked to the transgene, wherein at least one of the flanking ITR is a wild-type ITR, and; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b) wherein each of (i)-(iii) are comprised between at least two flanking cleavage sites, wherein the circular nucleic acid self-anneals.
Claims 38 and 40 are drawn to a method of manufacturing circular nucleic acid vectors containing a transgene, the method comprising: a) transforming a host system with a plasmid template, wherein the plasmid template comprises: i) a phage origin of replication (ORI); ii) a truncated phage ORI; iii) at least one Inverted Terminal Repeat (ITR), and iv) a promoter sequence operatively linked to a transgene, wherein the at least one Inverted Terminal Repeat (ITR) flanking both ends of the promoter sequence operatively linked to the transgene, wherein at least one of the flanking ITR is a wild-type ITR, wherein the plasmid template comprises, in the 5’ to 3’ direction, the sense sequence and the antisense sequence separated by a hairpin sequence that allows for annealing of the sense and anti-sense strain; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid produced, wherein the circular nucleic acid self-anneals.
9. With respect to claim 1, Samulski teach methods for manufacturing circular nucleic acid vectors containing a transgene; the method comprising contacting a host system with a template, wherein the host system contains at least one flanking cleavage site and at least one phage origin of replication (ORI); a promoter sequence operatively linked to a transgene; at least one Inverted Terminal Repeat (TR), wherein at least one of the ITR is a wild type ITR; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b), wherein the circular nucleic acid self-anneals, wherein each of (i)-(iii) are comprised between at least two flanking cleavage sites [see Abstract; paragraphs 0084-0085; 00160; 00277].
With respect to claim 2, Samulski teach the method wherein the template further comprises at least additional cleavage site immediately downstream of the ORI [see paragraphs 0084-0085; 00160].
With respect to claim 4, Samulski teach the method further comprising at least one of the step of cutting at least one cleavage site of the recovered circular nucleic acid, or following recovery, the step of in vitro replication of the circular nucleic acid [see paragraphs 00163, 00277].
With respect to claim 6, Samulski teach the method wherein the template further comprises at least one adapter sequence [see paragraph 00277].
With respect to claim 8, Samulski teach the method wherein the adaptor sequence induces closure of cleaved DNA [see paragraph 00277].
With respect to claim 10, Samulski teach the method wherein the recovered circular nucleic acid is used for delivery of the transgene or for viral vector production [see paragraph 00277].
With respect to claim 12, Samulski teach the method wherein the circular nucleic acid is self-annealed and double-stranded [see paragraph 00277].
With respect to claim 13, Samulski teach the method wherein the nucleic acid vector is single-stranded [see paragraph 00277].
With respect to claim 15, Samulski teach the method wherein the ORI is upstream of the left TR, or wherein the ORI is flanked by the ITRs and upstream of the promoter sequence operably linked to a transgene [see paragraph 00277].
With respect to claim 17, Samulski teach the method wherein the host system is a bacterial packaging cell, a cell-free system, a cell free system containing helper phage particles, and a host cell [see paragraph 00277].
With respect to claim 22, Samulski teach the method wherein the viral vector is an adeno associated virus, a lentivirus, a herpes simplex virus, an adeno virus, or a pox virus [see paragraph 00277].
With respect to claim 24, Samulski teach the method wherein the viral vector is an AAV and has a mutant ITR, wherein the mutant ITR is a Double D mutant ITR [see paragraph 00277].
With respect to claim 25, Samulski teach the method wherein the at least one ITR is a mutant ITR, a synthetic ITR, a wild type ITR, or a non-functional ITR [see paragraph 00277].
With respect to claim 28, Samulski teach the method wherein the at least one ORI is located upstream of the ITR and immediately downstream of the upstream ITR [see paragraph 00277].
With respect to claim 29, Samulski teach the method wherein the at least one phage ORI is selected from the group consisting of: M13 derived ORI, F1 derived ORI, and Fd derived ORI [see paragraph 00277].
With respect to claim 30, Samulski teach the method wherein the template further comprises a second ORI that is truncated that does not initiate replication [see paragraph 00277].
With respect to claim 31, Samulski teach the method wherein the truncated ORI is ORID29 [see paragraph 00277].
With respect to claim 38, Samulski teach a method comprising a) transforming a host system with a plasmid template, wherein the plasmid template comprises: i) a phage origin of replication (ORI); ii) a truncated phage ORI; iii) at least one Inverted Terminal Repeat (TR), and iv) a promoter sequence operatively linked to a transgene, wherein at least one of the ITR is a wild type ITR; wherein the plasmid template comprises, in the 5’ to 3’ direction, the sense sequence and the antisense sequence separated by a hairpin sequence that allows for annealing of the sense and anti-sense strain; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid produced, wherein the circular nucleic acid self-anneals [see Abstract; paragraphs 0084-0085; 00160; 00277].
With respect to claim 40, Samulski teach the method wherein the transgene contains the sense sequences and the anti-sense complement thereof separated by a linker sequence that will permit the sense and anti-sense strands to bind as a double strand [see paragraph 00277]. RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that the ‘544 fails to teach the use of a wild type ITR.
