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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/24/2025 has been entered.
Claim Status
1. The Amendment filed 06/24/2025 has been entered. Claims 1 – 3, 5 – 6, 9 – 12, 14, 17 and new claims 57 – 58 are pending and under consideration. Claims 26 – 29, 31 -32, 36 – 39, 41, and 44 have been cancelled.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 17 and 26 – 44) in the reply filed on 05/06/2024 is acknowledged.
3. Claims 18 – 25 and 45 – 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 05/06/2024.
Priority
4. This application is a U.S. national stage application under 37 U.S.C. 371 of PCT International Application PCT/US2019/034900, filed May 31, 2019, which claims benefit of U.S. Provisional Application No. 62/679,348 filed June 1, 2018 and U.S. Provisional Application No. 62/753,485 filed October 31, 2018.
Withdrawn Claim Rejections
5. The rejection of claims 1 – 3, 5 – 6 and 9 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claims.
6. The rejection of claims 10 – 12, 14, and 17 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to the claims.
7. The rejection of claims 26 – 29, 31 – 32, and 35 under 35 U.S.C. 103 is rendered moot by Applicant’s cancellation of these claims.
8. The rejection of claims 36 – 39, 41, and 44 under 35 U.S.C. 103 is rendered moot by Applicant’s cancellation of these 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
9. Claim(s) 1 – 3, 5 – 6, and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sather (US-20190136230-A1; previously cited), hereinafter Sather, in view of Lee (Lee DW, et. al. Lancet. 2015 Feb 7;385(9967):517-528; previously cited), hereinafter Lee in view of Sentman (WO-2015066262-A1; previously cited), hereinafter Sentman which is cited on the IDS filed 11/30/2020, in view of Brogdon (US-10221245-B2; previously cited), hereinafter Brogdon in view of Hercus (Hercus, Timothy R., et al. Proceedings of the National Academy of Sciences 91.13 (1994): 5838-5842.), hereinafter Hercus.
Regarding claim 1, Sather teaches a method of producing T cells expressing a chimeric antigen receptor (CAR) by introducing a nucleic acid molecule encoding a CAR into an ex vivo T cell (page 14, paragraph 0168; page 12, paragraph 0154) (“chimeric antigen receptor T cell”, “nucleic acid construct”, “ex vivo T cell”, “nucleic acid encoding said chimeric antigen receptor” of claim 1). Sather teaches in Example 4 transducing T cells with a nucleic acid encoding anti-CD19 CAR where the CAR includes an anti-CD19 scFv (“introducing a nucleic acid construct into an ex vivo T cell to form an CD19 CAR+ T cell” and “a nucleic acid encoding said chimeric antigen receptor” and “wherein the chimeric antigen receptor targets CD19 tumor-associated antigen”) (page 107, 1657) but does not teach SEQ ID NO: 2. Sather teaches the CAR has binding specificity for a tumor associated antigen such as CD19 (“wherein the chimeric antigen receptor targets CD19 tumor-associated antigen” of claim 1)(page 20, paragraph 0226). Sather teaches a method for genetic disruption in T cells genetically engineered to express CD19 CAR in Example 4, however, the targeted gene for disruption is PDCD1 and not GM-CSF of claim 1 (page 107 – 108, 1657 – 1658). Sather teaches the method of disruption in Example 4 comprises introducing a guide RNA and Cas9 RNP (“nucleic acid encoding a guide RNA”, step a) (page 108, 1658), however the guide RNA is not complementary to a GM-CSF mRNA and the RNP does not comprise a nucleic acid encoding a Cas nuclease. Sather teaches cells expressed the CAR and were negative for PD-1 expression(page 108, 1660 – 1661). Sather teaches the gRNA comprises a targeting domain which is complementary to a target nucleic acid (page 28, 0307 – 0308). Sather teaches nucleic acids encoding Cas9 (page 56, 0735 – 0740).
Regarding claims 5, 6, and 9, Sather teaches lentiviral transduction (claim 9) of the lentiviral vector (claim 5 and 6) comprising a nucleic acid encoding anti-CD19 CAR (page 107, 1657).
