DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional Application 63/341201, filed on 05/12/2022.
Information Disclosure Statement
The IDS filed 05/31/2023 and 07/11/2023 has been considered by the Examiner.
Status of Claims
Claims 1-20 are under examination.
Claim Objections
Objection to Claim 6 has been withdrawn in response to applicants amendments in the reply filed 11/26/2025.
Objections maintained:
Claims 3, 5, 7-8, 12-14, and 16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Rejections maintained:
Claims 1-2, 4, 6, 9-11, 15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Clark et al. (US 11,779,655 B2) in view of Huang (US 2013/0095558 A1) as evidenced by Gattoni et al. (JMB, 1986).
Regarding claim 1, Clark et al. teach polynucleotide expression from an AAV expression vector (cover page, abstract). (1) Clark et al. teach an Ad2 Region E4 which may encode E4 ORF1, E4 ORF2, E4 ORF3, E4 ORF4, E4 ORF6, and/or E4 ORF6/7 (column 7, lines 6-9). Clark et al. teach an embodiment where the Ad2 E4 region may comprise the nucleic acid sequence of SEQ ID NO: 3030, which does not include intron 1 (SEQ ID NO:1 of the present application) or 2 (SEQ ID NO:2 of the present application) of E4 ORF6/7 (column 27, lines). (3) Clark et al. teach the expression construct includes an adenovirus VA RNA encoding VAI RNA and VAII (column 6-7, lines 64-67&1-10). (4) Clark et al. teach Adeno-associated virus (AAV) which is a member of the Parvovirus family (column 38, lines 12-13). Clark et al. teach fragments of AAV may be readily utilized in a variety of vector systems (column 38, lines 34-35). Clark et al. further teach the AAV components the El , E2A, E4 and/or VA RNA region sequences from an Adenovirus (column 6, lines 43-45). (5) Clark et al. teach production of a recombinant adeno-associated virus (rAAV) vector (column 38, lines 5-7). (5.1) Clark et al. teach an expression cassette, wherein the expression cassette comprises a promoter active in target cells, operably linked to a polynucleotide (column 7, lines 10-20). (5.2) Clark et al. further teach the expression cassette includes both a 5’ AAV ITR and a 3' ITR (column 3, lines 4-9). Clark et al. teach a modified adenovirus where the adenovirus helper genes comprise the VA RNA region, E2 region, and E4 region (column 23, lines 20-30). (6) Clark et al. teach the expression cassette, vector, plasmid and virus described herein contain other appropriate transcription initiation, termination, enhancer sequences (column 43, lines 64-66). Clark et al. teach the rAAV expression cassette, the virus, the vector and/or the production plasmid further comprise post-transcriptional regulatory elements (column 42, lines 41-55). Clark et al. teach the required helper functions (adenovirus E1, E2a, VA and E4) are supplied in trans by the system. Clark et al. further teach regulation of the helper function expression can be controlled at the transcriptional or posttranscriptional level (column 41, lines 20-30). Clark et al. teach promoters for driving expression which include p5. Clark et al. further teach the rAAV vector genome may comprise a woodchuck post-transcriptional regulatory element (WPRE) or may comprises a modified WPRE (column 19, lines 13-15).
Clark et al. further do not teach a modified adenovirus E2a coding region that encodes a modified E2a protein.
Huang teaches a production process for recombinant human adenovirus in order to optimize the procedure for small batch and mass industrialization (cover page, abstract). (2) Huang further teaches a second-generation adenovirus vector in which the E2A gene was modified to introduce a temperature-sensitive mutation in order to reduce vector immunogenicity. Huang teaches an improved adenovirus vector that can produce high titer recombinant adenovirus and increase expression of biologically active human endostatin in a variety of cells (page 2, paragraph 0032).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Clark et al. for a polynucleotide AAV expression vector with the teachings of Huang for the modified E2A gene. Huang provides motivation by teaching that the temperature-sensitive mutation reduces vector immunogenicity. Huang further provides motivation by teaching a vector that can produce high titer recombinant adenovirus in a variety of cells. One of skill in the art would have had a reasonable expectation of success at combining Clark et al. and Huang because they both teach production of recombinant adenoviral vectors utilized for cell treatment.
Regarding claim 2, Clark et al. and Huang et al. teach an expression construct as described above in regard to claim 1. Clark et al. teach an embodiment where the Ad2 E4 region may comprise the nucleic acid sequence of SEQ ID NO: 3030, which does not include intron 1 (SEQ ID NO:1 of the present application) or 2 (SEQ ID NO:2 of the present application) of E4 ORF6/7 (column 27, lines).
