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 .
Applicant’s election without traverse of Group I claims 321-347 in the reply filed on 12/09/2025 is acknowledged.
Claims 348-373 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/09/2025.
Priority
This application claims the benefit of priority to U.S. Provisional Patent Applications Numbers 62962739, 62962730, and 62962764. Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional Applications 62962739, 62962730, and 62962764 filed on 01/17/2020.
This application claims the benefit of priority to Patent Application PCT/US21/13735. Acknowledgement is made of Applicants’ claim for benefit to prior filed to Patent Application
Number PCT/US21/13735, filed on 01/15/2021.
Information Disclosure Statement
The Information Disclosure Statements filed 03/10/2023, 04/13/2023, and 12/09/2025 has been considered by the Examiner.
Status of Claims
Claims 321-347 are under examination.
Claims 348-373 are withdrawn.
Claim 1-320 are cancelled.
Claim Objections
Claims, 332-333, and 347 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 321-331 and 334-346 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al. (WO-2018-096343) in view of Zhang et al. (WO-2019-071048).
Regarding claim 321, Vallier et al. teach a method for controlling transcription of a genetic sequence in a cell comprising targeted insertion of a gene encoding a transcriptional regulator protein into a first genetic safe harbor site. Vallier et al. further teach targeted insertion of an inducible cassette into a second genetic safe harbor site, wherein said inducible cassette comprises said genetic sequence operably linked to an inducible promoter, and is regulated by the transcriptional regulator protein (page 54, claim 1).
Vallier et al. do not teach a safety switch. Vallier further does not specifically teach the construct order is from 5' to 3' end: (1) a safety switch transgene; (2) a ribosomal skipping sequence and/or a sequence encoding a linker; (3) a hypoimmunity gene or an essential factor gene; or from 5' to 3' end: (1) a hypoimmunity gene or an essential factor gene; (2) a ribosomal skipping sequence or a linker; (3) a safety switch transgene.
Zhang et al. teach a construct which may be used to target nucleic acid-targeting activity to multiple target sequences within a cell (page 223, paragraph 0391). Zhang et al. teach the addition of a transgenic safety switch, protects the immuno-responsive cells previously vulnerable to exposure to a specific signal and further guard against possible adverse reactions (page 323, paragraph 0723). Zhang et al. teach a variety of linkers are used including flexible linkers (page 401, paragraph 0842). Zhang et al. teach the modified cell is a therapeutic T cell. Zhang et al. teach the modification may result in changes to hypoimmunity genes including reduced expression of an immune checkpoint receptor (e.g., PDA, CTLA4) and reduced expression of HLA proteins (e.g., B2M, HLA-A) (page 30, paragraph 152). Zhang et al. teach all of the elements of the expression vector. Zhang et al. teach nucleic acid-targeting system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5' with respect to ("upstream" of) or 3' with respect to ("downstream" of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a nucleic acid-targeting effector protein and the nucleic acid-targeting guide RNA, embedded within one or more intron sequences. Zhang et al. teach the nucleic acid-targeting effector protein and the nucleic acid-targeting guide RNA may be operably linked to and expressed from the same promoter. One of ordinary skill in the art would be experienced in vector design and is well equipped to order the components of the vector as described by Zhang et al.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Vallier et al. for a method for controlling transcription of a genetic sequence with the teachings of Zhang et al. for the addition of a transgenic safety switch. Zhang et al. provide motivation by teaching that the addition of a transgenic safety switch, to guard vulnerable immuno-responsive cells from possible adverse reactions. One of skill in the art would have had a reasonable expectation of success at combining Vallier et al. and Zhang et al. because both teach methods of modifying nucleic acids for modulation of transcription.
Regarding claim 322, Zhang et al. teach a construct which leads to endogenous gene disruptions in human cell lines (page 271, 0513) Vallier et al. teach once a DSB has been made, a donor template with homology to the targeted locus is supplied. Vallier et al. teach the DSB may be repaired by the homology-directed repair (HDR) pathway allowing for precise insertions (page 29, lines 3-4). Vallier et al. teach a donor plasmid was constructed that serves as a template DNA to facilitate homology directed repair of a Cas9n-induced DSB (page 39, lines 5-6). Vallier et al. teach two hROSA26 homology arms. Vallier et al. teach to target the hROSA26 locus, cells were transfected with the plasmid (page 39, lines 5-10).
Regarding claim 323, Vallier et al. teach targeted insertion of a gene encoding a transcriptional regulator protein into a first genetic safe harbor site (page 54, claim 1). Vallier et al. teaches two hROSA26 homology arms (page 39, lines 5-10).
Regarding claim 324, Vallier et al. teach the safe harbor sites can be locus, the AAVS1 locus, the CLYBL gene, or the CCR5 gene (page, claim 10).