Sather does not teach “expressing a reduced level of said GM-CSF polypeptides”, “said guide RNA is complementary to a GM-CSF messenger RNA”, SEQ ID NO: 2, or “wherein said CD19 CAR+ T cell comprises enhanced in vivo antitumor activity…” of claim 1 or SEQ ID NO: 1 of claim 2 or Cas9 of claim 3 or a nucleic acid construct comprising gRNA and Cas is a viral vector of claim 5 or a lentiviral vector of claim 6 or GM-CSF K/O CD19 CAR + T cell of claim 57. However, Sather teaches reduced tumor size of leukemic cell tumors with CAR+ T cells with deletion of PD1 in Figure 32 where knockout does not affect the antitumor activity of CAR+ T cells (page 117 – 118, 1722). Sather teaches PD-1 encoded by the PDCD1 gene suppresses activity of cytotoxic T cells and can inhibit tumor immunity to provide an immune escape for tumor cells (page 12, 0155). Sather teaches Sather teaches strategies are available for engineering immune cells expressing CARs and for suppression or repression of gene expression in the cells (page 1, 0004). Sather teaches improved strategies are needed to improve efficacy of the cells and improving the activity and/or survival of the cells upon administration (page 1, 0004). Sather teaches the cells can be used to treat hematological malignancies including leukemia including ALL (page 84, 1179). Sather teaches the anti-CD19 CAR T cells with PDCD1-deleted suppressed tumor growth and that deletion did not impair the in vivo anti-tumor function of the CAR T cells (page 117 – 119, paragraph 1722 and Figure 32). Sather teaches the step of introducing the nucleic acid encoding a CAR and the step of introducing the Cas9/gRNA agent can occur simultaneously (page 14, paragraph 0170). Sather teaches Cas9-enconding and guide RNA-encoding DNA can be delivered by a vector (page 69, paragraph 0999 – 1000).
Regarding GM-CSF of claim 1, Lee teaches infusion of T cells expressing CD19-CAR led to cytokine release syndrome where patients had elevated levels of GM-CSF (Abstract, Figure 3A, and page 525, left col. paragraph 3). Lee teaches the safety of CD19-CAR T cell therapy will improve with the adoption of standardized treatment algorithms aimed at preventing life-threatening cytokine release syndrome (page 527, left col. paragraph 3). Lee teaches B-ALL is the most common malignancy in childhood (page 517, left col. para. 1). Lee teaches cure of B-ALL requires prolonged therapy with substantial and short-term and long-term toxicities (page 517, left col.). Lee teaches patients with primary or recurrent refractory B-ALL who do not have complete remission negative for minimum residual disease with cytotoxic chemotherapy have dismal survival rates of less than 10% and outcomes for these patients have not improved substantially in the last two decades (page 517, left col.). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy.
Regarding “expressing a reduced level of said GM-CSF polypeptides” and “said guide RNA is complementary to a GM-CSF messenger RNA” and “nucleic acid encoding a Cas nuclease” of claim 1, Sentman teaches a CRISPR method for elimination of GM-CSF where the method comprises a nucleic acid encoding guide RNA and Cas nuclease in T cells (Figure 5; page 5, 0010). Sentman teaches that GM-CSF-deficient CAR T cells reduces cytokine levels and acute weight changes and toxicity are not observed when compared to wild-type or IFN-gamma deficient CAR T cells (Figure 1 – 4; page 5, 0011). Sentman teaches the method for making GM-CSF-deficient cells by contacting cells with an antisense nucleic acid that is complementary to the mRNA sequence encoding GM-CSF (page 16, paragraph 0032 and Table 1).
Regarding claim 2, Sentman teaches LGH-3 comprises SEQ ID NO: 1 in Figure 5 and Table 1 (page 5, 0010).
Regarding claim 3, Sentman teaches the nucleic acid encodes Cas9 in Figure 5 (page 5, 0010).
Regarding claim 5 and 6, Sentman teaches a lentiviral vector nucleic acid in Figure 5 (page 5, 0010).
Regarding claim 9, Sentman teaches transduction in Example 1 (page 39, 0076).
Regarding GM-CSFK/O CD19 CAR + T cell of claim 57, Sentman teaches GM-CSF-deficient cells can be the result of a GM-CSF deletion or disruption (page 4, 0005).
