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 .
Application Status
Claims 1-2, 4, 7-8, 10-11, 13-21, and 24-28 are pending and examined on the merits herein.
Claim Objections
Claim 26 is objected to because of the following informalities:
Line 2 recites “engineered T cells is suspected in” should read “engineered T cells is suspended in”;
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 21 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.
Claim 21 references tables 2-4 in the claim from the specification. MPEP 2173.05 (s) indicates where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant' s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
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.
Claims 1-2, 4, 11, 13-14, 16-21, 24-25, and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Benton (US 2021/0268026 A1; published Sep 2, 2021; PTO-892), Tang (JCI Insight. 2020 Feb 27;5(4):e133977; PTO-892) and Wei (Nature 576, 471–476 (2019); PTO-892).
Regarding claims 1, 16, and 27, Benton teaches a method for treating a B-cell malignancy in a human patient, the method comprising: (i) subjecting a human patient having a B-cell malignancy to a lymphodepletion treatment; and (ii) administering to the human patient a population of genetically engineered T cells after step (i), wherein the population of genetically engineered T cells comprising T cells that comprise: (a) a disrupted T cell receptor alpha constant (TRAC) gene, (b) a nucleic acid coding for a chimeric antigen receptor (CAR) that binds CD19, wherein the CAR comprises an anti-CD19 single chain variable fragment (scFv) that comprises a heavy chain variable region set forth in SEQ ID NO: 51, and a light chain variable region set forth in SEQ ID NO: 52, and wherein the nucleic acid is inserted in the disrupted TRAC gene, and (c) a disrupted beta 2-microglobulin (β2M) gene; wherein the population of genetically engineered T cells is administered to the human patient at a dose of about 1×107 to about 1×109 CAR+ T cells; and wherein the population of genetically engineered T cells is allogeneic to the human patient (claim 1). SEQ ID NO: 51 has 100% sequence identity to the instant claimed SEQ ID NO: 81; SEQ ID NO: 52 has 100% sequence identity to the instant claimed SEQ ID NO: 82. Benton further teaches that an anti-CD19 CAR disclosed herein may include a CD3ζ signaling domain (e.g., SEQ ID NO: 38) and a CD28 co-stimulatory domain (e.g., SEQ ID NO: 36) (para 0078).
Regarding claim 2, Benton teaches wherein the lymphodepletion treatment in step (i) comprises co-administration to the human patient fludarabine at about 30 mg/m2 and cyclophosphamide at about 500-750 mg/m2 per day for three days (claim 4), wherein the population of genetically engineered T cells is administered to the human patient at a dose of about 1×107, about 3×107, about 1×108, about 3×108, or about 1×109 CAR′ T cells (claim 6), wherein step (i) is performed about 2-7 days prior to step (ii) (claim 8).
Regarding claim 4, Benton teaches a human patient may be screened to determine whether the patient is eligible to undergo a conditioning regimen (lymphodepleting treatment) and/or an allogeneic anti-CD19 CAR-T cell therapy as disclosed herein. For example, a human patient who is eligible for lymphodepletion treatment does not show one or more of the following features: (a) significant worsening of clinical status, (b) requirement for supplemental oxygen to maintain a saturation level of greater than 90%, (c) uncontrolled cardiac arrhythmia, (d) hypotension requiring vasopressor support, (e) active infection, and (f) grade ≥2 acute neurological toxicity (para 0161).
Regarding claims 11 and 13, Benton teaches wherein the B cell malignancy is refractory and/or relapsed (claim 16), wherein the B cell malignancy is diffuse large B cell lymphoma (DLBCL), high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (FL), or grade 3b FL (claims 13-14).
Regarding claim 14, Benton teaches to be considered eligible to participate in this study, a subject must meet the inclusion criteria listed below (unless indicated as optional): Diagnosed with 1 of the following B cell malignancies: Histologically confirmed B cell NHLs: DLBCL NOS, high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed FL, or grade 3b FL. Refractory or relapsed disease, as evidenced by the following cohort-specific criteria: Two or more lines of prior therapy, including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen, and have failed prior autologous hematopoietic stem cell transplantation (HSCT) or ineligible for or refused prior autologous HSCT. For refractory disease, subjects must have progressive disease on last therapy, or have stable disease following at least 2 cycles of therapy with duration of stable disease of up to 6 months. For subjects with transformed FL, subjects must have received at least 1 line of chemotherapy for disease after transformation to DLBCL (paras 0367-0375).
Regarding claims 17-18, Benton teaches wherein the anti-CD19 scFv comprises the amino acid sequence of SEQ ID NO: 47; or wherein the CAR that binds CD19 comprises the amino acid sequence of SEQ ID NO: 40 (claim 25), SEQ ID NO: 47 has 100% sequence identity to the instant claimed SEQ ID NO: 77 and SEQ ID NO: 40 has 95.7 sequence identity to the instant claimed SEQ ID NO: 74 the difference between the 2 being the inclusion of the signal sequence as taught by Benton of SEQ ID NO: 30 (para 0063).
Regarding claim 19, Benton teaches the nucleic acid may replace a fragment in the TRAC gene, for example, a fragment comprising the nucleotide sequence of SEQ ID NO: 26 (para 0081); SEQ ID NO: 26 has 100% sequence identity to the instant claimed SEQ ID NO: 18.
Regarding claim 20, Benton wherein the disrupted TRAC gene comprises the nucleotide sequence of SEQ ID NO: 54 (claim 28); SEQ ID NO: 54 comprises 100% sequence identity to the instant claimed SEQ ID NO: 90.
Regarding claim 21, Benton teaches wherein the disrupted β2M gene in the population of genetically engineered T cells comprises at least one of the nucleotide sequence set forth in SEQ ID NOs: 9-14 (claim 29), SEQ ID NO: 9 has 100% sequence identity to the instant claimed SEQ ID NO: 29 contained in table 2.
Regarding claim 24, Benton teaches wherein at least 70% of the T cells in the population of genetically engineered T cells do not express a detectable level of TCR surface protein, wherein at least 50% of the T cells in the population of genetically engineered T cells do not express a detectable level of B2M surface protein; and/or wherein at least 30% of the T cells in the population of genetically engineered T cells express a detectable level of the CAR (claim 32).
Regarding claim 28, Benton teaches the CAR-T cells can be made using blood cells from one or more healthy human donors which minimizes the risk of unintentionally transducing malignant lymphoma/leukemia cells and potentially may improve the functionality of the CAR T cells (para 0150).
Benton does not teach a disrupted Reg1 gene or TGFBRII gene.
Regarding claims 1 and 25, Wei teaches that by using CRISPR to target REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours (abstract). Wei further teaches that REGNASE-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia (abstract). Wei further teaches that Regnase1 has been identified as a target for ACT against both solid and blood cancers and point to avenues to reprogramming T cell state and metabolism in cancer immunity and immunotherapy (discussion). Wei further teaches that insertion and deletion (indel) mutations after CRISPR targeted disruption in OT-I cells transduced with either control sgRNA or Regnase-1 sgRNA, via deep sequencing analysis of indels generated at the exonic target site of the Regnase-1 gene, including 97.3% of indel events in Regnase-1-sgRNA-transduced cells isolated from tumours compared to 1.3% in control-sgRNA-transduced cells (supp Fig 1f).
Regarding claims 1 and 25, Tang teaches that although chimeric antigen receptor–modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer but this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME) (abstract). Tang further teaches that TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line–derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically and further that the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets (abstract). Tang further teaches that upon optimization, a KO efficiency of 50%–80% was achieved (Supplemental Figure 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to disrupt the Reg1 gene as taught by Wei and disrupt the TGFBRII gene as taught by Tang in the method of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC and B2M as taught by Benton. The ordinary artisan would have been motivated to do so because Wei teaches that by using CRISPR to target REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours and Tang teaches that TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line–derived xenograft and patient-derived xenograft solid tumor models. The ordinary artisan has a reasonable expectation of success to improve efficacy and persistence of the CD19-CAR-T cells with TRAC and B2M disruption by further disrupting Reg1 and TGFBRII.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 7-8, 10, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Benton (US 2021/0268026 A1; published Sep 2, 2021; PTO-892), Tang (JCI Insight. 2020 Feb 27;5(4):e133977; PTO-892) and Wei (Nature 576, 471–476 (2019); PTO-892) as applied to claims 1-2, 4, 11, 13-14, 16-21, 24-25, and 27-28 above, and further in view of Gauthier (Blood. 2021 Jan 21;137(3):323-335; PTO-892).
The teachings of Benton, Tang and Wei regarding claims 1-2, 4, 11, 13-14, 16-21, 24-25, and 27-28 are detailed above.
Regarding claims 7, 10, and 15, Benton teaches further comprising (iii) monitoring the human patient for development of acute toxicity after step (ii); and (iv) managing the acute toxicity if occurs; wherein the acute toxicity comprises tumor lysis syndrome (TLS), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), B cell aplasia, hemophagocytic lymphohistiocytosis (HLH), cytopenia, graft-versus-host disease (GvHD), hypertension, renal insufficiency, or a combination thereof (claim 10). Benton further teaches only after assessment and confirmation of safety of DL2 in Cohort A by the Safety Review Committee (SRC) may subsequent Cohort B be opened/enrolled and begin dose escalation from DL2. Due to the study's dose limit of 7×104 TCR+ cells/kg, the study may proceed with DL4 in Cohort A and/or Cohort B if a subject weighs ≥60 kg (para 0302).