Regarding claim 325, Zhang et al. teach the construct comprises cis-acting long terminal repeats (page 325, paragraph 0397). Zhang et al. teach the minimum cis-acting LTRs are sufficient for replication and packaging of the vectors, which are then used to integrate the therapeutic gene into the target cell to provide permanent transgene expression (page 225, paragraph 0391). Vallier et al. teach the construct contains a splice acceptor site (page 39, lines 16-17). Zhang et al. teach the addition of a transgenic safety switch, in the form of a transgene that renders the immuno-responsive cells vulnerable to exposure to a specific signal to guard against possible adverse reactions (page 323, paragraph 0723). ). Zhang et al. teach a variety of linkers are used including flexible linkers such as GSG5 or less flexible linkers (page 401, paragraph 0842).
Zhang et al. teach nucleic acid-targeting system elements that are combined in a single vector may be arranged in any suitable orientation, such as one element located 5' with respect to ("upstream" of) or 3' with respect to ("downstream" of) a second element. The coding sequence of one element may be located on the same or opposite strand of the coding sequence of a second element, and oriented in the same or opposite direction. In some embodiments, a single promoter drives expression of a transcript encoding a nucleic acid-targeting effector protein and the nucleic acid-targeting guide RNA, embedded within one or more intron sequences. Zhang et al. teach the nucleic acid-targeting effector protein and the nucleic acid-targeting guide RNA may be operably linked to and expressed from the same promoter. One of ordinary skill in the art would be experienced in vector design and is well equipped to order the components of the vector as described by Zhang et al.
Regarding claim 326, Vallier et al. teach the construct is configured to integrate into a safe harbor site where the safe harbor sites can be the AAVS1 locus, the CLYBL gene, or the CCR5 gene (page, claim 10).
Regarding claim 327, Zhang et al. teach the safety switch is icaspase9 (page 323, paragraph 0723).
Regarding claim 328, Zhang et al. teach the hypoimmunity genes could be CTLA4 or HLA proteins, B2M, or HLA-A (page 30, paragraph 152).
Regarding claim 329, Vallier et al. teach targeting PSMA (page 35, line 1).
Regarding claim 330, Zhang et al. teach the construct includes a ribosomal skip sequence which comprises a sequence encoding an IRES sequence (page 218, paragraph 0384). Vallier et al. teach the ribosomal skipping sequence encodes 2A-coding sequence (page 39, line 17).
Regarding claim 331, Zhang et al. teach the safety switch is linked to a regulatory element (page 323, paragraph 0723). Zhang et al. further teach a polyadenylation signal can be included as a regulatory element (page 323, paragraph 0723). Vallier et al. teach the construct includes a polyadenylation signal at the 3’ end (page 10, figure 4 legend).
Regarding claim 334, Vallier et al. teach the transcriptional regulatory element is EF1α promoter or a CMV promoter. Zhang et al. further teach the promoter can be selected from a CMV, CAG, CBh, PGK, or an SV40 promoter.
Regarding claim 335, Vallier et al. teach a method of introducing a construct into a cell (cover page, abstract).
Regarding claim 336, Vallier et al. teach the construct is introduced by targeted integration by CRISPR-based methods (page 6, lines 29-33).
Regarding claim 337, Vallier et al. teach the method the construct is introduced into the cell via lipid-mediated transfection or electroporation (page 320, paragraph 0716).
Regarding claim 338, Vallier et al. and Zhang et al. teach an isolated cell or population comprising the construct as previously described in regard to claim 321.
Regarding claim 339, Zhang et al. teach reduced expression of B2M, HLA-A, or reduced expression of an endogenous TCR. (page 29, paragraph 0153).
Regarding claim 340, Vallier et al. teach the method may be used for any cell type but specifically cites stem cells (page 1, lines 5-6).
Regarding claim 341, Vallier et al. teach the differentiated cell can be an induced pluripotent stem cell (iPSC) or an embryonic stem cell (ESC). Zhang et al. further teach the cell can be a pluripotent stem cell (page 321, paragraph 0717).
Regarding claim 342, Vallier et al. teach a differentiated cell or a population prepared by culturing the stem cell to differentiate the cell into neuronal cells, pancreatic cells, and endothelial cells (Figure 15A).
Regarding claim 343, Vallier et al. teach the differentiated cell can be an induced pluripotent stem cell (iPSC) or an embryonic stem cell (ESC). Zhang et al. further teach the cell can be a pluripotent stem cell (page 321, paragraph 0717).
Regarding claim 344, Vallier et al. teach the differentiated cells is a pancreatic cell (page 33, lines 8-9).
Regarding claim 345, Zhang et al. teach a method of treating a patient in need of cell therapy comprising administering to the patient the differentiated cell (page 321, paragraph 0717).
Regarding claim 346, Zhang et al. teach a method of treating a patient in need of cell therapy comprising administering to the patient the differentiated cell (page 321, paragraph 0717).
Conclusion
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights