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 response filed on 03/17/2026 is acknowledged and has been entered into the application file.
Election/Restrictions
Applicants have previously elected without traverse Group 1, drawn to a method for producing a modified
immune cell with reduced immunogenicity and/or increased anti-neoplasia activity by multiplexed editing in the
reply filed on 08/16/2024. Claims 86, 88, 178, 180, 221, 265, 268, and 278 remain withdrawn from further
consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable
generic or linking claim. Election was made without traverse in the reply filed on 08/16/2024. Therefore, based on
the elected invention, claims 1, 3, 5, 9-10, 29-32, 34-35, 37, 43, 56-57, 65, 70- 71, 75-77, 185 and 187 are currently
under examination in the instant application.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1, 3, 5, 9-10, 29-32, 34-35, 37, 56-57, 65, 70- 71, 75-77, 185 and 187 under 35 U.S.C. 103 as being unpatentable over Zhao et al. (US20180312848A1) in view of Koonin et al. (US20180320163A1), and Liu et al. (US 10,167, 457 B2):
Applicants have traversed the rejection asserting that independent claim 1 presently recites additional limitations not taught or suggested by the applied combination. Present claim 1 requires (emphasis added) that:
"the single target nucleobase is in a splice donor site or a splice acceptor site”. This is not persuasive because Koonin et al. clearly teaches that the target sequence is a splice site (see Koonin et al. teachings on paragraph 0992).
Applicants have also argued that Zhao et al. and Koonin et al. are limited to CRISPR/Cas nucleases that introduce double strand breaks (DSBs) in the DNA, such that these beaks result in gene disruption through non-homologous end joining (NHEJ) and indel formation, which is antithesis of the single-base substitution as claimed.
Applicant's arguments have been fully considered but they are not persuasive. Although both Zhao et al. and Koonin et al. teaches gene-knockout through nucleases that introduce double strand breaks (DSBs) in the DNA, Liu et al. actually provides motivation to use single base-editing instead of introducing double strand breaks (DSBs) in the DNA. Liu et al. does actually teach introducing a premature stop codon in the coding sequence in order to disrupt the function of the gene which results in the expression of a truncated gene product, e.g., a truncated protein lacking the function of the full-length protein (see Liu et al. column 86, lines 5-8).
The rejection is therefore maintained.
RE: Rejection of claims 1 and 43 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (US20180312848A1), in view of Koonin et al. (US20180320163A1), and Liu et al., and further in view of Chen et al. (US12037583B2):
Applicants have traversed the rejection asserting that Chen et al. describes genome editing systems and methods for immuno-oncology and its disclosure is limited to the use of CRISPR/Cas nucleases (e.g., SpCas9) that introduce site-specific single- or double-strand breaks in DNA, resulting in gene modification through non-homologous end joining (NHEJ) or homology-directed repair (HDR). Chen does not describe or suggest the use of a base editor for targeted single-nucleobase conversion without introducing a double-strand break in the DNA. Thus, Chen fails to teach or suggest the base editor and "no double-strand breaks (DSB), of claim 1 as presented here.
Applicant's arguments have been fully considered but they are not persuasive. Chen et al. was only used to cure the deficiency of guide nucleic acid sequence comprising instant SEQ ID NO: 1. The rejection is therefore maintained.
New/maintained Grounds of Rejection
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, 3, 5, 9-10, 29-32, 34-35, 37, 56-57, 65, 70- 71, 75-77, 185 and 187 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (the US Patent Application Publication US20180312848A1, filed on 04/25/2018, and published on 11/01/2018) in view of Koonin et al. (the US Patent Application Publication US20180320163A1, filed on 12/14/2017, and published on 11/08/2018), and Liu et al. (the US Patent US 10,167, 457 B2, filed on 10/22/2016, and published 01/01/2019).
Regarding claim 1, 185, 187, Zhao et al. teaches a method for generating a modified T cell with a nucleic acid capable of downregulating endogenous gene expression selected from the group consisting of TCR α chain, TCR β chain, and beta-2 microglobulin (B2M) further comprising introducing a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR). Zhao et al. also teaches that the generation of modified T cells where the genes are depleted as a means to generate modified T cells with reduced immunogenicity and enhanced anti-tumor activity (Abstract and claim 18 of Zhao et al.). Zhao et al. further teaches that efficient multiplex genomic editing is required to generate universal T cells that are deficient in TCR, HLA and other genes (paragraph 0498).
However, Zhao et al. fails to teach that the modified immune cell comprises modifying the genes at a single target nucleobase in the immune cell wherein the one of the at least three genes or regulatory elements thereof is selected from the group consisting of: CD2, CD4, CD5, CD7, CD30, CD33, CD52, CD70, and CIITA.
