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 .
Claims Status
Claims 1-18 are pending and have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 12/16/2025 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 07/16/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
Claim Objections
Claims 4, 7, 13, 16 are objected to because of the following informalities: the claims recite “adenovirallate genes”. If the claims were amended to recite “adenoviral late genes” the objection would be overcome.
Claim Rejections - 35 USC § 103 (new)
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.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Brennan et al (US 9719107 B2; cited previously) in view of Wang et al (J of Cellular Physiology(2008)219:1-7; cited previously).
Regarding claim 1: The claim recites a method comprising three steps; 1) providing a cell line, 2) transfecting a fully deleted adenoviral vector module comprising both ITRs, a packaging signal and a DNA insert encoding a gene of interest, 3) transfecting a replication defective circular packaging expression plasmid, and 4) transfecting RNA fragments anti-sense of the gene of interest on the fully deleted adenoviral vector module.
Brennan teach a method that comprises the steps of the method of the instant claim 1. Brennan teach providing an adenovirus packaging cell line, transfecting a fully-deleted adenoviral construct into the cell line, and transfecting a packaging construct into the cell line (p18 col 6 ln43-53).
Brennan further teach the fully-deleted Adenoviral gene transfer vector construct includes both adenoviral inverted terminal repeats, the packaging signal, and at least one DNA insert encoding a protein of interest, but no adenoviral structural genes (claim 6). This reads on step 2) of the instant claim. Brennan also teach gene therapy generally involves the introduction into cells of therapeutic genes, known as transgenes (gene of interest), whose expression results in amelioration or treatment of genetic disorders, and that therapeutic genes involved bay be those that encode proteins, structural or enzymatic RNAs, inhibitory products such as antisense RNA or DNA, or any other gene product (p31 ln 48-60). Brennan also teach the vector can deliver genes encoding angiogenesis inhibitors or cell cycle inhibitors (p22 col35 ln 7-15).
Brennan teach the replication defective circular packaging construct has a subset of adenoviral late genes L1, L2, L3, L4, L5 and E4, while being absent of at least one inverted terminal repeat. This reads on the packaging plasmid of step 3) which requires a single inverted ITR.
Brennan do not teach the packaging construct of step 3) comprises one or more expression cassettes that code for an anti-sense construct or anti-sense constructs of the gene sequence encoding the protein of interest or proteins of interest.
Wang teach toxic transgene expression makes it difficult to generate adenoviral vectors in a packaging cell line (p1 para 1). Wang teach adenoviral vector particle yield is increased when transgene expression is silenced by shRNA (an anti-sense construct of the gene sequence encoding a protein of interest) and that this strategy can reduce the time and cost of producing adenoviral vectors for clinical use (abstract).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to modify the adenoviral packaging system taught by Brennan with the disclosure of Wang, to reduce overexpression of a cytotoxic transgene by post-transcriptional silencing of the cytotoxic transgene, as taught by Wang. Wang teach transgene (hlcon) expression is reduced by 80% with co-transfection of producer cell with shRNA plasmid and a plasmid express the transgene (p3 col2 ¶4). Wang further teach transfecting an increased amount of shRNA plasmid into the packaging cell line should enhance the capacity of the shRNA to silence the targeted gene (p6 col2 ¶3).
One would have been motivated to modify the method of Brennan drawn to a method for propagating a fully deleted adenoviral gene transfer vector by transfecting a fully deleted adenoviral vector module and transfecting a replication defective circular packaging expression plasmid by incorporating an expression cassette that codes for an anti-sense construct of the protein of interest as taught by Wang because Wang teach that incorporating a gene expression cassette comprising an shRNA construct that targets the transgene in a packaging cell improves viral particle yield 8.6-13.1 fold (p369, col1 ¶2).
It would further have been obvious to incorporate the expression cassette that codes for the anti-sense construct of the protein of interest in the packaging expression plasmid as taught by Brennan because the method of Brennan comprises two options for introducing an expression cassette that codes for an anti-sense construct- either 1) the fully deleted adenoviral vector module or 2) the packaging expression plasmid. Modifying the fully deleted adenoviral vector module by incorporating an expression cassette that codes for an anti-sense construct would cause the anti-sense construct to be included in the viral particle genome and thus transgene expression would be reduced in packaging cells and in virally transduced cells. Modifying the packaging expression plasmid of Brennan by incorporating an expression cassette that codes for an anti-sense construct would cause the desired effect of reducing transgene expression in the packaging cells while not effecting the ability of the viral particles to induce transgene expression in transduced cells, and thus incorporating the expression cassette comprising the anti-sense construct into the packaging plasmid of Brennan would be the obvious choice.
