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 .
Response to Amendment
The Amendment filed 11/14/2025 in which claims 1, 19 were amended and claim 15 was canceled, has been entered.
Claims 1, 6-13, 16-19, 25-30 are under examination on the merits.
Specification
(Previous objection, withdrawn) Applicant’s amendments to the Specification submitted on 11/05/2025 have overcome the objection previously set forth in the Non-Final Office Action mailed 05/06/2025.
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 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.
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.
(Previous objection, withdrawn as to claim 15, maintained and modified as necessitated by amendment as to claims 1, 6-13, 16-19, 25-30) Claims 1, 6-13, 16-19, 25-30 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. in view of Shiina and Labant, as evidenced by Tan et al., further in view of Hassinen et al., (prior art of record).
See claims 1, 6-13, 16-19, 25-30 as submitted on 11/14/2025.
The previous rejections of claim 15 is moot in view of Applicant’s cancelation of this claim.
Regarding amended claim 1, it is noted that two new limitations are recited by the amended claim. First, the limitation of VPC2.0 cells grown in suspension; and second, the limitation of production in an amount at least 500% greater than a method in which HEK293 cells are infected. However, as explained previously those limitations are already taught by the cited prior art. Specifically the prior art teaches as follows:
Zhang et al. teaches a method of producing (manufacturing, as recited in claim 1) purified viral compositions including adenovirus compositions of sufficient purity for therapeutic administration (Abstract). Zhang et al. further teaches Ad5-based vectors (¶ [0185], [0036]) for production in HEK293 cells grown in suspension (¶¶ [0017], [0111], [0112], [0113], [0118]) including 293SF cells (¶ [0017]). Zhang et al. also teaches 293 derived cell lines which do not require a helper vector given that such cell lines constitutively express adenoviral genes to support adenoviral replication (¶ [0112], [0113], [0114], [0115]). Zhang et al. further teaches the use of any cell type capable of supporting replication of an adenovirus (¶ [0017]). Zang et al. does not teach VPC2.0 cells capable of producing viral vectors in an amount 100% greater than the amount produced in HEK293 cells.
However, Shiina et al., as previously discussed, teaches a method of producing a recombinant adenoviral vector having a high infectious titer (Abstract; page 10, ¶ 5; page 7, ¶ 11) in commercially available VPC2.0 cells which are adapted for growth in suspension (page 8, ¶ 2).
Lanbant teaches virus production in VPC 2.0 cells, the clonal cell line derived from HEK293 cells, in an amount 10 times (10x) and 45 times (45x) greater than when HEK293 cells are used (page 2, ¶ 6; page 3, graph). It is noted that the recitation on amended claim 1 of “in an amount at least 500% greater” represents an amount of at least 5 times (5X) greater. The teachings of Labant demonstrate 10 times (10x) and 45 times (45X) greater virus production which are far greater than 5 times (5X) or 500%, as recited in amended claim 1. It is noted, that the graph in Labant’s teaching represents an adeno-associated virus vector. However, Labant further teaches multiple types of delivery vectors for high yield production including adeno-associated virus, adenovirus, lentivirus, and retroviruses (pages 4, 5). Further, as evidenced by Tan et al. both adenovirus-based vectors and adeno-associated virus-based vectors can be efficiently produced at large-scale in HEK293-based systems (pages 5, 6). Further, it is noted that the amount recited in claim 1 of “at least 500% greater” is considered to be one determined by routine optimization according to one of skill in the art in view of the teachings of Labant et al.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date, to have modified the method of Zhang et al. for adenoviral production to include the teachings of Shiina of the clonal cell line VPC2.0 and Labant for the benefit of increased virus production of up to 45X greater than production in HEK293 parental cells. See MPEP 2144.07. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
One of ordinary skill in the art would have had a reasonable expectation of success for modifying the method of adenovirus production taught by Zhang et al. with the VPC2.0 cells of Shiina and Labant given that the methods of large-scale virus production are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Neither Zhang et al. nor Shiina, nor Labant explicitly teach Nadofaragene firadenovec.
However, as previously indicated, Hassinen et al. teaches the adenovirus-based vector Nadofaragene firadenovec, also known as rAd-IFNα2b (¶ [0061], [0062], claim 40) in a therapeutic formulation for the treatment of superficial bladder cancer (¶ [0015]).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date, to have modified the method of Zhang et al. in view of Shiina and Labant, to include Nadofaragene firadenovec as taught by Hassinen et al. for the benefit of producing large quantities a purified adenoviral composition of sufficient purity for therapeutic administration comprising Nadofaragene firadenovec for the treatment of superficial bladder cancer. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)
One of ordinary skill in the art would have had a reasonable expectation of success for modifying the method of adenovirus production taught by Zhang et al. in view of Shiina and Labant with the adenovirus-based vector Nadofaragene firadenovec taught by Hassinen et al. given that the methods of large-scale production of adenovirus-based therapeutic compositions are known, successfully demonstrated, and commonly used as evidenced by the applied prior art.