This argument is found to be not persuasive. Samulski et al. explicitly teach wherein the ITR is a wild-type ITR [see p. 84].
10. The rejection of claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 25, and 28-29 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Beach et al. (US Patent Application Publication 2003/0082559 A1; cited on IDS filed on 08/05/2024) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
11. With respect to claim 1, Beach et al. teach a method for manufacturing circular nucleic acid vectors containing a transgene; the method comprising contacting a host system with a template, wherein the host system contains at least one flanking cleavage site and at least one phage origin of replication (ORI); a promoter sequence operatively linked to a transgene; at least one Terminal Repeat (TR) wherein the at least one TR is a wild type ITR, and; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b), wherein the circular nucleic acid self-anneals wherein the template further comprises at least one of a second flanking cleavage site and within the two sites are parts (i)-(iii) [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0171-0172, 0192-0193, 0205, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 2, Beach et al. teach the method wherein the template further comprises at least one additional cleavage site [see paragraphs 0171-0172].
With respect to claim 4, Beach et al. teach the method further comprising at least one step of cutting at least one cleavage site of the recovered circular nucleic acid [see paragraphs 0171-0172; 0180].
With respect to claim 6, Beach et al. teach the method wherein the template further comprises at least one adapter sequence [see paragraph 0130].
With respect to claim 8, Beach et al. teach the method wherein the adaptor sequence induces closure of cleaved DNA [see paragraphs 0130 and 0487].
With respect to claim 10, Beach et al. teach the method wherein the recovered circular nucleic acid is use for delivery of the transgene for recombinant viral vector production [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 12, Beach et al. teach wherein the circular nucleic acid is self-annealed and double stranded [see paragraphs 0014-0018, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 13, Beach et al. teach the method wherein the nucleic acid vector is single stranded [see paragraphs 0014-0018, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 15, Beach et al. teach the method wherein the ORI is upstream of the left TR, or wherein the ORI is flanked by the TRs and upstream of the promoter sequence operably linked to a transgene [see paragraphs 0014-0018, 0112, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 17, Beach et al. teach the method wherein the host system is a host cell [see paragraph 0112].
With respect to claim 22, Beach et al. teach the method wherein the viral vector is an adeno associated virus and lentivirus [see paragraphs 0135, 0198].
With respect to claim 25, Beach et al. teach the method wherein the at least one TR is a wild type ITR [see paragraph 0205].
With respect to claim 28, Beach et al. teach the method wherein the ORI is located upstream of the ITR and immediately downstream of the upstream ITR [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
With respect to claim 29, Beach et al. teach the method wherein the at least one phage ORI is F1 [see paragraphs 0192-0193; 0505].
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants in summary contend that there are substantial differences between lentivirus and AAV vectors and one skill in the art would not readily have any motivation to swap an ITR for an LTR based on the teachings of Beach et al.
This argument is found to be not persuasive because it is noted that the features upon which applicant relies (i.e., lentivirus and AAV) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Nevertheless, Beach et al. teach AAV vectors containing at least one flanking cleavage site and at least one phage origin of replication (ORI); a promoter sequence operatively linked to a transgene; at least one Terminal Repeat (TR) wherein the at least one TR is a wild type ITR, and; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b), wherein the circular nucleic acid self-anneals wherein the template further comprises at least one of a second flanking cleavage site and within the two sites are parts (i)-(iii) [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0171-0172, 0192-0193, 0205, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523].
Claim Rejections - 35 USC § 103
12. The rejection of claims 24, 26, 38 and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Beach et al. (US Patent Application Publication 2003/0082559 A1; cited on IDS filed on 08/05/2024) in view of Samulski et al. (US Patent No. 5,478,745, 1995; cited on PTO-892 mailed on 05/19/2025) is maintained for the reasons of record and the reasons set forth below.
13. The relevant teachings of Beach et al. as applied to claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 25, and 28-29 are set forth in the 102(a)(1) rejection above.
With respect to claims 24, 26, 38, and 40, Beach et al. teach a method for manufacturing circular nucleic acid vectors containing a transgene; the method comprising contacting a host system with a template, wherein the host system contains at least one flanking cleavage site and at least one phage origin of replication (ORI); at least one Terminal Repeat (TR) wherein the at least one TR is a wild type ITR, b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b), wherein the circular nucleic acid self-anneals [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523]. Beach et al. teach viral AAV constructs comprising sense and antisense sequences separated by nucleotide polylinkers [see paragraphs 0095, 0227, 0255].
However, Beach et al. does not teach the method of claim 24, wherein the vector has a mutant ITR that is a Double D mutant ITR; the method of claim 26, wherein the nucleic acid vector has flanking DD-ITRs, and in between the flanking DD-ITRs is a promoter operatively linked to a sense strand of a transgene, a replication defective ITR, and an antisense complement of the transgene and the method of claim 38, the sense sequence and the anti-sense sequence separated by a hairpin sequence.
