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 .
Status of Claims / Response to Amendments
The Amendments and Remarks filed 06/15/2026 in response to the Office Action of 12/15/2025 are acknowledged and have been entered.
Claims 1-20 are currently pending.
Claims 1, 2, 4, 5, 7, 10 and 13 have been amended by Applicant.
Claims 1-20 are currently under examination in the instant Office Action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
This Office Action contains New Rejections Necessitated by Amendments.
Objections Withdrawn
The specification objections are withdrawn.
The objections to claim 4 and 13 are withdrawn.
Claim Rejections Withdrawn
The rejection of claims 2 and 7 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), second paragraph has been withdrawn.
The rejection of claims 1-20 under 35 U.S.C. 103 as being unpatentable over Moriarity et al. (WO2017023803 Date Published 2017-02-09) in view of Minshull et al. (WO2015157579A2 Date Published 2015-10-15), Albers et al. (Life science alliance 2.2, 2019), Giering et al. (Molecular Therapy, Volume 16, Issue 9, 1630–1636, 2008) and Powell et al. (Discov Med. 2015 Jan;19(102):49-57) has been withdrawn.
Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103 – Necessitated by Amendments
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Martin et al. (WO2020206248A1 Date Published 2020-10-08).
Martin et al. teaches genetically-modified immune cells expressing a microRNA-adapted shRNA (shRNAmiR) that reduces the expression of a target endogenous protein (Abstract). They teach in Figure 28C, construct 73163 which comprises a JeT promoter, a CD19 CAR gene, an SV40 bi-directional polyA sequence, an EF1 alpha core promoter, an HLA-E gene comprising a synthetic intron which comprises a B2M-targeting shRNAmiR, and a BGH termination signal (Pg 50 lines 14-17 and Figure 28C; see Figure 1 below). They also teach that construct 73163 was introduced by adeno-associated viral vectors (AAV) into T cells and inserted into the TRAC locus within the genome of the immune cell (claim 71, Pg 50 lines 21-23 and Pg 76 line 30). They further teach that shRNAmiR used in the genetically-modified immune cells comprises a mir-E scaffold, and that the miRNA flanking sequences can be present on either or both the 5' and 3' ends of the shRNAmiR molecule (Figure 28C and Pg 81 lines 15-16 and lines 30-31).
Figure 1: Construct 73163 in Figure 28C (top) and construct 73151 in Figure 28A (bottom) as taught by Martin et al.
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Martin et al. also teaches that the transgene comprising a JeT promoter driving the expression of a CD 19 CAR (Example 1) and a shRNAmiR gene as a single transcript, is terminated with a bidirectional SV40 poly A signal, and wherein the transgene was flanked on either side by homology arms directing the transgene to insert at the TRC1-2 cut site in the TRAC gene (Example 16 and Pg 151 lines 15-19). They also teach construct 73151 which comprises a P2A/furin site (Figure 28A; see Figure 1 above).
Martin et al. further teach that T cells were electroporated for transduction with AAV packaged nucleic acid constructs of interest where recombination at endogenous locus of the cell of identical sequences present in the vector were confirmed (Pg 146 lines 18-21 and Pg 147 lines 12-13). They teach that prior to electroporation, T cells were activated using medium supplemented with IL-2 (Pg. 144 lines 14-16). They also teach a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and an effective amount of the genetically-modified immune cells that can be administered to a subject in need thereof wherein the subject has a disease that can be cancer (Pg 119 lines 16-19 and Pg 121 lines 18-24). They further teach such administration of genetically-modified immune cells is a form of immunotherapy as a method for the treatment of a cancer which can include breast cancer, lung cancer, melanoma, prostate cancer and renal cell carcinoma (Pg 121 lines 22-24, Pg 42 lines 23-26 and Pg 43 lines 6-9).
Martin et al. does not specifically teach a cell comprising an exogenous polynucleotide comprising: f) a sequence encoding an exogenous TCR, wherein the sequence encoding an exogenous TCR is under control of an endogenous promoter; or wherein the exogenous TCR recognizes a cancer neoantigen.