Regarding claims 6, 7 and 8, it is noted that no amendments were introduced to these claims in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches isolating the adenovirus from the adenovirus preparation at least about, at most about, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days after viral infection is completed (harvested at least 24 hours after infection, as recited in claim 6; harvested at least 36 hours after infection, as recited in claim 7; harvested about 48 hours after infection, as recited in claim 8) (¶ [0027]).
Regarding claim 9, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. Shiina et al. teaches VPC2.0 as the cell system for adenovirus production as described above (page 6, ¶ 2). It is well known in the art that VPC2.0 cells are 293-derived and specially adapted to grow in suspension (GibcoTM , VPC2.0 User Guide. Prior art of record.)
Regarding claims 10 and 11, it is noted that no amendments were introduced to these claims in the amendment filed on 11/14/2025. As discussed above, Zhang et al. further teaches infection of the cells at a multiplicity of infection (MOI) of the vector of at least about, at most about, or about 5, 10, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700 to about 500, 600, 700, 800, 900, 1000 MOI (MOI is about 100 to about 300, as recited in claim 10; MOI is about 175 to about 200, as recited in claim 11) (¶ [0024]).
Regarding claim 12, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As discussed above, Zhang et al. further teaches the cell culture in a bioreactor, wherein the cells are the 293 derived cell lines which are found to be equivalent to VPC2.0 cells as discussed above, and are at a cell seeding density of about 7.5 x 105 cells/mL (0.75 x 106 cells/mL, as recited in claim 12) (¶ [0080]).
Regarding claim 13, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As discussed above, Zhang et al. further teaches the infection cell density of about 5 x 105 to about 2 x 106 cells/mL. The range of infection cell density recited in claim 13 (from about 2 x 106 to about 4 x 106 viable cells/mL) is considered to be those determined by routine optimization according to one of skill in the art in view of the teachings of Zhang et al. (¶ [0087]).
Regarding claims 16, 17, and 18, it is noted that no amendments were introduced to these claims in the amendment filed on 11/14/2025. Zhang et al. further teaches harvesting virus supernatant after complete cell lysis, wherein the lysing step can be accomplished with a wide variety of agents (¶ [0212], Table 6) (lysing the producer cells with a lysis agent prior to harvesting, as recited in claim 16). Zhang et al. further teaches a step of density gradient centrifugation of the lysed cells (¶ [0257]) (centrifuging the lysed cells, as recited in claim 17). Zhang et al. further teaches purifying the viral vector after harvesting, to a pharmaceutically acceptable degree (¶ [0031]) (purifying the vector after harvesting, as recited in claim 18).
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. See MPEP 2144.04. Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.).
Regarding claim 19, the amended claim recites the new limitation of production in an amount at least 500% greater than a method in which HEK293 cells are infected. However, as explained previously those limitations are already taught by the cited prior art. Specifically the prior art teaches as follows:
The teachings of Zhang et al., Shiina, Labant and Hassinen et al. explained above and previously meet the limitations of amended claim 19. Zhang et al. teaches a method of producing purified viral compositions including adenovirus compositions of sufficient purity for therapeutic administration (Abstract), and Hassinen et al. teaches the vector Nadofaragene firadenovec, also known as rAd-IFNα2b (¶ [0061], [0062], claim 40). The cited prior art teaches the following limitations of claim 19:
Zhang et al. teaches infecting (¶ [0164]) HEK293 cells grown in suspension (¶ [0111], [0112], [0113], [0118]) with an Ad5-based vector and Shiina teaches specifically VPC2.0 cells (Shiina, page 8, ¶ 2).
Zhang et al. teaches target infection cell density ranges from about 5 x 105 to about 2 x 106 cells/mL (from about 1 x 106 to about 4 x 106 viable cells/mL, as recited in claim 19) (¶ [0080])
Zhang et al. teaches carrying out infection at an MOI range of 5-1000 (MOI of about 100 to about 300, as recited in claim 19) (¶ [0024]), and a duration of infection ranges from 1-10 or more days after viral infection (about 48 hours, as recited in claim 19) (¶ [0027])
Labant teaches viral production at 10 times (10x) and 45 times (45X) greater than when HEK293F cells are used (page 2, ¶ 6; page 3, graph), which are far greater than the recited amount of “500% greater”
Zhang et al. teaches harvesting the vector containing the transgene produced (¶ [0212])
Regarding claims 25, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches the isolating of the adenovirus from the adenovirus preparation occurs at least about, at most about, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more days after viral infection is completed (harvested at least 24 hours, at least 36 hours, or at least 48 hours after infection, as recited in claim 25) (¶ [0027]).