Samulski et al. teach a novel fragment of DNA which contains double-D mutant ITR sequences from AAV that can be synthesized in vivo or in vitro and used to engineer expression vectors and vectors for gene therapy [see column 2, lines 15-20]. Samulski et al. teach that the double-D sequence provides sufficient information in cis, for converting a circular duplex DNA molecule into a linear replicating molecule with covalently closed ends that provides a convenient and efficient means for transfer of genetic information into any cell or tissue of choice [see column 2, lines 21-35]. Samulski et al. teach that the viral ITR forms a hairpin structure and self primes the elongation process to produce a long T shaped hairpin structure containing D and D’ on the stem [see column 5].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to combine the teachings of Beach et al. and Samulski et al. to use the double-D mutant ITR of Samulski et al. in the circular vectors of Beach et al. because Beach et al. teach circular nucleic acid vectors built around phage origins of replication for the production and expression of transgenes. Samulski et al. teach that DNA containing a double-D mutant ITR sequences from AAV that can be synthesized in vivo or in vitro and used to engineer expression vectors and vectors for gene therapy and provides a convenient and efficient means for transfer of genetic information into any cell or tissue of choice. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability, and would have been motivated to combine the teachings of Beach et al. and Samulski et al. because Samulski et al. acknowledges that DNA containing a double-D mutant ITR sequences from AAV provides a convenient and efficient means for transfer of genetic information into any cell or tissue of choice. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 9 of applicants’ remarks, applicants contend that the references fail to provide teachings or suggestions to modify lentiviral systems to arrive at the amended claims and the Samulski reference fails to remedy the deficiency.
This argument is found to be not persuasive for the reasons set forth above regarding Beach et al.
14. The rejection of claims 30-31 under 35 U.S.C. 103 as being unpatentable over Beach et al. (US Patent Application Publication 2003/0082559 A1; cited on IDS filed on 08/05/2024) in view of Specthrie et al. (Journal of Molecular Biology, 1992; cited on PTO-892 mailed on 05/19/2025) is maintained for the reasons of record and the reasons set forth below.
15. The relevant teachings of Beach et al. as applied to claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 25, and 28-29 are set forth in the 102(a)(1) rejection above.
With respect to claims 30-31, Beach et al. teach a method for manufacturing circular nucleic acid vectors containing a transgene; the method comprising contacting a host system with a template, wherein the host system contains at least one flanking cleavage site and at least one phage origin of replication (ORI); at least one Terminal Repeat (TR), and a promoter sequence operatively linked to a transgene; b) incubating the host system for a time sufficient for replication to occur resulting in circular nucleic acid production; and c) recovering the circular nucleic acid vectors produced in b), wherein the circular nucleic acid self-anneals [see Abstract; Figures 1-23; paragraphs 0014-0015, 0138, 0148, 0192-0193, 0215-0220, 0228, 0233, 0246, 0252, 0255, 0264, 0273, 0505, 0511 and 0522-0523]. Beach et al. teach viral AAV constructs comprising sense and antisense sequences separated by nucleotide polylinkers [see paragraphs 0095, 0227, 0255]. Beach et al. teach the method wherein the at least one phage ORI is F1 [see paragraphs 0192-0193; 0505].
However, Beach et al. does not teach the method of claims 30-31, wherein the template further comprises a truncated ORI that does not initiate replication and wherein the truncated ORI is ORID29.
Specthrie et al. teach the intergenic region in the genome of f1, Fd and M13 phages has essential functions in DNA replication and phage morphogenesis, and teach that the functional domains of this region including the origin of replication may be inserted into separate sites of a plasmid to function independently [see Abstract]. Specthrie et al. teach that truncation of the first 29 nucleotides of the ORI eliminates viral plus strand initiation but retains its function as a terminator [see p. 722, figure 1].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Beach et al. and Specthrie et al. to include a truncated ORI in the nucleic acid vectors of Beach et al. because Beach et al. teach circular nucleic acid vectors designed around a phage origin of replication for expression of transgenes. Specthrie et al. teach that the functional domains of the genome of f1, Fd and M13 phages can be inserted in separate sites of a plasmid to function independently and that truncation of the ORI eliminates strand initiation but retains its function as a terminator. One of ordinary skill in the art desiring to use a phage origin or replication for the design of expression vectors would have a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Beach et al. and Specthrie et al. because Specthrie et al. acknowledges that truncation of ORI eliminates strand initiation but retains its function as a terminator, and one of ordinary skill in the art would desire to include a terminator function in order to regulate and control expression and replication of the transgene. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: The examiner has reviewed the remarks filed on 11/18/2025 and found no traversal of the rejection over claims 30 and 31.
Accordingly, the rejection is maintained for the reasons already of record.
Conclusion
16. Status of the claims:
Claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 24-26, 28-30, 38, 40, 42, 70, and 74 are pending.
Claims 42, 70, and 74 stand withdrawn pursuant 37 CFR 1.142(b).
Claims 1-2, 4, 6, 8, 10, 12-13, 15, 17, 22, 24-26, 28-30, 38, and 40 are rejected.
No claims are in condition for an allowance.
THIS ACTION IS MADE FINAL. 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 PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656