Regarding claim 4, Clark et al. teach various deletions in the generation of the expression construct including deletion of introns of the Ad2 E4 region as evidenced above in regard to claim 2. Furthermore, it is well known in the art that introns can be excised and therefore would be obvious to try. It is known that intron 1 is excised as a whole early and intron 2 is also excised as a whole during infection as evidenced by Gattoni et al.(abstract). It would have been obvious to try modifying or removing introns of E2A to replicate viral action.
Regarding claim 6, Clark et al. and Huang teach an expression construct as described above in regard to claim 1. Clark et al. teach the recombinant parvovirus is an rAAV (column 2, lines 44-54). Clark et al. teach parvovirus protein coding region comprises an AAV Rep coding region encoding a AAV Rep protein and an AAV Cap coding region encoding an AAV Cap protein (column 2, lines 3-12).
Regarding claim 9, Clark et al. and Huang teach the rAAV vector. Clark et al further teach the rAAV vector genome with a size between about 3 kilo bases (kb) to about 6 kb, about 4.7 kb to about 5 kb, about 3 kb to about 5.5 kb, or about 4.7 kb to 5.5 kb (column 42, lines 25-29), which reads on having a size of less than 20 kilobases.
Regarding claim 10, Clark et al. and Huang teach adeno-associated virus (AAV) constructs. Clark et al. teach a method for producing the improved recombinant AAV (rAAV) vectors through co-transfection. Clark et al. teach the co-transfection includes a plasmid containing the rAAV vector genome, encoding a gene and a second plasmid encoding the AAV Rep and Cap protein ("Rep/Cap plasmid"), and one or more virus helper plasmids. Clark et al. teach cells and compositions containing these AAV constructs which may be collected for use in a treatment (column 3, lines 3-16).
Regarding claim 11, Clark et al. teach a polynucleotide expression construct for production of a recombinant parvovirus (cover page column 2, abstract& lines 44-54). (a) Clark et al. teach the Ad2 Region E4 may or may not include E4 ORF6/7 (column 7, lines 7-10). (ii) Clark et al. teach an embodiment where the Ad2 E4 region may comprise the nucleic acid sequence of SEQ ID NO: 3030, which does not include intron 1 (SEQ ID NO:1 of the present application) or 2 (SEQ ID NO:2 of the present application) of the E4 ORF6/7 (column 27, lines). (c) Clark et al. teach the expression construct includes an adenovirus VA RNA encoding VAI RNA and VAII (column 6-7, lines 64-67&1-10). Clark et al. teach a recombinant adeno-associated virus (rAAV) vector (column 38, lines 34-35). Clark et al. teach a modified adenovirus and the adenovirus helper genes which comprise the VA RNA region, E2 region, and E4 region (column 26, lines 9-14). (d) Clark et al. teach the expression cassette, vector, plasmid and virus described herein contain other appropriate transcription initiation, termination, enhancer sequences (column 43, lines 64-66). Clark et al. teach the rAAV expression cassette, the virus, the vector and/or the production plasmid further comprise post-transcriptional regulatory elements (column 42, lines 41-55). Clark et al. further teach the expression cassette comprises a promoter active in target cells, operably linked to a polynucleotide (column 7, lines 10-20). Clark et al. teach the required helper functions (adenovirus E1, E2a, VA and E4) are supplied in trans by the system (column 41, lines 20-30). Clark et al. further teach regulation of the helper function expression can be controlled at the transcriptional or posttranscriptional level (column 41, lines 20-30). Clark et al. teach promoters for driving expression which include p5. Clark et al. teach the rAAV vector genome may comprise a woodchuck post-transcriptional regulatory element (WPRE) (column 19, lines 13-15).
Clark et al. further do not teach a modified adenovirus E2a coding region that encodes a modified E2a protein.
Huang teaches a production process for a recombinant human adenovirus in order to optimize the procedure for small batch and mass industrialization (cover page, abstract). (b) Huang further teaches a second-generation adenovirus vector in which the E2A gene was modified to introduce a temperature-sensitive mutation in order to reduce vector immunogenicity. Huang teaches an improved adenovirus vector that can produce high titer recombinant adenovirus and increase expression of a gene of interest in a variety of cells (page 2, paragraph 0032).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Clark et al. for a polynucleotide AAV expression vector with the teachings of Huang for the modified E2A gene. Clark et al. provide motivation by teaching that a temperature-sensitive mutation can reduce vector immunogenicity. Huang further provides motivation by teaching a vector that can produce high titer recombinant adenovirus in a variety of cells. One of skill in the art would have had a reasonable expectation of success at combining Clark et al. and Huang because they both teach production of recombinant adenoviral vectors utilized for cell treatment.