One would have had a reasonable expectation of success because the inventions are drawn to the generation of viral particles comprising a transgene by expression of a viral vector and a packaging plasmid in mammalian packaging cell lines and modification of a packaging expression plasmid would require molecular biology methods that are well known in the art and thus would have a reasonable expectation of success.
Regarding claim 4: The claim comprises the active steps of as recited in claim 1, and further requires the step of transfecting RNA fragments anti-sense of the gene of interest on the fully deleted adenoviral vector module.
The teachings of Brannon and Wang are discussed above. Regarding transfecting RNA fragments anti-sense of the gene of interest: suppression of the gene of interest as taught by Wang requires the shRNA sequence to be encoded in an expression cassette. This reads on transfecting RNA fragments anti-sense of the gene of interest because transcription of the coding sequence for the shRNA produces the shRNA which comprises RNA fragments anti-sense of the gene of interest.
Regarding claim 7: The claim comprises the active steps of as recited in claim 1, and further requires the step of transfecting DNA fragments anti-sense of the gene of interest on the fully deleted adenoviral vector module.
The teachings of Brannon and Wang are discussed above. Regarding transfecting DNA fragments anti-sense of the gene of interest: suppression of the gene of interest as taught by Wang requires the shRNA sequence to be encoded in an expression cassette. This reads on transfecting DNA fragments anti-sense of the gene of interest because of the coding sequence for the shRNA comprises two strands of DNA and one will be anti-sense to the gene of interest.
Regarding claims 2, 5, and 8: The teachings of Brennan and Wang are described supra.
Brennan teach a system comprising an adenovirus packaging cell line, a fully-deleted adenoviral vector construct, and a packaging construct wherein the encapsidated fully-deleted adenoviral gene transfer vector is absent of adenoviral structural genes (claim 6). An adenoviral helper virus is absent from the system disclosed by Brennan and thus and therefore reads on the instant claims.
Regarding Claim 3, 6 and 9: The teachings of Brannon and Wang are discussed supra.
Wang teach that the transgene of the packaging cell can interfere with the packaging cell metabolism and cell growth by exhausting nutrient (p7 col1 ¶1) and that the yield of adenoviral vectors can be increased at least 10-fold by using a cell line which encodes an shRNA silencing the transgene (p7 col1 ¶2).
Because silencing of the transgene hlcon increased the adenoviral vector yield 8.6-13.1 fold (p5 col1 ¶3), the expression of the transgene is considered detrimental to the cell. The purpose of the producer cell is to produce adenoviral vectors, and thus a condition that results in a reduced yield is considered detrimental.
Regarding claims 10, 13 and 16: The claims require transducing an encapsidated fully deleted adenoviral vector. This is interpreted as a method of use (transduction) of the fully deleted adenoviral based gene therapy vector generated by the method of claim 1.
The teachings of Brennan and Wang are discussed supra. As discussed supra, Brannan teach providing an adenovirus packaging cell line, transfecting a fully-deleted adenoviral vector construct into the cell line, and transfecting a packaging construct into the cell line, resulting in the encapsidation of a fully-deleted adenoviral vector independent of helper adenovirus (abstract). Brennan further teach a target cell can be transduced with the encapsidated fully-deleted adenoviral vector (abstract).
As discussed supra, Brennan also teach a method that comprises the steps of the method of the instant claim 1. Brennan teach providing an adenovirus packaging cell line, and transfecting a packaging construct into the cell line (p18 col 6 ln43-53).