However, Martin et al. further teaches that constructs or cassettes (used interchangeably) comprising shRNAmiR-encoding sequence optionally also include nucleic acid sequences encoding exogenous TCR and promoters (Pg 76 lines 9-10 and Pg 87 lines 21-24). They teach that the exogenous TCR may comprise alpha and beta chains, and may have specificity to any antigen or epitope of interest (Pg 94 lines 15-19). They teach that nucleic acid coding sequences may be operably linked to an endogenous promoter following insertion into the genome and that the T cell receptor alpha gene comprises an endogenous promoter (Pg 75 line 28 and Pg 88 line 31 to Pg 89 line 1).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and using a genetically-modified T cell, or a polynucleotide, or a vector, or a composition comprising said T cell, which comprises construct 73163 as taught by Martin et al. comprising a JeT promoter, a CD19 CAR gene, an SV40 bi-directional polyA sequence, an EF1 alpha core promoter and a shRNAmiR, wherein the construct is integrated at the TRAC endogenous locus within the genome of the cell and wherein the shRNAmiR (Payload) comprises a mir-E scaffold that is under the control of the exogenous promoter EF1 alpha (all of which are as taught by Martin et al.), and substituting the CD19 CAR gene with an exogenous TCR that can be specific for any tumor antigen of interest that is also taught by Martin et al., and further substituting the JeT promoter with the TCRα endogenous promoter as taught by Martin et al. such that the exogenous TCR is under control of said TCRα endogenous promoter, because of the advantage that a TCR can recognize intracellular tumor proteins making a T cell that is modified with an exogenous TCR (that recognizes specific intracellular tumor antigens) highly specific towards cancer cells; and because this creates a customizable cancer immunotherapy using TCRs that are unique and tailored precisely to individual’s specific cancer; and further because of the added advantage of an exogenous nucleic acid encoding a mir-E scaffold that simultaneously knocks-down unwanted genes in the T cell such as endogenous TCRs or immune checkpoints in a relatively simple genome-editing method. Even further, as taught by Martin et al. there is advantage in using genetically-modified immune cells that are able to replicate and expand in vivo because these can result in long term persistence in a therapy for sustained control of a disease such as cancer when compared to antibody therapies that do not have the ability to replicate and expand once administered to a subject (Pg 121 lines 25-27). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 8, it would have been obvious to perform the combined method of Martin et al. as described above and include an exogenous TCR that recognizes a cancer neoantigen since Martin et al. teaches that the exogenous TCR can have specificity to any antigen or epitope of interest and because neoantigens are new, abnormal protein markers that exist only in tumor cells when DNA mutates, they act like unique “fingerprints”, and thus engineered neoantigen specific TCR-T cells would have the advantage of selectively attacking cancer cells while sparing normal, healthy organs from damage. Further, a patient's tumor DNA can be sequenced to find such unique mutations or neoantigens and the sequences of the unique TCRs that recognize said neoantigens can be isolated to be incorporated into immune cells to arrive at a tailored personalized cancer treatment that is highly specific to eliminate the patient’s specific cancer.
Response to Arguments
In the Reply of 06/15/26, Applicant directed arguments towards (1) obviousness to modify the teachings of Moriarity to incorporate an HS4 insulator and (2) amendments to claims 1 and 10 to recite “wherein the 3' of the at least one Payload comprises a sequence encoding a 2A peptide and a sequence encoding a protease cleavage peptide or wherein the payload is an inhibitory RNA molecule and comprises a mir-E scaffold” and the unexpected results outlined in paragraphs [0455]-[0467] and [0478]-[0483].
Examiner’s Response:
Regarding the obviousness to modify the teachings of Moriarity to incorporate an HS4 insulator because Minshull teaches that HS4 insulators are able to improve heterologous gene expression, absolute predictability is not a necessary prerequisite to a case of obviousness; rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. See MPEP 2145.
Regarding the amendment of claims 1 and 10 to recite “wherein the 3' of the at least one Payload comprises a sequence encoding a 2A peptide and a sequence encoding a protease cleavage peptide or wherein the payload is an inhibitory RNA molecule and comprises a mir-E scaffold” and the unexpected results outlined in paragraphs [0455]-[0467] and [0478]-[0483], the evidence showing the unexpected results do not appear to be commensurate in scope with the invention as claimed.
Conclusion
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.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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