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
This application is a national stage entry of 35 U.S.C. 371 of PCT/US2022/025403 (filed on 04/19/2022) and claim benefits of US provisional 63/177,300 (filed on 04/20/2021).
Election/Restrictions
Applicants’ election without traverse of invention group I drawn to a recombinant retroviral packaging cell filed on 06/22/2026 is acknowledged. Applicants’ election without traverse of species of invention of c) one or more mammalian genes that regulates the DNA damage response pathway is filed on 06/22/2026 is acknowledged.
Claims Status
Claims 1,3,8,19,21,23-25,32-33,35,39,41-42,45-46,50-52, and 54 are pending.
Claims 23-24,51-52, and 54 are withdrawn per election of invention and species.
Claims 1,3,8,19,21,25,32-33,35,39,41-42,45-46, and 50 have been examined on the merits.
Claim Interpretation
For clarity of the record the following comments are made regarding claim interpretation under broadest reasonable interpretation:
None of the ‘optionally’ limitations are considered as required by the claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1,3,8,21,25,39,41,42,45,46, and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al (Gene Therapy, 2018) and evidenced by AddGene pMDL information sheet (https://www.addgene.org/12251/) .
Hu et al teaches that PKR response to transfection negatively affects viral titers and shRNA mediated knock down of PKR in packaging cells increases viral titers when compared to other vectors and cell types (See, Abstract).
Regarding claims 1, 8, 21, 25, and 39, Hu et al teaches the vector producing cells are HEK 293T cells or SODK0 cells and the short-hairpin RNAs (shRNAs) were delivered by lentivirus to target hPKR and hβ-globin (HBB) (See, p3 paragraph 1).
This reads on, a recombinant retroviral packaging cell,…comprising a mammalian cell wherein one or more genes that inhibit virus production are knocked down, said one or more mammalian genes that inhibit virus production comprise (c) one or more mammalian genes that regulates DNA damage response pathway of claim 1.
This reads on, wherein said one or more mammalian genes that regulates the DNA damage response pathway or regulates transcription comprise the PKR gene of claim 8. This reads on, wherein said one or more mammalian genes that are knocked out or knocked down comprising a member of the PKR [gene family] of claim 21.
This reads on, wherein said one or more mammalian genes that are knocked out or knocked down comprise PKR of claim 25.
This reads on, wherein said mammalian cell is…HEK293T of claim 39.
Regarding claim 3, following the discussion above, Hu et al also teaches the lentiviral vectors pTK485, pTK945, pTK979 and the packaging cassettes ΔNRF, pTK939(Int-), VSV-G envelope, pMDL, and the Rev plasmids, were used for the experiments. pTK945 has the expression cassette CMV-GFP (See, p3 paragraph 2). pMDL plasmid recodes for internal structural proteins (Gag) and essential enzymes (Pol) for retrovirus replication (See, Addgene pMDL information sheet). Hu et al teaches that viral vector production with 3 plasmids transiently transfected was use throughout and absence of competent retroviruses were verified (See, p4 paragraph 1).
This reads on, wherein said cell is modified to provide at least two packaging components for surface or envelope of a retrovirus of claim 3, as pMDL provides Gag and Pol genes, and VSV-G envelope is included.
Regarding claim 41, following the discussion above, Hu et al teaches the transfection of defective recombinant retroviral genome, as lentiviral vectors are utilized and exemplified, produces a complete virion as they were used for in vivo gene delivery and visualized in mice (See, p11 paragraph 2 – p12 paragraph 2, Figure 7).
This reads on, wherein said cell, when transfected with a defective recombinant retroviral genome, produces complete virion at a higher titer….. of claim 41.
Regarding claim 42, following the discussion above, Hu et al teaches that lentiviral vectors generated in PKR deficient 293T cells resulted in an increase in viral titers of ECOO-comprising vectors (See, p7 paragraph 1 and Figure 2). Figure 2 of Hu et al also teaches that there is an increase in viral titers in conventional lentiviral vectors when compared to packaging cells expressing PKR (See, Figure 2B). This reads on, wherein said packaging cell increases lentiviral vector titer, increases titer for complex lentiviral vectors, or increases titer for lentiviral vectors in reverse orientation.
Regarding claim 45, following the discussion above, Hu et al transfected the downregulated PKR packaging cells with vectors containing a GFP cassette, quantified titers and GFP MFI in Figure 4 (See, p 8 paragraph 2, Figure 4). This reads on, wherein said cell is further transfected with a defective, recombinant retroviral genome containing a nucleotide sequence of interest, as GFP is a gene of interest.
Regarding claim 46, following the discussion above, Hu et al teaches the use of lentiviruses for transfection of the modified packaging cells. This reads on, wherein said defective, recombinant retroviral genome comprises a lentiviral (LV) genome.