However, Koonin et al. teaches methods of treating and/or increasing survival of a subject having a disease, such as a neoplasia, for example by administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a selected antigen, wherein the binding activates the immunoreponsive cell, thereby treating or preventing the disease (such as a neoplasia) (paragraph 1512). Koonin et al. also teaches a non-naturally occurring or engineered composition, or one or more polynucleotides encoding components of said composition, or vector or delivery systems comprising one or more polynucleotides encoding components of said composition for use in modifying a target cell in vivo, ex vivo or in vitro and, may be conducted in a manner alters the cell such that once modified the progeny or cell line of the CRISPR modified cell retains the altered phenotype (paragraph 0901). Koonin et al. also teaches that modifying CAR19 T cells eliminates the risk of graft-versus-host disease (GVHD) through the disruption of T-cell receptor expression and CD52 targeting. Such cells can be modified by knocking out, or otherwise modulating targets, for example to remove or modulate CD52, such that compositions, cells, and method of the invention can be used to modulate immune responses and to treat malignancies, viral infections, and immune disorders, in conjunction with modification of administration of T cells or other cells to patients (paragraph 1362). Koonin et al. further teaches that CD52 cells were targeted such that they became insensitive to Alemtuzumab, and thus allowed Alemtuzumab to prevent host-mediated rejection of HLA mismatched CAR19 T-cells (paragraph 1362). Koonin et al. further teaches that the target sequence is a splice site (paragraph 0992).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method for generating a modified T cell of Zhao et al. to further modify CD52 at a single target nucleobase in the immune cell with a reasonable expectation of success. One would have been motivated to have done so because disrupting CD52 results in making it insensitive to Alemtuzumab so that Alemtuzumab can be co-administered with the modified T cells to patients in need to suppress the GVHD, modulate immune responses and to treat malignancies, viral infections, and immune disorders as taught by Koonin et al.
Additionally, Liu et al. teaches a fusion protein comprising programmable DNA-binding protein that comprises a Cas9 domain, wherein the Cas9 domain when in conjunction with a bound guide RNA (gRNA) specifically binds to a target nucleic acid sequence, a cytidine deaminase domain, wherein the cytidine deaminase domain deaminates a cytosine base in a single-stranded portion of the target nucleic acid sequence when in conjunction with the Cas9 domain and the gRNA, and a base editor comprising a uracil glycosylase inhibitor (UGI) domain (claim 1 and Column 3, lines 60-67). Liu et al. also teaches way to introduce a premature stop codon in the coding sequence in order to disrupt the function of the gene which results in the expression of a truncated gene product, e.g., a truncated protein lacking the function of the full-length protein (column 86, lines 5-8). Liu et al. also teaches that base editors are capable of modifying a specific nucleotide base without generating a significant proportion of indels and capable of generating a greater proportion of intended modifications (e.g., point mutations or deaminations) versus indels (column 6, lines 21-25 and 30-35).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have substituted knocking out the genes in Zhao et al. by introducing double-stranded breaks in the DNA with the targeted single-base editing strategy of Liu et al. to disrupt the function of the gene without generating a significant proportion of indels in the modified immune cell with predictable results.
Regarding claim 3: Following discussion of claim 1 above, Zhao et al. teaches downregulating endogenous gene expression of beta-2 microglobulin (B2M) (claim 18 of Zhao et al.), which is an immune response regulation gene.
Regarding claim 5: Following discussion of claim 1 above, Zhao et al. teaches that efficient multiplex genomic editing is required to generate universal T cells that are deficient in TCR, HLA and other genes (paragraph 0498). “deficient” reads on 100% reduction in the gene expression.
Regarding claim 9: Following discussion of claim 1 above, Zhao et al. teaches introducing a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR) (claim 18 of Zhao et al.).
Regarding claim 10: Following discussion of claim 1 above, Zhao et al. teaches downregulating endogenous gene expression of beta-2 microglobulin (B2M) (claim 18 of Zhao et al.).
Regarding claim 29-32, 34, 35: Following discussion of claim 1 above, Zhao et al. teaches that the method for generating a modified T cell with a nucleic acid capable of downregulating the endogenous gene expressions comprises introducing a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on a target cell or an electroporated nucleic acid encoding a chimeric antigen receptor (CAR) (Abstract and claim 18 of Zhao et al.).
However, Zhao et al. fails to teach that the method for generating the modified T cell comprises deaminating the single target nuclease that is performed by a polypeptide comprising cytidine deaminase.