Brennan teach the fully-deleted Adenoviral gene transfer vector construct includes both adenoviral inverted terminal repeats, the packaging signal, and at least one DNA insert encoding a protein of interest, but no adenoviral structural genes (claim 6). This reads on step 2) of the instant claim. Brennan also teach gene therapy generally involves the introduction into cells of therapeutic genes, known as transgenes (gene of interest), whose expression results in amelioration or treatment of genetic disorders, and that therapeutic genes involved bay be those that encode proteins, structural or enzymatic RNAs, inhibitory products such as antisense RNA or DNA, or any other gene product (p31 ln 48-60). Brennan also teach the vector can deliver genes encoding angiogenesis inhibitors or cell cycle inhibitors (p22 col35 ln 7-15).
Brennan teach the replication defective circular packaging construct has a subset of adenoviral late genes L1, L2, L3, L4, L5 and E4, while being absent of at least one inverted terminal repeat. This reads on the packaging plasmid of step 3) which requires a single inverted ITR.
Brennan do not teach the packaging construct of step 3) comprises one or more expression cassettes that code for an anti-sense construct or anti-sense constructs of the gene sequence encoding the protein of interest or proteins of interest.
Wang teach toxic transgene expression makes it difficult to generate adenoviral vectors in a packaging cell line (p1 para 1). Wang teach adenoviral vector particle yield is increased when transgene expression is silenced by shRNA (an anti-sense construct of the gene sequence encoding a protein of interest) and that this strategy can reduce the time and cost of producing adenoviral vectors for clinical use (abstract).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to modify the adenoviral packaging system taught by Brennan with the disclosure of Wang, to reduce overexpression of a cytotoxic transgene by post-transcriptional silencing of the cytotoxic transgene, as taught by Wang. Wang teach transgene (hlcon) expression is reduced by 80% with co-transfection of producer cell with shRNA plasmid and a plasmid express the transgene (p3 col2 ¶4). Wang further teach transfecting an increased amount of shRNA plasmid into the packaging cell line should enhance the capacity of the shRNA to silence the targeted gene (p6 col2 ¶3). Transfecting shRNA reads on one or more expression cassettes that code for an anti-sense construct of the gene sequence encoding a protein of interest, as required by claim 10. Also, as discussed above, an expression construct for an shRNA reads on transfecting into the cell line fragments anti-sense of the gene of interest as required by claim 13 and DNA fragments anti-sense of the gene of interest as required by claim 16.
One would have been motivated to modify the method of Brennan drawn to a method for propagating a fully deleted adenoviral gene transfer vector by transfecting a fully deleted adenoviral vector module and transfecting a replication defective circular packaging expression plasmid by incorporating an expression cassette that codes for an anti-sense construct of the protein of interest as taught by Wang because Wang teach that incorporating a gene expression cassette comprising an shRNA construct that targets the transgene in a packaging cell improves viral particle yield 8.6-13.1 fold (p5col1 ¶2).
It would further have been obvious to incorporate the expression cassette that codes for the anti-sense construct of the protein of interest in the packaging expression plasmid as taught by Brennan because the method of Brennan comprises two options for introducing an expression cassette that codes for an anti-sense construct- either the fully deleted adenoviral vector module or the packaging expression plasmid. Modifying the fully deleted adenoviral vector module by incorporating an expression cassette that codes for an anti-sense construct would cause the anti-sense construct to be included in the viral particle genome and thus transgene expression would be reduced in packaging cells and in virally transduced cells. Modifying the packaging expression plasmid of Brennan by incorporating an expression cassette that codes for an anti-sense construct would cause the desired effect of reducing transgene expression in the packaging cells while not effecting the ability of the viral particles to induce transgene expression in transduced cells, and thus incorporating the expression cassette comprising the anti-sense construct into the packaging plasmid of Brennan would be the obvious choice.
One would have had a reasonable expectation of success because the inventions are drawn to the generation of viral particles comprising a transgene by expression of a viral vector and a packaging plasmid in mammalian packaging cell lines and modification of a packaging expression plasmid would require molecular biology methods that are well known in the art and thus would have a reasonable expectation of success.
Thus the combination of Brennan and Wang teach the active steps of the claimed method. With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Therefore, the claimed order of steps is an obvious variant of the steps of the cited prior art.
Regarding claims 11, 14 and 17: The teachings of Brannon and Wang are discussed above.
