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 .
Claim Status
Applicant’s submission filed 01/30/2026 has been received and entered. Claims 6-9 and 11 have been cancelled. Claims 1-2, 10, 12-13, 15-19 and 21 have been amended. Claims 22 and 23 have been new added. Claims 13-19 were previously withdrawn as being directed to non-elected inventions, however, since claims 15-19 are amended to indirectly depend upon claim 1, they are hereby rejoined for examination. Claims 13-14 remain withdrawn. Accordingly, claims 1-5, 10, 12, 15-19 and 21-23 are pending and under current examination.
Status of Prior Rejections/Response to Argument
The objection to Specification is withdrawn:
Applicant’s amendment to Specification is effective to obviate the current objection on record. The objection is withdrawn.
The objection to Drawing is withdrawn:
Applicant’s submission of replacement sheets is effective to obviate the current objection on record. The objection is withdrawn.
The rejection to claims 1-12 and 21 is withdrawn:
The cancellation of claims 6-9 and 11 renders the rejection thereto moot.
Applicant’s amendment to claims 1-2, 10 and 21 replacing “having” with “comprising” obviates the current rejection on record. The rejection is withdrawn.
The rejection to claims 1-5 under 35 U.S.C. 102(a)(1) and (a)(2) over Buchholz et al. is withdrawn:
Applicant’s amendment to claim 1 adds limitations as recited in parts (b) and (c), since Buchholz et al. do not teach limitations such as (b) the mammalian cell expressing adenovirus E1A and E1B proteins, the amendment is effective to obviate the current rejection on record. The rejection is withdrawn.
The rejection to claims 1-7 under 35 U.S.C. 103 over Sayedahmed et al. in view of Buchholz et al., as evidenced by Zhou et al. is withdrawn:
The cancellation of claims 6-7 renders the rejection thereto moot.
Applicant’s amendment to claim 1 adds the limitations as recited in parts (b) and (c). Neither Sayedahmed et al. or Buchholz et al. teach the limitation in (c) a recombinant helper adenovirus genome vector comprising two inverted terminal repeats (ITRs) and a packaging signal flanked by a site-specific recombinase recognition site. Therefore the amendment is effective to obviate the current rejection on record, the rejection is withdrawn.
The rejection to claims 1-4, 8-12 and 21 under 35 U.S.C. 103 over Parks et al. in view of Buchholz et al. is withdrawn:
The cancellation of claims 8-9 and 11 renders the rejection thereto moot.
Regarding claim Applicant’s amendment to claim 1 adds the limitation as recited in (b) and (c). Neither Parks et al. or Buchholz et al. teach the limitation in (b) (an isolated mammalian cell) stably expressed adenovirus E1A and E1B proteins. Therefore amendment is effective to obviate the current rejection on record, the rejection is withdrawn.
New grounds of rejection are set forth as necessitated by Applicant’s amendment.
New claim Rejections
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.
Claims 1-5, 10, 12,15-19 and 21-23 are newly rejected under 35 U.S.C. 103 as being unpatentable over Kiem et al. (WO 2021003432 A1, published 01/07/2021) in view of Buchholz et al. (US 9.428,754 B2, patented in 2016), as evidenced by Shaikh et al. (J Biol Chem. 1997 Feb 28;272(9):5695-702) and Xu et al. (BMC Biotechnol. 2018 Aug 31;18(1):52). The rejection is necessitated by Applicant’s amendment.
Kiem et al. teach helper-dependent adenoviral serotype 35 (Ad35) vectors (Abstract).
