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
Acknowledgment is made of Applicants’ claim for benefit to prior filed US Provisional application 63/239,789 (filed 09/01/2021).
Election/Restrictions
Applicant’s election without traverse of Group (i), corresponding to claims 1-14, and the biomarker, EGFP, in the reply filed 27 April 2026 is acknowledged. Claim 15 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 27 April 2026.
In view of Examiner’s search in regards to the biomarker, the species election is withdrawn.
Specification
The specification is objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)).
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP §
608.02 (V)).The different views must be numbered in consecutive Arabic numerals,
starting with 1,independent of the numbering of the sheets and, if possible, in the order
in which they appear on the drawing sheet(s). Partial views intended to form one
complete view, on one or several sheets, must be identified by the same number
followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.”
Where only a single view is used in an application to illustrate the claimed invention, it
must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in
reply to the Office action to avoid abandonment of the application. Any amended
replacement drawing sheet should include all of the figures appearing on the immediate
prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure
is to be canceled, the appropriate figure must be removed from the replacement sheet,
and where necessary, the remaining figures must be renumbered and appropriate
changes made to the brief description of the several views of the drawings for
consistency. Additional replacement sheets may be necessary to show the renumbering
of the remaining figures. Each drawing sheet submitted after the filing date of an
application must be labeled in the top margin as either “Replacement Sheet” or “New
Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner,
the applicant will be notified and informed of any required corrective action in the next
Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 14 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 14, the phrase "e.g." in lines 4, 12, and 13 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
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.
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.
Claims 1-3 and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhen, et al. (Hum Gene Ther. 2004 Jul;15(7):709-15., NPL-IDS, filed, 01/09/2023, hereinafter “Zhen”) and further in view of Zhang, et al. (Gene Ther. 2001 May;8(9):704-12. , NPL-IDS, filed, 09/28/2022, hereinafter “Zhang”) and evidenced by Green, et al. (Virology. 2008 Feb 5;371(1):1-7., hereinafter “Green”).
Regarding claims 1-2, Zhen teaches a highly sensitive assay for determining the infectious titre of recombinant adeno-associated viruses (rAAVs) comprising a 96-well U-bottom plate containing a population of HeLa cells infected with ten-fold serial dilutions of rAAVs and adenoviruses and then using a transgene as a representative of the number of AAVs to determine titer (pg. 710, Infection and Cellular DNA extraction). Zhen does not teach that the adenoviruses are recombinant adenoviruses that compromise the rep gene. However, Zhang teaches using recombinant adenoviruses expressing AAV cap and rep proteins to support production of high-titre rAAVs (title).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Zhen for a method of determining the titre of rAAVs using cells expressing the rep/cap proteins, rAAVs, and WT adenoviruses with the teachings of Zhang for recombinant adenoviruses expressing the rAAV rep and cap proteins. Zhang provides motivation by teaching that rAAVs require the rep/cap proteins to replicate but do not express these proteins themselves. One of skill in the art would have a reasonable expectation of success in combining the teachings of Zhen and Zhang because they both teach co-infection with rAAV and adenoviruses.
Regarding claim 3, Zhen teaches using HeLa cells for the method. As evidenced by Green, HeLa cells do not have adenoviral early genes integrated into their genome (pg. 3 ¶2).
Regarding claim 10, Zhen teaches that the HeLa cells used in the assay are Rep/Cap-expressing HeLa cells (pg. 710 Rep/Cap HeLa cell line D7-4). While, Zhen does not explicitly teach that the rAAVs do not comprise a rep gene, absence of evidence to the contrary, the HeLa cell line was modified to express the Rep/Cap proteins because the other assay components do not possess the genes required to express these necessary proteins.
Regarding claim 11, Zhen teaches that the biomarker is a transgene (Pg. 711, Assay design and sensitivity).
Regarding claims 12-13, Zhen teaches that the purified rAAVs were added to the well in 10-fold serial dilutions (pg. 710, column 1 ¶1) with an n of 5 (Fig 1) and that the transgene was representative of the amount of rAAV (pg. 711 column 1).
Regarding claim 14, Zhen and Zhang teach the method of claim 1 (see above). Zhen further teaches calculating the TCID50 using the formula
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(pg. 710, TCID50 analysis of limiting dilution/Q-PCR data).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Zhen and Zhang as applied to claims 1-3 and 10-14 above, and further in view of Schaack, et al. (Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3124-9., hereinafter “Schaack”).
Claims 1-3 and 10-14 were rendered prima facie obvious over Zhen and Zhang as discussed above.