Regarding claim 50, following the discussion above, Hu et al teaches the use of the PKR-deficient packaging cells to evaluate the production of lentiviral vector CCL-βAS3-FB, developed for hematopoietic stem cell gene therapy in sickle cel disease (See, p12 paragraph 1). Hu et al teaches that PKR-deficient packaging cells produced a higher vector titer than naïve HEK293T cells (See, p12 paragraph 1, Figure 7). This reads on, wherein said LV genome comprises Lenti/ βAS3-FB.
Therefore, claims 1,3,8,21,25,39,41,42,45,46, and 50 are anticipated by Hu et al and evidenced by Addgene.
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 19 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al (Gene Therapy, 2018; as cited in IDS filed on 04/08/2024) as applied to claims 1,3,8,21,25,39,41,42,45,46, and 50 above, and further in view of Cimprich and Cortez (Nature Reviews. Molecular cell biology, 2008).
The teachings of Hu et al is set forth above.
Regarding claim 19, following the discussion above, Hu et al teaches the knock down of PKR gene, a regulator of DNA damage response pathway.
Hu et al does not teach the knock down of ATR, another regulator of DNA damage response pathway.
Cimprich and Cortez teach, ataxia-telangiectasia mutated (ATM) and ATM and Rad3 related (ATM) protein kinases are master regulators of DNA damage response and the that ATR is critical for maintaining genome integrity (See, Preface)
Cimprich and Cortez teaches, ATR is a master regulator of DNA damage response pathway and targets substrates that promote cell cycle arrest and DNA repair (See, p1 paragraph 3).
Given that Hu et al teaches knocking down PKR, a DNA damage response pathway regulator in packaging cells to improve viral titers, and Cimprich and Cortez
Cimprich and Cortez teach that ATR is a regulator of DNA damage response pathway, one would have been motivated to substitute or also knock down ATR in packaging cells as taught in Hu et al to increase or further increase viral titers. It would have been prima facie obvious to a person having ordinary sill in the art to have modified the packaging cell of Hu et al such that ATR is knocked down in the packaging cell, as both PKR and ATR are regulators of DNA damage response pathway. This conclusion of obviousness is based on teaching suggestion motivation rationale. One would have been motivated to make this modification to modify the gene of the regulator of the DNA damage response pathway because they both known to prevent replication within the cell and Hu et al shows success with knocking down PKR for increased viral titers in deficient packaging cells, thus one would have had a reasonable expectation of success evidenced by Hu et al.
Therefore, claim 19 is rendered obvious by Hu et al in view of Cimprich and Cortez.
Claims 32, 33, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al (Gene Therapy, 2018; as cited in IDS filed on 04/08/2024) as applied to claims 1,3,8,21,25,39,41,42,45,46, and 50 above, and further in view of Decker (Journal of Molecular Biology, 2021; as cited in the IDS filed on 06/24/2025; Online version published September 25, 2020).
The teachings of Hu et al is set forth above.
Regarding claims 32 and 33, Hu et al teaches the knock down of PKR gene, a regulator of DNA damage response pathway.
While HEK293T endogenously express SPT4 and SPT5, Hu et al does not teach the packaging cell being further modified to express or overexpress a transcription elongation factor, such as SPT4 or SPT5.
Decker teaches Spt4-Spt5 (DSIF) is a transcription regulatory factor that provides productive elongation (See, Abstract).
Decker teaches that Spt4-Spt5 regulate elongation rate and play a role in transcription coupled DNA repair (TCR) (See, p6 col 1 paragraph 2). Decker also teaches that DSIF impacts DNA damage repair by modulating continuous transcription (See, p7 col 1 paragraph 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the packaging cell of Hu et al such that it overexpresses Spt4 and/or Spt5. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have been motivated to make this modification by the teachings Hu et al, where modulating or downregulating DNA damage response pathways increase titers of lentivectors of interest, therefore, there would be motivation combined with Decker to increase the expression of Spt4 and/or Spt5 (DSIF) to have continuous transcription to increase processivity of transcription (See, Decker p5 col 1 paragraph 2). One would have had a reasonable expectation of success evidenced by Hu et al and Decker.
Regarding claim 35, following the discussion above, Hu et al teaches expression cassettes are episomal in the packaging cell with lentiviral vectors (See, Methods p3 paragraph 2).
Therefore, it would be prima facie obvious to a person having ordinary skill in the art to have introduced the transcription elongation factors SPT4 and/or SPT5 episomal into the packaging cell as taught by Hu et al. This conclusion of obviousness is based on the teaching suggestion motivation rationale. One would have been motivated to use this method of gene expression in the packaging cells by the teachings of Hu et al. One would have had a reasonable expectation of success evidenced by Hu et al.
Therefore, claims 32,33, and 35 are rendered obvious by Hu et al in view of Decker.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Caroline M Lara whose telephone number is (571)272-4262. The examiner can normally be reached 7:00 to 4:30pm M-Th.
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/CAROLINE M LARA/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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