Regarding claim 1, Kiem et al. teach helper-dependent adenoviral serotype 35 (Ad35) vectors and provides newly-designed Ad35 helper vectors (see parag 0008). Kiem et al. teach using site-specific recombinase systems. Examples of recombinase systems include the Flp/Frt system, the Cre/loxP system, the Dre/rox system, the Vika/vox system, and the PhiC31 system (parag 0586). It is known and Shaikh et al. provide evidence that recombinase (i.e., Cre recombinase) cleaves a recombinase recognition site (i.e., loxP) (see Abstract). Kiem et al. teach the HDAd donor genome can be delivered to cells, such as 293 cells (HEK293) that expresses Cre recombinase (parag 0582). This teaching of 293 cells (HEK293) expressing Cre recombinase reads on an isolated mammalian cell (i.e., HEK293 cell) comprising (a) a recombinant DNA comprising an open reading frame encoding a recombinase (i.e., Cre recombinase), wherein the recombinase cleaves a recombinase recognition site (i.e., loxP). Kiem et al. teach an Ad35 helper virus typically includes all of the viral genes except for those in E1, as E1 expression products can be supplied by complementary expression from the genome of a producer cell line (parag 0282, also see parag 0286), and E1 region includes E1A and E1B (see parag 0266). Kiem et al. also teach adenoviral vectors cannot replicate on their own but can be produced in E1 -expressing mammalian cell lines such as HEK293 cells. This teaching reads on a mammalian cell (HEK 293 cell) also comprising: b) stably expressed adenovirus E1A and E1B proteins. Kiem et al. further teach in certain HDAd vector systems, the HDAd donor genome includes the adenoviral ITRs which are required for genome replication, and Ψ which is the packaging sequence or a functional fragment thereof required for encapsidation of the genome into the capsid (parag 0280). The HDAd donor genome can be delivered to cells, such as 293 cells (HEK293) that expresses Cre recombinase. The same cells can be an E1 -deleted Ad vector bearing a packaging sequence or functionally contributing (e.g., functionally required) fragment thereof flanked by loxP sites so that following infection of 293 cells expressing Cre recombinase, the packaging sequence or functionally contributing (e.g., functionally required) fragment thereof is excised from the helper genome by ere-mediated site-specific recombination between the loxP sites (parag 0282). Also see figure 95 the illustration of helper virus. This teaching reads on a mammalian cell comprising (c) a recombinant helper adenovirus genome vector comprising two inverted terminal repeats (ITRs) and a packaging signal flanked by a site-specific recombinase recognition site (i.e., herein loxP).
Kiem et al. teach helper-dependent adenoviral vectors (HDAd) with Cre/loxP system , also listed other recombinases such as Flp/Frt system, the Dre/rox system, the Vika/vox system, and the PhiC31 system (see parag 0586). Kiem et al. do not teach recombinase comprising at least 80% amino acid sequence identity to SEQ ID NO:1, as well as the ITRs and packaging signal flanked by a site-specific recombinase recognition site comprising at least 90% nucleic acid sequence identity to SEQ ID NO:4. However, this was disclosed by Buchholz et al. at the time of instant invention.
Buchholz et al. teach the use of a protein with recombinase activity to catalyze a site-specific DNA recombination and a method for producing a site-specific DNA recombination (Abstract).
Regarding claim 1, Buchholz et al. teach a nucleic acid that encodes for a protein with recombinase activity, preferably Vika, wherein the protein preferably comprises an amino acid sequence exhibiting at least 70%, preferably at least 80%, preferably at least 90%, particularly preferred at least 95%, even more preferred at least 99% amino acid sequence identity to SEQ ID No. 1 (Col 9, L8-14). Herein the SEQ ID NO. 1 is 100% identical to SEQ ID NO: 1 in instant claim. Moreover, Buchholz et al. teach the recognition site of the site-specific recombinase Vika is referred to herein as “vox-site' or simply “vox'. A vox-site is characterized by its nucleic acid sequence according to SEQ ID No. 2 (Col 2, L43-46), it is the target for the site-specific recombination of Vika (Col 2, L52-53). Herein the SEQ ID No. 2 is 100% identical to SEQ ID No: 4 in instant claim.
Regarding claim 2, following the discussion above, Buchholz et al. teach a protein with recombinase activity, preferably Vika, wherein the protein preferably comprises an amino acid sequence exhibiting at least 70%, preferably at least 80%, preferably at least 90%, particularly preferred at least 95%, even more preferred at least 99% amino acid sequence identity to SEQ ID No. 1 (Col 9, L8-14). Herein the SEQ ID NO. 1 is 100% identical to SEQ ID NO:22 in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kiem et al.’s helper-dependent adenoviral vectors, and use Vika/vox recombinase system with the sequence of SEQ ID NO: 1 and 2 as taught by Buchholz et al.. The only difference between instant claim and Kiem et al.’s HDAd is instant claim having Vika/vox system with the recombinase comprising at least 80% amino acid sequence identity to SEQ ID NO:1, as well as a site-specific recombinase recognition site comprising at least 90% nucleic acid sequence identity to SEQ ID NO:4. Given that Buchholz et al. teach Vika shows a Cre recombinase-like activity (Col 3, L15) and provide the sequence of Vika/Vox, one of ordinary skill in the art would have substituted the loxP-Cre recombinase system, and use Vika/vox recombinase system with such sequence encoded recombinase and site specific recombinase recognition site depends on their research interest or research preference. This simple substitution of one known element (using Vika/vox recombinase system in an AdV vector) for another known element (using loxP-Cre recombinase system in an AdV vector) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claims 3 and 4, Kiem et al. teach the HDAd donor genome can be delivered to cells, such as 293 cells (HEK293) that expresses recombinase (i.e., Cre recombinase) as well as the helper vector (parag 0282). HEK293 cells are human cells which belong to primate cell.