Regarding claim 4, Zhen and Zhang do not teach that the recombinant adenovirus has functional E1A and E1B genes. Zhen does teach wild-type adenoviruses which have functional E1A and E1B genes (pg. 710 column 2). However, Schaack teaches that E1A and E1B are required for replication, as removing these genes renders recombinant adenovirus replication deficient (pg. 3124, column 1 last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention have combined the teachings of Zhen and Zhang for a method of determining the titre of rAAVs with the teachings of Schaack for requiring E1A and E1B genes for adenovirus replication. Zhen teaches that the assay requires replication competent adenoviruses (pg. 710 column 2) and Schaack teaches that E1A and E1B are required for replication competent adenoviruses (Pg. 3124 column 1 last paragraph). Together they provide motivation for having functional E1A and E1B genes in the recombinant adenovirus so that the recombinant adenovirus can replicate and be used in the assay. One of skill in the art would have had a reasonable expectation of success in combining the teachings of Zhen, Zhang, and Schaack because they all teach adenoviruses.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Zhen and Zhang as applied to claims 1-3 and 10-14 above, and further in view of Schmidt, et al. (J Virol. 2000 Oct;74(20):9441-50., hereinafter “Schmidt”).
Claims 1-3 and 10-14 were rendered prima facie obvious over Zhen and Zhang as discussed above.
Regarding claim 5, Zhen and Zhang do not teach that the rep gene is not operably associated with a functional promoter. However, Schmidt teaches that while Rep is required for DNA replication, integration, and gene regulation it is toxic to cells by activating caspase-3 (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention have combined the teachings of Zhen and Zhang for a method of determining the titre of rAAVs with the teachings of Schmidt that Rep is toxic to cells. With the knowledge that Rep is toxic to cells but it required for DNA replication, etc. one of skill in the art would be motivated to not associate the rep gene with a functional promoter so that Rep would be produced in low levels for replication but not in high enough levels to be toxic to cells and cause cell death. One of skill in the art would have a reasonable expectation of success in combining the teachings of Zhen, Zhang, and Schmidt because they all teach AAVs.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Zhen and Zhang as applied to claims 1-3 and 10-14 above, and further in view of Sitaraman, et al. (Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14294-9., NPL-IDS, filed, 09/28/2022, hereinafter “Sitaraman”).
Claims 1-3 and 10-14 were rendered prima facie obvious over Zhen and Zhang as discussed above.
Regarding claim 6, Zhen and Zhang do not teach the rAAV genome comprises a scrambled p40 cis-inhibitory sequence. However, Sitaraman teaches that the AAV rep gene can be tolerated within an adenovirus by scrambling the p40 DNA sequence (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have combined the teachings of Zhen and Zhang for a method of determining the titre of rAAVs with the teachings of Sitaraman for scrambling the p40 DNA sequence. Sitaraman provides motivation by teaching that adenoviruses cannot tolerate the AAV rep gene normally but can tolerate the required rep gene when then p40 DNA sequence in scrambled. One of ordinary skill in the art would have a reasonable expectation of success in combining the teachings of Zhen, Zheng, and Sitaraman because they all teach adenoviruses and AVVs.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zhen and Zhang as applied to claims 1-3 and 10-14 above, and further in view of Cawood, et al. (WO 2019020992, FOR-IDS, filed 09/28/2022, hereinafter “Cawood”).
Claims 1-3 and 10-14 were rendered prima facie obvious over Zhen and Zhang as discussed above.
Regarding claim 7, Zhen and Zhang do not teach a repressor element in the Major Late Promoter. Cawood teaches the insertion of a repressor element into the Major Late Promoter (pg. 2 line 29).
It would be prima facie obvious to one of skill in the art before the effective filing date of the invention to have combined the teachings of Zhen and Zhang for a method of determining the titre of rAAVs with the teachings of Cawood for adding a repressor element in the MLP. Cawood provides motivation by teaching that switching off expression of the Late genes, the cell’s protein-manufacturing capabilities can be diverted toward the production of a desired recombinant protein (pg. 2 lines 30-31). One of skill in the art would have had a reasonable expectation success in combining the teachings of Zhen, Zhang, and Cawood because they all teach adenoviruses.
Regarding claim 8, Cawood teaches wherein one or more of the repressor elements are inserted downstream of the MLP TATA box (pg. 4 lines 10-13).
Regarding claim 9, Cawood teaches that the repressor is a tetracycline repressor binding site (claim 9).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Conclusion
NO CLAIMS ARE ALLOWED
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Cassandra Senn Grizer whose telephone number is (571)272-2292. The examiner can normally be reached M-Th 0630 - 1700 ET.
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/CASSANDRA SENN GRIZER/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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