Regarding claim 15, Clark et al. and Huang teach an expression construct described above in regard to claim 11. Clark et al. teach the expression construct comprises an AAV Rep coding region and an AAV cap coding region (column 23, lines 20-30).
Regarding claim 17, Clark et al. and Huang teach an expression construct as described above in regard to claim 11. Clark et al. teach an adenovirus-associated viral vector (AAV) which encompasses recombinant viral particles comprising a recombinant vector genome encoding a gene of interest (column 11, lines 40-45). Clark et al. teach an expression cassette, wherein the expression cassette comprises a promoter active in target cells, operably linked to a polynucleotide and both a 5’ AAV ITR and a 3' ITR (page 83, claim 1).
Regarding claim 18, Clark et al. and Huang teach an expression construct as described above in regard to claim 11. Clark et al. teach the coding sequences for the replication (rep) and/or capsid (cap) are removed from the AAV genome and supplied in trans (column 40, lines 53-59). Clark et al. teach a packaging cell line to generate the AAV vector (column 40, lines 53-60). Clark et al. teach methods for generating and isolating AAV viral vectors suitable for delivery to a subject are known in the art (column 40, lines 53-67). Clark et al. teach the producer cell line is transiently transfected with a construct that encodes the transgene flanked by ITRs and a plasmid that encodes rep and cap (column 40, lines 56-67).
Regarding claim 19, Clark et al. teach a suitable for delivery to a subject are known in the art. Clark et al. teach a method for producing a recombinant AAV (column 31, lines 22-25). Clark et al. teach culturing the host cell harboring the expression construct (cis plasmid) and an AAV rep/cap plasmid (trans plasmid) prior to harvesting the recombinant AAV particles (column 58, Example 6). Clark et al teach introducing an expression construct as described above in regard to claim 15 and a plasmid encoding an AAV Rep protein and an AAV Cap protein into a host cell (column 40, lines 41-67). Clark et al. teach culturing the host cell harboring the expression construct and AAV rep/cap plasmid prior to harvesting the recombinant AAV particles (column 58, Example 6).
Regarding claim 20, Clark et al. and Huang teach a method for producing a recombinant AAV (column 31, lines 22-25). Clark et al teach introducing an expression construct as described above in regard to claim 17 and a plasmid encoding an AAV Rep protein and an AAV Cap protein into a host cell (column 40, lines 41-67). Clark et al. teach culturing the host cell harboring the expression construct and AAV rep/cap plasmid prior to harvesting the recombinant AAV particles (column 58, Example 6).
Response to Arguments
Applicant's arguments filed 11/26/2025 have been fully considered but they are not persuasive.
Applicant argument: Clark does not teach or suggest a single polynucleotide expression construct comprising all components of claim 1 of the present application.
Examiner’s response: Clark teaches expression constructs which may contain various features. Clark teaches various embodiments which can be one vector or multiple vectors. Clark further teaches the nucleic acid molecules, the expression cassette and vectors described may be delivered in a single composition (column 17, lines 16-20). Clark teaches the isolated polynucleotide, rAAV vector can be delivered in a single dose (column 31, lines 19-21).
Applicant’s argument: Applicants argue (page 9, par. 2-3) that Huang fails to cure the deficiencies of Clark because Huang generally mentions production of recombinant human adenovirus using a vector comprising E2a gene modified to introduce a temperature-sensitive mutation and is cited for its teaching a modified E2a gene in a single polynucleotide expression construct.
Examiner’s response: Huang further teaches a second-generation adenovirus vector in which the E2A gene was modified to introduce a temperature-sensitive mutation in order to reduce vector immunogenicity. While Huang independently does not teach all of the features of the vector, the combination of Huang and Clark et al. It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Clark et al. for a polynucleotide AAV expression vector with the teachings of Huang for the modified E2A gene. The combination of Clark et al. and Huang make obvious the invention of the present application. Huang et al. provide motivation to combine by teaching that the vector will have improved safety and higher titer in cells. The improved safety of decreasing immunogenicity while simultaneously increasing the vector introduced to cells, are both desirable improvements to the vector of Clark et al. The improvements of the vector taught by Huang would make the combination of the vector of Clark et al. with the with the teachings of Huang for the modified E2A gene an obvious modification.
Conclusion
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.
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635