Regarding claim 5, Kiem et al. do not teach the open reading frame further encodes a nuclear localization signal (NLS). However, Buchholz et al. teach recombinase expression plasmids pNPK-NLS-Cre, pNPK-NLS-VCre and pNPK-NLS-Vika (Col 20, L19-20). Herein the pNPK-NLS-Vika reads on the open reading frame further encodes a nuclear localization signal, as recited in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kiem et al.’s helper-dependent adenoviral vectors, and use Vika/vox recombinase system with a nuclear localization signal for the recombinase as taught by Buchholz et al.. The only difference between instant claim and Kiem et al.’s helper-dependent adenoviral vectors (HDAd) is instant claim using Vika/vox recombinase system and a nuclear localization signal for the Vika recombinase. Given that Buchholz et al. teach Vika shows a Cre recombinase-like activity (Col 3, L15), and use the pNPK-NLS-Vika plasmid as a recombinase expression plasmid (Col 20, L19-20, to target the Vika recombinase to nucleus), one of ordinary skill in the art would have substituted the loxP-Cre recombinase system, and use Vika/vox recombinase system and NLS-Vika recombinase depends on their research interest or research preference. This simple substitution of one known element (using Vika/vox system and NLS-Vika recombinase in a AdV vector) for another known element (using recombinase system without NLS in a AdV vector) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 10, as discussed above, Buchholz et al. teach the recognition site of the site-specific recombinase Vika is referred to herein as “vox-site' or simply “vox'. A vox-site is characterized by its nucleic acid sequence according to SEQ ID No. 2 (Col 2, L43-46), it is the target for the site-specific recombination of Vika (Col 2, L52-53). Herein the SEQ ID No. 2 is 100% identical to SEQ ID No: 4 in instant claim.
Regarding claim 12, following the discussion above, Kiem et al. teach the HDAd donor genome can be delivered to cells, such as 293 cells (HEK293) that expresses a recombinase (i.e., Cre recombinase), optionally where the HDAd donor genome is delivered to the cells in a non-viral vector form, such as a bacterial plasmid form (e.g., where the HDAd donor genome is constructed as a bacterial plasmid (pHDAd) and is liberated by restriction enzyme digestion) (parag 0282).
Regarding claim 21, it is noted that the limitation “kit” is interpreted under broad reasonable interpretation (BRI) as a combination or coexisting of a) to c). Following the discussion above, Kiem et al. teach 293 cells (HEK293) that expresses Cre recombinase (parag 0282), helper virus comprising two adenovirus ITRs and an adenvirus packaing signal flanked by loxP (i.e., see figure 95). Herein the HEK293 that expresses Cre recombinase reads on (a) an isolated mammalian cell that stably expresses a recombinase, and helper virus reads on c) a helper dependent adenovirus vector comprising a genome having two adenovirus ITRs, an adenovirus packaging signal flanked by a pair of site-specific recombinase recognition sites (helper virus with Cre/loxP). Kiem et al. teach other site-specific recombinase systems can be used. Examples of recombinase systems include the Flp/Frt system, the Cre/loxP system, the Dre/rox system, the Vika/vox system, and the PhiC31 system (parag 0586). Kiem et al. do not teach vika/vox system in the helper virus with the sequence of vika and vox as recited in b). However, as discussed above, Buchholz et al. teach the sequences. Specifically, Buchholz et al. teach a nucleic acid that encodes for a protein with recombinase activity, preferably Vika, wherein the protein preferably comprises an amino acid sequence exhibiting at least 70%, preferably at least 80%, preferably at least 90%, particularly preferred at least 95%, even more preferred at least 99% amino acid sequence identity to SEQ ID No. 1 (Col 9, L8-14). Herein the SEQ ID NO. 1 is 100% identical to SEQ ID NO: 1 in instant claim. Moreover, Buchholz et al. teach the recognition site of the site-specific recombinase Vika is referred to herein as “vox-site' or simply “vox'. A vox-site is characterized by its nucleic acid sequence according to SEQ ID No. 2 (Col 2, L43-46), it is the target for the site-specific recombination of Vika (Col 2, L52-53). Herein the SEQ ID No. 2 is 100% identical to SEQ ID No: 4 in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kiem et al.’s helper-dependent adenoviral vector system having a HEK293 cell stably expressing recombinase and helper virus using Cre/loxP system, and having HEK293 cell stably expressing recombinase, helper virus with Cre/loxP system, as well as helper virus with Vika/vox recombinase system, wherein the Vika comprising a sequence set forth in SEQ ID NO: 1, the vox-site comprising a sequence set forth in SEQ ID NO: 4, as taught by Buchholz et al.. The only difference between instant claim and Kiem et al.’s helper-dependent adenoviral vector system is instant claim using Vika/vox system, and determining the sequence of Vika and vox. Given that Buchholz et al. teach Vika shows a Cre recombinase-like activity (Col 3, L15), one of ordinary skill in the art would have substituted the loxP-Cre recombinase system, and also use Vika/vox recombinase system with the Vika comprising a sequence set forth in SEQ ID NO: 1, the vox-site comprising a sequence set forth in SEQ ID NO: 4 in addition to Cre/loxP system, depends on their research interest or research preference. This simple substitution of one known element (using Vika/vox recombinase system in an AdV vector) for another known element (using loxP-Cre recombinase system in an AdV vector) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claims 22, Kiem et al. teach helper-dependent adenoviral vectors (HDAd) engineered to lack all viral coding sequences can efficiently transduce a wide variety of cell types, and can mediate long-term transgene expression with negligible chronic toxicity. By deleting the viral coding sequences and leaving only the cis-acting elements necessary for genome replication (ITRs) and encapsidation (Ψ), cellular immune response against the Ad vector is reduced. HDAd vectors have a large cloning capacity of up to 37 kb, allowing for the delivery of large payloads. These payloads can include large therapeutic genes or even multiple transgenes and large regulatory components to enhance, prolong, and regulate transgene expression (parag 0280, also see vector figure 95). Kiem et al. also teach the therapeutic gene is under the transcriptional control of i.e., a β-globin promoter (p190, claim 40).
Regarding claims 23 and 15, following the discussion above, Kiem et al. teach HDAd vectors comprising payloads can include large therapeutic genes or even multiple transgenes and large regulatory components to enhance, prolong, and regulate transgene expression (parag 0280). Kiem et al. also teach HDAd using Cre/loxP system, as well as listed other recombinases such as Flp/Frt system, the Dre/rox system, the Vika/vox system, and the PhiC31 system (see parag 0586). Cre/loxP system works in the way that if the open reading frame is in reverse orientation relative to the transcriptional control sequence (i.e., a promoter), the open reading frame is flanked by a pair of site-specific recombinase recognition sites, as evidenced by Xu et al.. Xu et al. teach an in vitro protocol to invert the ORF in FLEX based plasmids (Abstract). Figure 2A and 2B shows that the open reading frame is in reverse orientation relative to the transcriptional control sequence (EF1a or smCBA promoter), the open reading frame is flanked by a pair of site-specific recombinase recognition sites (p4, figure 2).
Regarding claim 16, following the discussion of claim 22, Kiem et al. further teach regulatory sequences comprising promoter regulatory sequences (parag 0536), promoters can include general promoters, tissue-specific promoters, cell-specific promoters, and/or promoters specific for the cytoplasm (parag 0538).
Regarding claims 17-18, following the discussion of claim 22, Kiem et al. further teach a nucleic acid (e.g., a therapeutic gene) encoding a protein or nucleic acid of interest (parag 0556).
Regarding claim 19, following the discussion above, Kiem et al. teach the integrated cassettes in figure 1 which comprising selection marker in the cassette (parag 0693).
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 QINHUA GU whose telephone number is (703)756-1176. The examiner can normally be reached M-F: 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, Christopher Babic can be reached at (571)272-8507. 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.
/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
Prosecution Insights