Regarding claim 8, Benton teaches that the allogeneic CAR− T cell therapy disclosed herein showed treatment efficacies in human patients having B cell malignancies disclosed herein, including complete responses in certain patients and long durability of responses (para 0004).
Benton, Tang, and Wei do not teach lymphodepletion before every round of CAR-T cell therapy administration.
Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies but fail to induce durable response in most patients (abstract). Gauthier further teaches that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2 (abstract). Gauthier teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response (page 331, col 1, para 2-3). Gauthier further teaches that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients who received an increased CART2 dose and Cy-Flu lymphodepletion before CART1 (summary).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to precede each CAR-T infusion with a lymphodepletion as taught by Gauthier in the method of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by Benton, Wei and Tang. The ordinary artisan would have been motivated to do so because as Gauthier is directed to improving treatment of B cell malignancy with CD19-CAR T cells. Gauthier teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response. Gauthier further teaches that CD19-CAR T-cell therapy has shown significant efficacy for B cell malignancy but fails to induce durable response in most patients but that that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients. The ordinary artisan has a reasonable expectation of success to improve efficacy of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII with a second CAR-T infusion preceded by lymphodepletion.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Benton (US 2021/0268026 A1; published Sep 2, 2021; PTO-892), Tang (JCI Insight. 2020 Feb 27;5(4):e133977; PTO-892) and Wei (Nature 576, 471–476 (2019); PTO-892) as applied to claims 1-2, 4, 11, 13-14, 16-21, 24-25, and 27-28 above, and further in view of Pennybaker (Cytotherapy, 2020, 22S134; PTO-892).
The teachings of Benton, Tang and Wei regarding claims 1-2, 4, 11, 13-14, 16-21, 24-25, and 27-28 are detailed above.
Regarding claim 26, Benton teaches the population of genetically engineered T cells may be suspended in a cryopreservation solution (para 0032).
Benton does not teach that the cryopreservation solution contains human serum albumin.
Pennybaker teaches that the need for a stable final cell product to be delivered to the patient is essential to ensure product efficacy and safety with cellular therapies and further that it is well known that human serum albumin has critical cryoprotective activity for cell-based products in final formulations that are to be administered to the patient (background). Pennybaker further teaches a novel recombinant human serum albumin that is incorporated into an optimized chemically defined and blood-free cryopreservation media to enhance the stability of previously expanded T lymphocytes that demonstrated prolonged stability of the expanded cell product (conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use recombinant human serum albumin in the cryopreservation medium as taught by Pennybaker for the CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by Benton, Wei and Tang. The ordinary artisan would have been motivated to do so because Pennybaker teaches that it is well known that human serum albumin has critical cryoprotective activity for cell-based products in final formulations that are to be administered to the patient and further that a novel recombinant human serum albumin that is incorporated into an optimized chemically defined and blood-free cryopreservation media to enhance the stability of previously expanded T lymphocytes that demonstrated prolonged stability of the expanded cell product. The ordinary artisan has a reasonable expectation of success to incorporate recombinant human serum albumin into the cryopreservation media for CAR-T cells for patient administration with prolonged stability.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1, 7, 11, 16-18 and 27-28 are rejected under 35 U.S.C. 103 as being obvious over Dequeant (US 2022/0016173 A1; PTO-892) and Gauthier (Blood. 2021 Jan 21;137(3):323-335; PTO-892).
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claims 1 and 16-18, Dequeant teaches a method for treating cancer, the method comprising administering to a subject in need thereof a population of genetically engineered T cells, wherein the genetically engineered T cells comprise: (i) a disrupted Regnase-1 (Reg1) gene; (ii) a disrupted Transforming Growth Factor Beta Receptor II (TGFBRII) gene; and (iii) a nucleic acid encoding a chimeric antigen receptor (CAR) that binds a tumor antigen (claim 1), wherein the genetically engineered T cells comprise a disrupted T cell receptor alpha chain constant region (TRAC) gene and a disrupted beta-2-microglobulin (β2M) gene (claims 6 and 8), wherein the nucleic acid encoding the CAR is inserted in the disrupted TRAC gene (claim 9), the CAR binds CD19 and comprises an extracellular antigen binding domain specific to CD19, wherein the extracellular antigen binding domain comprises a single chain variable fragment (scFv) that comprises the amino acid sequence of SEQ ID NO: 120 (claim 10), wherein the CAR that binds CD19 comprises the amino acid sequence of SEQ ID NO: 117 or SEQ ID NO:353 (claim 11), wherein the CD19+ cancer is a hematologic cancer (claims 11-12). SEQ ID NO: 117 and 120 have 100% sequence identity with the instant claimed SEQ ID NO: 74 and 77 respectively. Dequeant further teaches a CAR includes a CD3ζ signaling domain and a CD28 co-stimulatory domain (para 0230). Dequeant further teaches that treatment groups received a single 200 μl intravenous dose of 1×107 anti-CAR+ T cells (para 0424).
Regarding claim 27, Dequeant teaches wherein the genetically engineered T cells are allogeneic to the subject (claim 20).
Regarding claim 28, Dequeant teaches wherein the genetically engineered T cells are prepared from immune cells of one or more human donors (claim 19).
Dequeant does not teach the treatment comprising lymphodepletion prior to the cell therapy or that the hematological cancer is a B cell malignancy.
Regarding claims 1, 7, and 11, Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies but fail to induce durable response in most patients (abstract). Gauthier further teaches that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2 (abstract). Gauthier teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response (page 331, col 1, para 2-3). Gauthier further teaches that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients who received an increased CART2 dose and Cy-Flu lymphodepletion before CART1 (summary). Gauthier further teaches CART1 were administered at 2x10^5/kg, 2x10^6/kg, or 2x10^7/kg, while CART2 were administered at 2x10^6/kg or 2x10^7/kg (page 324, col 1, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to precede each CAR-T infusion with a lymphodepletion to treat relapsed or refractory B cell malignancies as taught by Gauthier in the method of treating a hematological malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by Dequeant. The ordinary artisan would have been motivated to do so because Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Gauthier further teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response. Gauthier further teaches that CD19-CAR T-cell therapy has shown significant efficacy for B cell malignancy but fails to induce durable response in most patients but that that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients. The ordinary artisan has a reasonable expectation of success to improve efficacy of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII with a second CAR-T infusion preceded by lymphodepletion.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1, 7, 11, 13, 17-21, 24-25, and 28 are rejected under 35 U.S.C. 103 as being obvious over Ghonime (US 2023/0303713 A1; PTO-892) and Gauthier (Blood. 2021 Jan 21;137(3):323-335; PTO-892).
The applied reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claims 1, Ghonime teaches a population of genetically engineered T cells, comprising: (i) a disrupted T cell receptor alpha chain constant region (TRAC) gene, (ii) a disrupted beta-2-microglobulin (B2M) gene, (iii) a disrupted Regnase-1 (Reg 1) gene, (iv) a disrupted Transforming Growth Factor Beta Receptor II (TGFBRII) gene, and (v) a nucleic acid encoding a chimeric antigen receptor (CAR) that binds human CD19 (anti-CD19 CAR), wherein the anti-CD19 CAR comprises a single chain variable fragment (scFv) that binds CD19 (anti-CD19 scFv), a co-stimulatory domain of CD28, and a CD3zeta cytoplasmic signaling domain, the anti-CD19 scFv comprising (a) a heavy chain variable region (VH) that comprises the same heavy chain complementary determining regions (CDRs) as those in SEQ ID NO: 81; and (b) a light chain variable region (VL) that comprises the same light chain CDRs as those in SEQ ID NO: 82; and wherein the nucleic acid encoding the anti-CD19 CAR is inserted at the disrupted TRAC gene (claims 1 and 4), a method for treating a CD19+ cancer, comprising administering to a subject in need thereof an effective amount of the population of genetically engineered T cells of claim 1 (claim 14), wherein the subject is a human patient having a B cell malignancy (claim 15), wherein the effective amount of the population of genetically engineered T cells ranges from about 1x10^7 to about 6x10^8 CAR+ T cells (claim 18).
Regarding claim 11, Ghonime teaches wherein the B cell malignancy is a refractory or relapsed B cell malignancy (claim 16).
Regarding claim 13, Ghonime teaches wherein the B cell malignancy is non-Hodgkin lymphoma, which optionally is selected from the group consisting of diffuse large B cell lymphoma (DLBCL), which optionally is DLBCL not otherwise specified (NOS), high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (FL), and grade 3b FL (claim 17).
Regarding claim 17 Ghonime teaches wherein the anti-CD19 scFv comprises the amino acid sequence of SEQ ID NO: 77 (claim 5)
Regarding claim 18, Ghonime teaches wherein the anti-CD19 CAR comprises the amino acid sequence of SEQ ID NO: 74 (claim 6)
Regarding claim 19, Ghonime teaches wherein a fragment comprising the nucleotide sequence of SEQ ID NO: 18 in the TRAC gene is deleted and replaced by the nucleic acid encoding the anti-CD19 CAR (claim 7).
Regarding claim 20, Ghonime teaches wherein the disrupted TRAC gene comprises the nucleotide sequence of SEQ ID NO: 91 (claim 8)
Regarding claim 21, Ghonime teaches wherein the disrupted B2M gene in the T cells comprises one or more of the nucleotide sequences listed in Table 2 (claim 9), wherein the disrupted Reg1 gene in the T cells comprises one or more of the nucleotide sequences listed in Table 4 (claim 10), wherein the disrupted TGFBRII gene in the T cells comprises one or more of the nucleotide sequences listed in Table 3 (claim 11).
Regarding claim 24, Ghonime teaches wherein at least 50% of the T cells in the population express the anti-CD19 CAR, wherein at least 90% of the T cells in the population are TCR-, wherein at least 60% of the T cells in the population are B2M-, wherein at least 80% of the T cells in the population are TGFBRII-, and/or wherein at least 90% of the T cells in the population are Reg 1- (claim 2).
Regarding claim 25, Ghonime teaches wherein the population of genetically engineered T cells of claim 2, wherein: (a) at least 75% of the T cells express the anti-CD19 CAR; (b) at least 99% of the T cells are TCR-; ( c) about 65 % to about 80% of the T cells are B2M-; (d) about 80% to about 90% of the T cells are TGFBRII-; and/or (e) about 95% to about 97% of the T cells are Reg1- (claim 3).
Regarding claim 28, Ghonime teaches wherein the T cells are derived from one or more healthy human donors (claims 12-13).
The sequences disclosed in the claims are identical to the same number instant claimed sequences.
The copending claims do not teach a lymphodepletion step prior to CAR-T administration.
Regarding claims 1, 7, and 11, Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies but fail to induce durable response in most patients (abstract). Gauthier further teaches that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2 (abstract). Gauthier teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response (page 331, col 1, para 2-3). Gauthier further teaches that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients who received an increased CART2 dose and Cy-Flu lymphodepletion before CART1 (summary). Gauthier further teaches CART1 were administered at 2x10^5/kg, 2x10^6/kg, or 2x10^7/kg, while CART2 were administered at 2x10^6/kg or 2x10^7/kg (page 324, col 1, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to precede each CAR-T infusion with a lymphodepletion as taught by Gauthier in the method of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by Ghonime. The ordinary artisan would have been motivated to do so because Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Gauthier further teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response. Gauthier further teaches that CD19-CAR T-cell therapy has shown significant efficacy for B cell malignancy but fails to induce durable response in most patients but that that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients. The ordinary artisan has a reasonable expectation of success to improve efficacy of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII with a second CAR-T with each infusion preceded by lymphodepletion.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2, 11, 13, 16-18, 20-21, 24-25, and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9-11, 15, , 17-19 of U.S. Patent No. 11,389,481 B2 in view of Tang (JCI Insight. 2020 Feb 27;5(4):e133977; PTO-892) and Wei (Nature 576, 471–476 (2019); PTO-892).
Regarding claims 1, 16, and 27, the patented claims teach a method for treating a B-cell malignancy in a human patient, the method comprising: (i) subjecting a human patient having a B-cell malignancy to a lymphodepletion treatment; and (ii) administering to the human patient a population of genetically engineered T cells after step (i), wherein the population of genetically engineered T cells comprising T cells that comprise: (a) a disrupted T cell receptor alpha constant (TRAC) gene, (b) a nucleic acid coding for a chimeric antigen receptor (CAR) that binds CD19, wherein the CAR comprises an anti-CD19 single chain variable fragment (scFv) that comprises a heavy chain variable region set forth in SEQ ID NO: 51, and a light chain variable region set forth in SEQ ID NO: 52, and wherein the nucleic acid is inserted in the disrupted TRAC gene, and (c) a disrupted beta 2-microglobulin (β2M) gene; wherein the population of genetically engineered T cells is administered to the human patient at a dose of about 1×107 to about 1×109 CAR+ T cells; and wherein the population of genetically engineered T cells is allogeneic to the human patient (claim 1). SEQ ID NO: 51 has 100% sequence identity to the instant claimed SEQ ID NO: 81; SEQ ID NO: 52 has 100% sequence identity to the instant claimed SEQ ID NO: 82.
Regarding claim 2, the patented claims teach wherein the lymphodepletion treatment in step (i) comprises co-administration to the human patient fludarabine at about 30 mg/m2 and cyclophosphamide at about 500-750 mg/m2 per day for three days (claim 3-4), wherein the population of genetically engineered T cells is administered to the human patient at a dose of about 1×107, about 3×107, about 1×108, about 3×108, or about 1×109 CAR′ T cells (claim 5), wherein step (i) is performed about 2-7 days prior to step (ii) (claim 6).
Regarding claims 11 and 13, the patented claims teach wherein the B cell malignancy is refractory and/or relapsed (claim 11), wherein the B cell malignancy is diffuse large B cell lymphoma (DLBCL), high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (FL), or grade 3b FL (claims 9-10).
Regarding claims 17-18, the patented claims teach wherein the anti-CD19 scFv comprises the amino acid sequence of SEQ ID NO: 47; or wherein the CAR that binds CD19 comprises the amino acid sequence of SEQ ID NO: 40 (claim 15), SEQ ID NO: 47 has 100% sequence identity to the instant claimed SEQ ID NO: 77 and SEQ ID NO: 40 has 95.7 sequence identity to the instant claimed SEQ ID NO: 74 the difference between the two sequences being the inclusion of the signal sequence as evidenced by the instant specification in Table 5, SEQ ID NO: 51.
Regarding claim 20, the patented claims teach wherein the disrupted TRAC gene comprises the nucleotide sequence of SEQ ID NO: 54 (claim 17); SEQ ID NO: 54 comprises 100% sequence identity to the instant claimed SEQ ID NO: 90.
Regarding claim 21, the patented claims teach wherein the disrupted β2M gene in the population of genetically engineered T cells comprises at least one of the nucleotide sequence set forth in SEQ ID NOs: 9-14 (claim 18), SEQ ID NO: 9 has 100% sequence identity to the instant claimed SEQ ID NO: 29 contained in table 2.
Regarding claim 24, the patented claims teach wherein at least 70% of the T cells in the population of genetically engineered T cells do not express a detectable level of TCR surface protein, wherein at least 50% of the T cells in the population of genetically engineered T cells do not express a detectable level of B2M surface protein; and/or wherein at least 30% of the T cells in the population of genetically engineered T cells express a detectable level of the CAR (claim 19).
The patented claims do not teach a disrupted Reg1 gene or TGFBRII gene.
Regarding claims 1 and 25, Wei teaches that by using CRISPR to target REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours (abstract). Wei further teaches that REGNASE-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia (abstract). Wei further teaches that Regnase1 has been identified as a target for ACT against both solid and blood cancers and point to avenues to reprogramming T cell state and metabolism in cancer immunity and immunotherapy (discussion). Wei further teaches that insertion and deletion (indel) mutations after CRISPR targeted disruption in OT-I cells transduced with either control sgRNA or Regnase-1 sgRNA, via deep sequencing analysis of indels generated at the exonic target site of the Regnase-1 gene, including 97.3% of indel events in Regnase-1-sgRNA-transduced cells isolated from tumours compared to 1.3% in control-sgRNA-transduced cells (supp Fig 1f).
Regarding claims 1 and 25, Tang teaches that although chimeric antigen receptor–modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer but this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME) (abstract). Tang further teaches that TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line–derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically and further that the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets (abstract). Tang further teaches that upon optimization, a KO efficiency of 50%–80% was achieved (Supplemental Figure 2).
It would have been obvious to one of ordinary skill in the art to disrupt the Reg1 gene as taught by Wei and disrupt the TGFBRII gene as taught by Tang in the method of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC and B2M as taught by the patented claims. The ordinary artisan would have been motivated to do so because Wei teaches that by using CRISPR to target REGNASE-1, CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours and Tang teaches that TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line–derived xenograft and patient-derived xenograft solid tumor models. The ordinary artisan has a reasonable expectation of success to improve efficacy and persistence of the CD19-CAR-T cells with TRAC and B2M disruption by further disrupting Reg1 and TGFBRII.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1, 16-18 and 27-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-12, and 18-20 of U.S. Patent No. 11,497,773 B2 in view of Benton (US 2021/0268026 A1; published Sep 2, 2021; PTO-892).
Regarding claims 1 and 16-18, the patented claims teach a method for treating cancer, the method comprising administering to a subject in need thereof a population of genetically engineered T cells, wherein the genetically engineered T cells comprise: (i) a disrupted Regnase-1 (Reg1) gene; (ii) a disrupted Transforming Growth Factor Beta Receptor II (TGFBRII) gene; and (iii) a nucleic acid encoding a chimeric antigen receptor (CAR) that binds a tumor antigen (claim 1), wherein the genetically engineered T cells comprise a disrupted T cell receptor alpha chain constant region (TRAC) gene and a disrupted beta-2-microglobulin (β2M) gene (claims 6-7), wherein the nucleic acid encoding the CAR is inserted in the disrupted TRAC gene (claim 8), the CAR binds CD19 and comprises an extracellular antigen binding domain specific to CD19, wherein the extracellular antigen binding domain comprises a single chain variable fragment (scFv) that comprises the amino acid sequence of SEQ ID NO: 120 (claim 9 and 18), wherein the CAR that binds CD19 comprises the amino acid sequence of SEQ ID NO: 117 or SEQ ID NO:353 (claim 10), wherein the CD19+ cancer is a hematologic cancer (claims 11-12). SEQ ID NO: 117 and 120 have 100% sequence identity with the instant claimed SEQ ID NO: 74 and 77 respectively.
Regarding claim 27, the patented claims teach wherein the genetically engineered T cells are allogeneic to the subject (claim 20).
Regarding claim 28, the patented claims teach wherein the genetically engineered T cells are prepared from immune cells of one or more human donors (claim 19).
The patented claims do not teach the domains of the CAR except the extracellular domain; the dose of CAR-T cells administered to the patient; the treatment comprising lymphodepletion prior to the cell therapy or that the hematological cancer is a B cell malignancy.
Regarding claims 1, 16, and 27, Benton teaches a method for treating a B-cell malignancy in a human patient, the method comprising: (i) subjecting a human patient having a B-cell malignancy to a lymphodepletion treatment; and (ii) administering to the human patient a population of genetically engineered T cells after step (i), wherein the population of genetically engineered T cells comprising T cells that comprise: (a) a disrupted T cell receptor alpha constant (TRAC) gene, (b) a nucleic acid coding for a chimeric antigen receptor (CAR) that binds CD19, wherein the CAR comprises an anti-CD19 single chain variable fragment (scFv) that comprises a heavy chain variable region set forth in SEQ ID NO: 51, and a light chain variable region set forth in SEQ ID NO: 52, and wherein the nucleic acid is inserted in the disrupted TRAC gene, and (c) a disrupted beta 2-microglobulin (β2M) gene; wherein the population of genetically engineered T cells is administered to the human patient at a dose of about 1×107 to about 1×109 CAR+ T cells; and wherein the population of genetically engineered T cells is allogeneic to the human patient (claim 1). SEQ ID NO: 51 has 100% sequence identity to the instant claimed SEQ ID NO: 81; SEQ ID NO: 52 has 100% sequence identity to the instant claimed SEQ ID NO: 82. Benton further teaches that an anti-CD19 CAR disclosed herein may include a CD3ζ signaling domain (e.g., SEQ ID NO: 38) and a CD28 co-stimulatory domain (e.g., SEQ ID NO: 36) (para 0078).
It would have been obvious to one of ordinary skill in the art to use the complete structure of the CD19-CAR, the established CAR-T dosing with preceding lymphodepletion and to treat B cell malignancy as taught by Benton in the method of treating a CD19+ hematological cancer with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by the patented claims. The ordinary artisan would have been motivated to do so because the patented claims and Benton teach the same structure used in the treatment so it would be obvious that the treatment could also be administered for B cell malignancy in particular at the established dosing taught by Benton. The ordinary artisan would have a reasonable expectation of success to use the complete structure of the CD19-CAR, the established CAR-T dosing with preceding lymphodepletion to treat B cell malignancy in the method of treating a CD19+ hematological cancer with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII.
Claims 1, 7, 11, 13, 17-21, 24-25, and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 18/188,436 (reference application) in view of and Gauthier (Blood. 2021 Jan 21;137(3):323-335; PTO-892).
Regarding claims 1, the copending claims teach a population of genetically engineered T cells, comprising: (i) a disrupted T cell receptor alpha chain constant region (TRAC) gene, (ii) a disrupted beta-2-microglobulin (B2M) gene, (iii) a disrupted Regnase-1 (Reg 1) gene, (iv) a disrupted Transforming Growth Factor Beta Receptor II (TGFBRII) gene, and (v) a nucleic acid encoding a chimeric antigen receptor (CAR) that binds human CD19 (anti-CD19 CAR), wherein the anti-CD19 CAR comprises a single chain variable fragment (scFv) that binds CD19 (anti-CD19 scFv), a co-stimulatory domain of CD28, and a CD3zeta cytoplasmic signaling domain, the anti-CD19 scFv comprising (a) a heavy chain variable region (VH) that comprises the same heavy chain complementary determining regions (CDRs) as those in SEQ ID NO: 81; and (b) a light chain variable region (VL) that comprises the same light chain CDRs as those in SEQ ID NO: 82; and wherein the nucleic acid encoding the anti-CD19 CAR is inserted at the disrupted TRAC gene (claims 1 and 4), a method for treating a CD19+ cancer, comprising administering to a subject in need thereof an effective amount of the population of genetically engineered T cells of claim 1 (claim 14), wherein the subject is a human patient having a B cell malignancy (claim 15), wherein the effective amount of the population of genetically engineered T cells ranges from about 1x10^7 to about 6x10^8 CAR+ T cells (claim 18).
Regarding claim 11, the copending claims teach wherein the B cell malignancy is a refractory or relapsed B cell malignancy (claim 16).
Regarding claim 13, the copending claims teach wherein the B cell malignancy is non-Hodgkin lymphoma, which optionally is selected from the group consisting of diffuse large B cell lymphoma (DLBCL), which optionally is DLBCL not otherwise specified (NOS), high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, transformed follicular lymphoma (FL), and grade 3b FL (claim 17).
Regarding claim 17, the copending claims teach wherein the anti-CD19 scFv comprises the amino acid sequence of SEQ ID NO: 77 (claim 5)
Regarding claim 18, the copending claims teach wherein the anti-CD19 CAR comprises the amino acid sequence of SEQ ID NO: 74 (claim 6)
Regarding claim 19, the copending claims teach wherein a fragment comprising the nucleotide sequence of SEQ ID NO: 18 in the TRAC gene is deleted and replaced by the nucleic acid encoding the anti-CD19 CAR (claim 7).
Regarding claim 20, the copending claims teach wherein the disrupted TRAC gene comprises the nucleotide sequence of SEQ ID NO: 91 (claim 8)
Regarding claim 21, the copending claims teach wherein the disrupted B2M gene in the T cells comprises one or more of the nucleotide sequences listed in Table 2 (claim 9), wherein the disrupted Reg1 gene in the T cells comprises one or more of the nucleotide sequences listed in Table 4 (claim 10), wherein the disrupted TGFBRII gene in the T cells comprises one or more of the nucleotide sequences listed in Table 3 (claim 11).
Regarding claim 24, the copending claims wherein at least 50% of the T cells in the population express the anti-CD19 CAR, wherein at least 90% of the T cells in the population are TCR-, wherein at least 60% of the T cells in the population are B2M-, wherein at least 80% of the T cells in the population are TGFBRII-, and/or wherein at least 90% of the T cells in the population are Reg 1- (claim 2).
Regarding claim 25, the copending claims teach wherein the population of genetically engineered T cells of claim 2, wherein: (a) at least 75% of the T cells express the anti-CD19 CAR; (b) at least 99% of the T cells are TCR-; ( c) about 65 % to about 80% of the T cells are B2M-; (d) about 80% to about 90% of the T cells are TGFBRII-; and/or (e) about 95% to about 97% of the T cells are Reg1- (claim 3).
Regarding claim 28, the copending claims teach wherein the T cells are derived from one or more healthy human donors (claims 12-13).
The sequences disclosed in the claims are identical to the same number instant claimed sequences.
The copending claims do not teach a lymphodepletion step prior to CAR-T administration.
Regarding claims 1, 7, and 11, Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies but fail to induce durable response in most patients (abstract). Gauthier further teaches that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2 (abstract). Gauthier teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response (page 331, col 1, para 2-3). Gauthier further teaches that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients who received an increased CART2 dose and Cy-Flu lymphodepletion before CART1 (summary). Gauthier further teaches CART1 were administered at 2x10^5/kg, 2x10^6/kg, or 2x10^7/kg, while CART2 were administered at 2x10^6/kg or 2x10^7/kg (page 324, col 1, para 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to precede each CAR-T infusion with a lymphodepletion as taught by Gauthier in the method of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII as taught by the copending claims. The ordinary artisan would have been motivated to do so because Gauthier teaches that CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Gauthier further teaches that Cy-Flu lymphodepletion correlates with better in vivo CAR T-cell peak expansion and persistence after both CART1 and CART2 and that CD8+ and CD4+ CAR T-cell peak expansion after CART2 was strongly associated with response. Gauthier further teaches that CD19-CAR T-cell therapy has shown significant efficacy for B cell malignancy but fails to induce durable response in most patients but that that second infusions of CD19 CAR T cells were feasible and led to durable responses in a subset of patients. The ordinary artisan has a reasonable expectation of success to improve efficacy of treating a B cell malignancy with CD19-CAR T cells with disrupted TRAC, B2M, Reg1, and TGFRII with a second CAR-T with each infusion preceded by lymphodepletion.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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