Sentman does not teach SEQ ID NO: 1 or wherein said CD19 CAR+ T cell comprises enhanced in vivo antitumor activity as compared to a comparable CD19 CAR+ T cell expressing a wild-type level of GM-CSF polypeptides” of claim 1. However, Sentman teaches the cells can be used to treat ALL (page 37, 0072). Sentman teaches the method prevents toxicity of adoptive cell therapy of CAR-bearing T cells (page 3, paragraph 0005). Sentman teaches tumor specific antigens targeted by the CARs can be CD19 (page 30, paragraph 0059). Sentman teaches infusion of GM-CSF-deficient CAR T cells reduces serum cytokine levels, and acute weight changes and toxicity are not observed (page 4, paragraph 006; page 5, paragraph 0011 and Figures 1 – 3). Sentman teaches immune cells lacking functional GM-CSF result in much less toxicity (page 5, paragraph 0012). Sentman teaches an effective amount of immune cells to reduce the size of a tumor or eliminate tumor growth or regrowth (page 36, 0069). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF with the teachings of Sentman regarding knocking out GM-CSF in CAR+ T cells to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy.
Regarding SEQ ID NO: 2 of claim 1, Brogdon teaches chimeric antigen receptor specific to CD19 where SEQ ID NO: 99 of Brogdon (col. 32 lines 8 – 9 and col. 257 – 259) is SEQ ID NO: 2 of claim 1. Brogdon teaches leukemias including ALL and B-ALL are associated with CD19 (col. 12, lines 44 – 67).
Regarding “wherein said CD19 CAR+ T cell comprises enhanced in vivo antitumor activity as compared to a comparable CD19 CAR+ T cell expressing a wild-type level of GM-CSF polypeptides” of claim 1, Hercus teaches GM-CSF may play a role in the pathogenesis of leukemia where some leukemic cells require GM-CSF for proliferation and survival (page 5838, left col. para. 2 and right col. para. 1). Hercus teaches mutant GM-CSF act as antagonists of GM-CSF-dependent proliferation in leukemic cells (page 5838, right col. last para.; page 5840, left col. para. 2; Table 2). Hercus teaches potential applications of GM-CSF antagonists in vivo are inhibition of tumor cell growth (page 5841, right col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Sather regarding a method of making CD19 CAR+ T cells having reduced levels of PD-1 with the teachings of Lee regarding infusion of T cells expressing CD19-CAR led to cytokine release syndrome where patients had elevated levels of GM-CSF with the teachings of Sentman regarding a method of reducing the level of GM-CSF in CAR+ T cells by CRISPR/Cas with the teachings of Brogdon regarding the nucleic acid sequence of a CD19 CAR for treating leukemia with the teachings of Hercus regarding reduced activity of GM-CSF can inhibit leukemic cell growth to arrive at the claimed method where CD19 CAR+ T cells with reduced levels of GM-CSF and PD-1 are madee that enhance in vivo antitumor activity compared to CD19 CAR+ T cells with wild type levels of GM-CSF. One would have been motivated to combine the teachings of Sather, Lee, Sentman, Brogdon, and Hercus in a method to produce CD19 CAR+ T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in leukemia patients undergoing CD19 CAR T cell therapy as Sather teaches improved strategies are needed to improve efficacy of the cells and improving the activity and/or survival of the cells upon administration, Lee teaches patients with primary or recurrent refractory B-ALL who do not have complete remission negative for minimum residual disease with cytotoxic chemotherapy have dismal survival rates of less than 10% and outcomes for these patients have not improved substantially in the last two decades and Hercus teaches GM-CSF may play a role in the pathogenesis of leukemia where some leukemic cells require GM-CSF for proliferation and survival. One would have a reasonable expectation of success in combining the teachings as Sather teaches reduced tumor size of leukemic cell tumors with CAR+ T cells with deletion of PD1, Sentman teaches infusion of GM-CSF-deficient CAR T cells reduces serum cytokine levels, and acute weight changes and toxicity are not observed and Hercus teaches mutant GM-CSF act as antagonists of GM-CSF-dependent proliferation in leukemic cells.
10. Claim(s) 10 – 12, 14, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sather (US-20190136230-A1; previously cited), hereinafter Sather, in view of Lee (Lee DW, et. al. Lancet. 2015 Feb 7;385(9967):517-528; previously cited), hereinafter Lee, in view of Sentman (WO-2015066262-A1; previously cited), hereinafter Sentman which is cited on the IDS filed 11/30/2020, in view of Brogdon (US-10221245-B2; previously cited), hereinafter Brogdon in view of Hercus (Hercus, Timothy R., et al. Proceedings of the National Academy of Sciences 91.13 (1994): 5838-5842.), hereinafter Hercus.