Brennan teach a system comprising an adenovirus packaging cell line, a fully-deleted adenoviral vector construct, and a packaging construct wherein the encapsidated fully-deleted adenoviral gene transfer vector is absent of adenoviral structural genes (claim 6). An adenoviral helper virus is absent from the system and therefore reads on the instant claim.
Regarding claims 12, 15 and 18: The teachings of Brannon and Wang discussed above.
Wang also teach that the transgene of the packaging cell can interfere with the packaging cell metabolism and cell growth by exhausting nutrient (p7 col1 ¶1) and that the yield of adenoviral vectors can be increased at least 10-fold by using a cell line which encodes an shRNA silencing the transgene (p7 col1 ¶2).
Because silencing of the transgene hlcon increased the adenoviral vector yield 8.6-13.1 fold (p5 col1 ¶3), the expression of the transgene is considered detrimental to the cell. The purpose of the producer cell is to produce adenoviral vectors, and thus a condition that results in a reduced yield is considered detrimental to the producer cell.
Response to Arguments
The responses are directed to the Arguments filed 12/16/2025.
Regarding Arguments directed to 35 USC § 112(a):
Applicant's arguments filed on 12/16/2025 have been fully considered and they are persuasive. Specifically, the amendments to the claims remove the second recitation of “packaging signal” in claim 1 (c) and this is considered to overcome the rejection. The rejection is withdrawn.
Regarding Arguments directed to 35 USC § 112(b):
Applicant's arguments filed on 12/16/2025 have been fully considered and they are persuasive. The claim amendments overcome the rejection and the rejection is withdrawn.
Regarding Arguments directed to 35 USC § 103:
Applicant's arguments filed on 12/16/2025 have been fully considered and they are persuasive. Applicant argues that claim 1 includes claim limitations that were not addressed in the prior rejection; specifically the previous rejection does not address a replication defective circular packaging expression plasmid comprising a single inverted terminal repeat (ITR) as required by amended claim 1. The limitations were introduced in the present amendments, and thus the rejection is withdrawn due to the claim amendments.
In regards to arguments relevant to the instant rejection directed to 103:
Applicant argues that the secondary references fail to disclose or suggest the claimed vector architectures including the presence of a single ITR and antisense functionally integrated into the packaging expression plasmid.
The previous rejection under 103 addressed previously filed claims (filed 09/30/2022) which did not require the antisense sequence to be functionally integrated into the packaging expression plasmid and did not require the presence of a single ITR. The previous claim 1 required transfecting an inhibitory expression vector that carried code for an anti-sense construct as a separate and distinct step (d) compared to the packaging expression plasmid (step c) of the previous claim.
A new rejection addressing an antisense construct functionally integrated into the packaging expression plasmid is discussed in the new rejection under 103 (see above).
Applicant argues that Wang does not involve helper virus-free systems, fully deleted adenoviral vectors, or minimal late gene packaging plasmids.
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).
Wang is relied upon to modify the primary reference of Brennan, and thus arguments directed to only to Wang are unpersuasive.
Applicant argues that Wang teaches away from transiently introducing regulatory elements into packaging constructs. Wang teaches both stable cellular modifications and transiently introducing expression elements, and teaches 81% transgene suppression using plasmid delivery of shRNA (p3 col2 ¶4). Wang further discloses delivering increased shRNA by increasing the amount of shRNA plasmid transfected into packaging cell lines should enhance the capacity of shRNA silencing target gene expression (p6 col2 ¶3). This is not considered teaching away from transiently introducing expression elements as 81% transgene suppression is substantial and Wang discusses well known methods to improve transgene suppression if such is required.
Thus Wang do not teach away from using shRNA delivered transiently via a plasmid, but rather teach two equally obvious methods; stable integration or transient transfection of the antisense construct. Furthermore, Wang teach strategies to optimize delivery of the shRNA using a plasmid, which highlights the benefit of a transient system in which the amount of antisense delivered can be optimized.
Additionally, as discussed supra, Wang is relied upon to modify Brennan, which utilizes a replication defective circular packaging expression plasmid to deliver adenoviral late genes, and it would have been obvious to modify the expression vector system as taught by Brennan to incorporate the expression of an shRNA as taught by Wang, as discussed above.
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 ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
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, James (Doug) Schultz can be reached at 571-272-0763. 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.
/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
Prosecution Insights