Regarding claim 26, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches the 293 are cultured in suspension (¶ [0123]).
Regarding claim 27, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. teaches infection of the cells at a multiplicity of infection (MOI) of the vector of at least about, at most about, or about 5, 10, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700 to about 500, 600, 700, 800, 900, 1000 MOI (MOI is about 175 to about 200, as recited in claim 27) (¶ [0024]).
Regarding claim 28, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches inoculating the cell culture in a bioreactor, wherein the producer cells are at a cell seeding density of about 7.5 x 105 cells/mL (0.75 x 106 cells/mL, as recited in claim 28) (¶ [0080]).
Regarding claim 29, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches harvesting virus supernatant after complete cell lysis, wherein the lysing step can be accomplished with a wide variety of agents (¶ [0212], Table 6) (lysing the cells with a lysis agent prior to harvesting, as recited in claim 29).
Regarding claim 30, it is noted that no amendments were introduced to this claim in the amendment filed on 11/14/2025. As previously explained, Zhang et al. further teaches purifying the viral vector after harvesting, to a pharmaceutically acceptable degree (¶ [0031]).
Accordingly, the invention as a whole would was prima facie obvious to one of ordinary skill in the art before the effective filing date, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 04/15/2025 have been fully considered but they are not persuasive.
Applicant contends on page 7 of the Remarks submitted on 11/14/2025:
Applicant surprisingly discovered that infecting suspension-grown VPC2.0 cells with Nadofaragene firadenovec, produced Nadofaragene firadenovec in an amount at least 500% greater than a method in which HEK293 or HEK293F cells were infected with Nadofaragenefiradenovec. Thus, even assuming there was a motivation to combine Zhang, Shiina, and Labant (as evidenced by Tan et al. and Hassinen et al.), a person skilled in the art would have had no reasonable expectation of success based on the evidence and unexpected results discussed herein. In view thereof, reconsideration and withdrawal of the rejection are respectfully requested.
In response:
As to applicant’s alleging surprising results, this is not persuasive because as explained in detail above and previously VPC 2.0 cells were specifically developed for growth in suspension and for enhanced production of viral vectors. The cited prior art demonstrates this. Applicant’s results of production of a viral vector comprising an exogenous well known gene Nadofaragene firadenovec is both entirely expected or unsurprising and entirely consistent with the teachings of the cited prior art. Applicant has not explained nor provided any evidence as to why a person of ordinary skill in the art would not have found such results entirely predictable and therefore obvious. 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). As to Applicant’s remarks about reasonable expectation of success, this is not persuasive because as evidenced by the cited prior art methods of large scale production of exogenous genes using viral vectors in suspension cells are routinely practiced in the art, these are well known methods, successfully demonstrated and regularly optimized. It is herein maintained that a person of ordinary skill in the art would have had reasonable expectation of success in arriving at the claimed method.
Response to Declaration under 37 C. F. R. § 1.132
Applicant’s Rule 132 Declaration filed on 11/14/2025 has been thoroughly reviewed and considered.
The Declaration under 37 CFR 1.132 filed on 11/14/2025 is insufficient to overcome the rejection of instant claims as set forth in this Office Action because of the reasons explained below.
Turning to the arguments and data provided in Applicant’s Declaration, as indicated above, instant claims encompass a method of manufacturing Nadofaragene firadenovec in VPC2.0 in an amount at least 500% greater that a method in which HEK293 cells are infected. The Examiner acknowledges Ms. Leinonen explanation and experimental results in regards to productivity of a recombinant adenoviral vector expressing thymidine kinase (rAd-TK) versus a recombinant adenoviral vector containing the transgene for IFN in HEK293 cells. It is noted that the instant rejection is in view of instant claim language. 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). The instant claims do not mention nor require any limitation in regards to a recombinant adenoviral vector expressing thymidine kinase (rAd-TK). Further, it is not clear how or why in the instant case, an adenoviral vector expressing thymidine kinase serves as a reference point to which expression of the viral vector comprising Nadofaragene firadenovec is compared to. In other words, it is not explained why the data of a recombinant adenoviral vector expressing thymidine kinase (rAd-TK) is relevant to the instant case. Accordingly, the explanation and the data provided in the Declaration are of no relevance to the rejections of record. Further, it is not clear how the data provided in the Declaration demonstrated that a person skill in the art would not have expected that infecting suspension VPC 2.0 cells would have resulted in enhanced viral production as asserted in the Remarks (page 6). Neither the arguments nor the data presented in the Declaration provide any support nor evidence of nonobviousness to overcome the rejections of record.
Conclusion
No claims are allowed.
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 MARLENE V BUCKMASTER whose telephone number is (703)756-5371. The examiner can normally be reached M-F 8-5.
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/MARLENE V BUCKMASTER/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672