Regarding claim 10 , 12, and 14, Sather teaches a method of producing T cells expressing a chimeric antigen receptor (CAR) by introducing a nucleic acid molecule encoding a CAR into an ex vivo T cell (page 14, paragraph 0168; page 12, paragraph 0154) (“chimeric antigen receptor T cell”, “nucleic acid construct”, “ex vivo T cell” and “nucleic acid encoding said chimeric antigen receptor”). Sather teaches in Example 4 transducing T cells with a nucleic acid encoding anti-CD19 CAR where the CAR includes an anti-CD19 scFv (“introducing a nucleic acid construct into an ex vivo T cell to form an CD19 CAR+ T cell” and “a nucleic acid encoding said chimeric antigen receptor” and “wherein the chimeric antigen receptor targets CD19 tumor-associated antigen”) (page 107, 1657) but does not teach SEQ ID NO: 2. Sather teaches the CAR has binding specificity for a tumor associated antigen such as CD19 (“wherein the chimeric antigen receptor targets CD19 tumor-associated antigen”)(page 20, paragraph 0226). Sather teaches a method for genetic disruption in T cells genetically engineered to express CD19 CAR in Example 4, however, the targeted gene for disruption is PDCD1 and not GM-CSF (page 107 – 108, 1657 – 1658). Sather teaches the method of disruption in Example 4 comprises introducing a guide RNA and Cas9 RNP (“complex”, guide RNA, and Cas of claim 10, Cas9 of claim 12, ribonucleoprotein of claim 14) (page 108, 1658). Sather teaches cells expressed the CAR and were negative for PD-1 expression(page 108, 1660 – 1661). Sather teaches the gRNA comprises a targeting domain which is complementary to a target nucleic acid (page 28, 0307 – 0308). Sather teaches nucleic acids encoding Cas9 (page 56, 0735 – 0740).
Regarding claim 17, Sather teaches the RNP can be delivered by electroporation (page 12 – 13, 0159).
Sather does not teach “expressing a reduced level of GM-CSF polypeptides” or “a nucleic acid encoding a guide RNA, wherein said guide RNA is complementary to GM-CSF mRNA”, or SEQ ID NO: 2 or “wherein said CD19 CAR + T cell comprises enhanced in vivo antitumor activity …” of claim 10 or SEQ ID NO: 1 of claim 11 or GM-CSF K/O of claim 58. However, Sather teaches reduced tumor size of leukemic cell tumors with CAR+ T cells with deletion of PD1 in Figure 32 where knockout does not affect the antitumor activity of CAR+ T cells (page 117 – 118, 1722). Sather teaches PD-1 encoded by the PDCD1 gene suppresses activity of cytotoxic T cells and can inhibit tumor immunity to provide an immune escape for tumor cells (page 12, 0155). Sather teaches Sather teaches strategies are available for engineering immune cells expressing CARs and for suppression or repression of gene expression in the cells (page 1, 0004). Sather teaches improved strategies are needed to improve efficacy of the cells and improving the activity and/or survival of the cells upon administration (page 1, 0004). Sather teaches the cells can be used to treat hematological malignancies including leukemia including ALL (page 84, 1179). Sather teaches the anti-CD19 CAR T cells with PDCD1-deleted suppressed tumor growth and that deletion did not impair the in vivo anti-tumor function of the CAR T cells (page 117 – 119, paragraph 1722 and Figure 32). Sather teaches the step of introducing the nucleic acid encoding a CAR and the step of introducing the Cas9/gRNA agent can occur simultaneously (page 14, paragraph 0170). Sather teaches Cas9-enconding and guide RNA-encoding DNA can be delivered by a vector (page 69, paragraph 0999 – 1000).
Regarding GM-CSF of claim 10, Lee teaches infusion of T cells expressing CD19-CAR led to cytokine release syndrome where patients had elevated levels of GM-CSF (Abstract, Figure 3A, and page 525, left col. paragraph 3). Lee teaches the safety of CD19-CAR T cell therapy will improve with the adoption of standardized treatment algorithms aimed at preventing life-threatening cytokine release syndrome (page 527, left col. paragraph 3). Lee teaches B-ALL is the most common malignancy in childhood (page 517, left col. para. 1). Lee teaches cure of B-ALL requires prolonged therapy with substantial and short-term and long-term toxicities (page 517, left col.). Lee teaches patients with primary or recurrent refractory B-ALL who do not have complete remission negative for minimum residual disease with cytotoxic chemotherapy have dismal survival rates of less than 10% and outcomes for these patients have not improved substantially in the last two decades (page 517, left col.). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy.