However, Liu et al. teaches a fusion protein comprising programmable DNA-binding protein that comprises a Cas9 domain, wherein the Cas9 domain when in conjunction with a bound guide RNA (gRNA) specifically binds to a target nucleic acid sequence, a cytidine deaminase domain, wherein the cytidine deaminase domain deaminates a cytosine base in a single-stranded portion of the target nucleic acid sequence when in conjunction with the Cas9 domain and the gRNA, and a base editor comprising a uracil glycosylase inhibitor (UGI) domain (claim 1 and Column 3, lines 60-67).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have substituted introducing a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on the target cell with the deaminating technique using cytidine deaminese to deplete the genes at a single target nucleobase of the modified immune cell with predictable results.
Regarding claim 37: Following discussion of claim 35 above, Liu et al. teaches that the use of a UGI domain may increase the editing efficiency of a nucleic acid editing domain that is capable of catalyzing a C to U change. For example, fusion proteins comprising a UGI domain may be more efficient in deaminating C residues (Column 5, lines 55-65 and FIG 15A).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have substituted introducing a nucleic acid encoding a modified T cell receptor (TCR) comprising affinity for a surface antigen on the target cell with the deaminating technique using
fusion proteins comprising a uracil glycosylase inhibitor (UGI) domain to deplete the genes at a single target nucleobase of the modified immune cell and increase the editing efficiency of the target nucleic acid with predictable results.
Regarding claim 56-57: Following discussion of claim 1 above, Zhao et al. teaches gRNAs were designed to target either a sequence within exon 1 of the TCR (paragraph 0397). Koonin et al. teaches that the target sequence is a splice site (paragraph 0992).
Regarding claim 65: Following discussion of claim 1 above, Zhao et al. teaches that the TCR may be modified on any cell comprising a TCR, including, for example, a helper T cell, a cytotoxic T cell, a memory T cell, regulatory T cell, natural killer T cell (paragraph 0230). Also, Zhao et al. teaches that the immune cell is derived from a human (paragraphs 0290, 0395, and 0522).
Regarding claim 70: Following discussion of claim 1 above, Zhao et al. teaches that the immune cell is derived from a human, specifically, from a single human donor (paragraphs 0290, 0395, and 0522).
Regarding claim 71: Following discussion of claim 1 above, Zhao et al. teaches that universal TCR or CAR-T cells were generated by combining lentiviral (LV) delivery of CAR and CRISPR RNA electroporation to disrupt endogenous TCR and B2M genes simultaneously (paragraph 0497).
Regarding claim 75: Following discussion of claim 71 above, Koonin et al. teaches methods of treating and/or increasing survival of a subject having a disease, such as a neoplasia, for example by administering an effective amount of an immunoresponsive cell comprising an antigen recognizing receptor that binds a selected antigen, wherein the binding activates the immunoreponsive cell, thereby treating or preventing the disease (such as a neoplasia) (paragraph 1512).
Regarding claim 76: Following discussion of claim 75 above, Zhao et al. teaches examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia (paragraph 0174).
Regarding claim 77: Following discussion of claim 76 above, Zhao et al. teaches the antigen binding domain may bind one or more antigens, such as BCMA (paragraph 0247).
Claims 1 and 43 is rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (the US Patent Application Publication US20180312848A1, filed on 04/25/2018, and published on 11/01/2018) in view of Koonin et al. (the US Patent Application Publication US20180320163A1, filed on 12/14/2017, and published on 11/08/2018) and Liu et al. (the US Patent US 10,167, 457 B2, filed on 10/22/2016, and published 01/01/2019).
as applied to claims 1, 3, 5, 9-10, 29-32, 34-35, 37, 56-57, 65, 70- 71, 75-77, 185 and 187 above, and further in view of Chen et al. (the US Patent Application Publication US12037583B2, filed on 12/02/2016).
Regarding claim 1, the teachings of Zhao et al., Koonin et al., and Liu et al. are set forth in detail above.
However, Zhao et al. in view of Koonin et al. and Liu et al. fails to teach that that the modifying comprises a guide nucleic acid sequence comprising SEQ ID NO: 1.
However, Chen et al. teaches a method of preparing cells for immunotherapy comprising modifying cells by reducing or eliminating expression of a component of a T-cell receptor (TCR) comprising introducing into said cells a gRNA molecule comprising a targeting domain (claim 52 of Chen et al.). Chen et al. further teaches that the guide RNA comprises SEQ ID NO: 10865, that is at bases 5-24, 100% identical to instant SEQ ID NO: 1.
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have substituted the nucleic acid sequence of Zhao et al. with the guide RNA comprising SEQ ID NO: 10865 as this substitution represents nothing more than the substitution of one nucleic acid sequence with another with predictable results.
Conclusion
THIS ACTION IS MADE FINAL. 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 HANAN ISAM ABUZEINEH whose telephone number is (571)272-9596. The examiner can normally be reached Mon- Fri 8:30-5:00.
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Hanan Isam Abuzieneh
/H.I.A./ Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633
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