Regarding “expressing a reduced level of said GM-CSF polypeptides” and “said guide RNA is complementary to a GM-CSF messenger RNA” and “nucleic acid encoding a Cas nuclease” of claim 10, Sentman teaches a CRISPR method for elimination of GM-CSF where the method comprises a nucleic acid encoding guide RNA and Cas nuclease in T cells (Figure 5; page 5, 0010). Sentman teaches that GM-CSF-deficient CAR T cells reduces cytokine levels and acute weight changes and toxicity are not observed when compared to wild-type or IFN-gamma deficient CAR T cells (Figure 1 – 4; page 5, 0011). Sentman teaches the method for making GM-CSF-deficient cells by contacting cells with an antisense nucleic acid that is complementary to the mRNA sequence encoding GM-CSF (page 16, paragraph 0032 and Table 1).
Regarding claim 11, Sentman teaches LGH-3 comprises SEQ ID NO: 1 in Figure 5 and Table 1 (page 5, 0010).
Regarding GM-CSFK/O CD19 CAR + T cell of claim 58, Sentman teaches GM-CSF-deficient cells can be the result of a GM-CSF deletion or disruption (page 4, 0005).
Sentman does not teach SEQ ID NO: 1 or wherein said CD19 CAR+ T cell comprises enhanced in vivo antitumor activity as compared to a comparable CD19 CAR+ T cell expressing a wild-type level of GM-CSF polypeptides” of claim 1. However, Sentman teaches the cells can be used to treat ALL (page 37, 0072). Sentman teaches the method prevents toxicity of adoptive cell therapy of CAR-bearing T cells (page 3, paragraph 0005). Sentman teaches tumor specific antigens targeted by the CARs can be CD19 (page 30, paragraph 0059). Sentman teaches infusion of GM-CSF-deficient CAR T cells reduces serum cytokine levels, and acute weight changes and toxicity are not observed (page 4, paragraph 006; page 5, paragraph 0011 and Figures 1 – 3). Sentman teaches immune cells lacking functional GM-CSF result in much less toxicity (page 5, paragraph 0012). Sentman teaches an effective amount of immune cells to reduce the size of a tumor or eliminate tumor growth or regrowth (page 36, 0069). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF with the teachings of Sentman regarding knocking out GM-CSF in CAR+ T cells to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy.
Regarding SEQ ID NO: 2 of claim 10, Brogdon teaches chimeric antigen receptor specific to CD19 where SEQ ID NO: 99 of Brogdon (col. 32 lines 8 – 9 and col. 257 – 259) is SEQ ID NO: 2 of claim 1. Brogdon teaches leukemias including ALL and B-ALL are associated with CD19 (col. 12, lines 44 – 67).
Regarding “wherein said CD19 CAR+ T cell comprises enhanced in vivo antitumor activity as compared to a comparable CD19 CAR+ T cell expressing a wild-type level of GM-CSF polypeptides” of claim 10, Hercus teaches GM-CSF may play a role in the pathogenesis of leukemia where some leukemic cells require GM-CSF for proliferation and survival (page 5838, left col. para. 2 and right col. para. 1). Hercus teaches mutant GM-CSF act as antagonists of GM-CSF-dependent proliferation in leukemic cells (page 5838, right col. last para.; page 5840, left col. para. 2; Table 2). Hercus teaches potential applications of GM-CSF antagonists in vivo are inhibition of tumor cell growth (page 5841, right col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Sather regarding a method of making CD19 CAR+ T cells having reduced levels of PD-1 with the teachings of Lee regarding infusion of T cells expressing CD19-CAR led to cytokine release syndrome where patients had elevated levels of GM-CSF with the teachings of Sentman regarding a method of reducing the level of GM-CSF in CAR+ T cells by CRISPR/Cas with the teachings of Brogdon regarding the nucleic acid sequence of a CD19 CAR for treating leukemia with the teachings of Hercus regarding reduced activity of GM-CSF can inhibit leukemic cell growth to arrive at the claimed method where CD19 CAR+ T cells with reduced levels of GM-CSF and PD-1 are madee that enhance in vivo antitumor activity compared to CD19 CAR+ T cells with wild type levels of GM-CSF. One would have been motivated to combine the teachings of Sather, Lee, Sentman, Brogdon, and Hercus in a method to produce CD19 CAR+ T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in leukemia patients undergoing CD19 CAR T cell therapy as Sather teaches improved strategies are needed to improve efficacy of the cells and improving the activity and/or survival of the cells upon administration, Lee teaches patients with primary or recurrent refractory B-ALL who do not have complete remission negative for minimum residual disease with cytotoxic chemotherapy have dismal survival rates of less than 10% and outcomes for these patients have not improved substantially in the last two decades and Hercus teaches GM-CSF may play a role in the pathogenesis of leukemia where some leukemic cells require GM-CSF for proliferation and survival. One would have a reasonable expectation of success in combining the teachings as Sather teaches reduced tumor size of leukemic cell tumors with CAR+ T cells with deletion of PD1, Sentman teaches infusion of GM-CSF-deficient CAR T cells reduces serum cytokine levels, and acute weight changes and toxicity are not observed and Hercus teaches mutant GM-CSF act as antagonists of GM-CSF-dependent proliferation in leukemic cells.
Applicant’s Arguments/ Response to Arguments
11. Applicant Argues: On page 6, paragraph 2, Applicant argues that the combination of cited references do not teach or suggest that a person having ordinary skill in the art should make or use CD19 CAR+ T cells expressing a reduced level of the GM-CSF polypeptides.
Response to Arguments: This is not found persuasive because Lee teaches infusion of T cells expressing CD19-CAR led to cytokine release syndrome where patients had elevated levels of GM-CSF (Abstract, Figure 3A, and page 525, left col. paragraph 3). Lee teaches the safety of CD19-CAR T cell therapy will improve with the adoption of standardized treatment algorithms aimed at preventing life-threatening cytokine release syndrome (page 527, left col. paragraph 3). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy. Sentman teaches that GM-CSF-deficient CAR T cells reduces cytokine levels and acute weight changes and toxicity are not observed when compared to wild-type or IFN-gamma deficient CAR T cells (Figure 1 – 4; page 5, 0011). One would have been motivated to combine the teachings of Sather regarding a method of making CD19 CAR T cells for treating ALL with the teachings of Lee regarding CD19 CAR T cell treatment of ALL can result in cytokine release syndrome that includes elevated levels of GM-CSF with the teachings of Sentman regarding knocking out GM-CSF in CAR+ T cells to make CD19 CAR T cells with reduced levels of GM-CSF to prevent cytokine release syndrome in ALL patients undergoing CD19 CAR T cell therapy.
Applicant Argues: On page 6, paragraph 3, Applicant argues the claimed invention provides unexpected results where GM-CSF K/O CART19 cells exhibit enhanced overall survival in vivo compared to wild type CART19 cells in a high tumor burden relapse xenograft model of ALL.
Response to Arguments: This is not found persuasive because Sentman teaches that GM-CSF-deficient CAR T cells reduces cytokine levels and acute weight changes and toxicity are not observed when compared to wild-type or IFN-gamma deficient CAR T cells (Figure 1 – 4; page 5, 0011). Additionally, in the new rejection set forth above, Hercus teaches that GM-CSF mutants devoid of measurable agonistic activity were able to antagonize GM-CSF-dependent proliferation of leukemic cells (page 5838, right col. last para.). Hercus teaches potential applications of GM-CSF antagonists in vivo are inhibition of tumor cell growth (page 5841, right col. last para.). Therefore, combining a known therapy for leukemia of CD19 CAR+ T cells with reducing GM-CSF levels would be expected to have enhanced in vivo antitumor activity because of the reduced cytokine release syndrome in GM-CSF deficient CAR T cells as taught by Sentman and because leukemic cells relying on GM-CSF for proliferation and survival would not longer be able to proliferate and survive without GM-CSF. Therefore, the teachings of Sentman combined with Lee would make obvious treating leukemia with CART 19 cells with reduced GM-CSF obvious and increased survival predictable.
Conclusion
No claims allowed.
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/Z.M.B./Examiner, Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632