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 .
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 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.
Priority
The instant application, filed 04/14/2023, is a 371 filing of PCT/US21/71892, filed 10/14/2021, and claims domestic benefit of 63/198,386, filed 10/14/2020.
Status of Application, Amendments, and/or Claims
Applicant’s amendment of 04/08/2026 is acknowledged. Claims 7, 15, and 20 are amended and claim 19 is cancelled. Claims 1-18 and 20 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 12/08/2025,
Claim 15 was rejected under 35 USC 112(b). Applicant’s amendment to remove “ratio” and claim the percentage of CD8+ TIL relative to their percentage in the native sample has overcome the rejection and the rejection is withdrawn.
Claims 7-10 and 12 were rejected under 35 USC 103 over Wei; claims 11 and 17 were rejected under 35 USC 103 over Wei in view of WO’664; claims 13 and 14 were rejected under 35 USC 103 over Wei in view of WO’636; claim 15 was rejected under 35 USC 103 over Wei in view of Prieto; claim 16 was rejected under 35 USC 103 over Wei in view of WO’190, Miyaura, and Forget; and claim 18 was rejected under 35 USC 103 over Wei in view of Kerkar. Applicant’s amendment to independent claim 7 to recite that the TILs are administered along with therapeutically effective amounts of PD-1 inhibitor and a hypomethylating agent has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are either maintained or new as necessitated by applicant’s amendment to the claims.
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.
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.
Claims 1-2 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as evidenced by Kaminskas, E., et al (2005) FDA Drug approval summary: Azacitidine (5-azacytidine, VidazaTM) for injectable suspension The Oncologist 10; 176-182.
Wei teaches that there is a need for novel therapies for acute myeloid leukemia (AML) including immune-based therapies (page 3193, left column, paragraph 2).
Wei teaches that reports in the literature suggest that adoptive cell therapy (ACT) using autologous TIL was promising in patients with solid tumors and T cells that are reactive to tumor-specific antigens might mediate tumor regression. Twenty percent of metastatic melanoma patients were reported to experience durable complete regression after treatment with autologous TIL in the light of reactivity with autologous tumor cells. In postoperative treatment of NSCLC the three-year survival rate was significantly higher in patients who underwent TIL ACT compare to that of untreated patients. In patients with pancreatic adenocarcinomas, infiltration of CD4+ T and CD8+ T cells were noted to be associated with improved prognosis and a markedly better five-year survival rate. A recent study demonstrated that the infiltration of CD3+ T cells correlated with improved clinical outcomes in patients with epithelial ovarian cancer. T cell immune responses in patients with solid tumors suggest the potential application of TIL (paragraph bridging columns, page 3193).
Whether AML harbor TIL had been debated for decades. In the study presented, Wei demonstrates the presence of AML TIL and demonstrates that they are able to specifically recognize autologous AML cells. The major observation on a small cohort of AML patients is: 1) TIL could be identified in bone marrow of 50% AML patients as revealed by immunophenotyping and IFN-γ Elispot assay; 2) AML TIL exerted anti-AML reactivity and anti-leukemic cytotoxicity; 3) AML TIL exhibited a higher anti-AML reactivity and anti-leukemia cytotoxicity compared with those of aPBL; 4) AML TIL were expandable; and 5) enrichment of expandable AML-reactive TIL is feasible (page 3193, right column, paragraph 2).
Wei concludes that the study demonstrates TIL in 50% of AML patient cohort and that AML TIL express CD137 (4-1BB) and secrete IFN-γ. They exhibit profound anti-AML reactivity and cytotoxicity. They are also expandable in cultures, which might translate to ACT for AML in the future (page 3194, left column, paragraph 3).
Wei further teaches that the TIL detected in the bone marrow samples highly expressed CD137 and PD-1 (abstract, results).
In the study performed by Wei, TIL isolated from AML patients and expanded ex vivo in a culture system (page 3189, patient characteristics; expansion of TIL; phenotype characterization of expanded TIL; abstract).
Wei, however, does not disclose that the TIL are administered along with therapeutically effective amounts of an inhibitor of PD-1 and a hypomethylating agent.
Chen teaches that immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to PD-L1/PD-1 therapy requires establishing an integrated immune cycle. Damage to any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of the tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and improve clinical outcomes of checkpoint blockade therapy (abstract).
Chen teaches that cancer immunotherapy is based on the stimulation and engineering of the immune system, such as the restoration of T lymphocytes to combat cancer. One of the most promising ways to activate the immune system is blockade of the immune checkpoints. Chen teaches that immune checkpoint molecules can mediate tumor immune escape, leading to malignant tumor progression. Targeting the immune checkpoint pathway has achieved an unprecedented long-lasting response rate in various cancers. The sustained response rate can be achieved primarily by blockade of the PD-1/PD-L1 pathway (page 724, left column, paragraph 1). Chen further teaches that initial studies suggested that the PD-L1/PD-1 pathway mediates CD8+ T cell exhaustion and PD-1 is considered to be a marker of exhausted T cells (page 728, right column, paragraph 4).
Chen further teaches that each step of the immune cycle can be regulated by epigenetic therapies to improve antigen presentation, T cell trafficking and infiltration and disruption of the immunosuppressive state. Epigenetic therapy, combined with immune checkpoint inhibitors, can restore immune recognition and tumor elimination, thus improving clinical response rates (page 725, right column, paragraph 2). Chen teaches that results have indicated a potential synergy between immune checkpoint inhibitors and epigenetic agents, as the former could upregulate expression of immune checkpoints, which may improve the therapeutic sensitivity of immune checkpoint inhibitors (page 730, left column, paragraph 1). Epigenetic reprogramming has been demonstrated to play a vital role in protecting tumor cells from immune surveillance. All of these studies suggest that epigenetic reprograming influences both cancer cells and immune cells and suggests a potential combination of epigenetic agents and anti-PD-L1 and PD-1 immunotherapy (page 730, left column, paragraph 2).
Chen teaches clinical trials that are designed to evaluate the effect of PD-L1/PD-1 antibodies combined with epigenetic agents among different cancer types summarized in Table 1. The studies include treatment of AML with azacitidine (targeting DNMT1) in combination with the anti-PD-L1 antibody, avelumab (page 729, Table 1). Chen also teaches trials in which epigenetic drugs are used in combination with anti-PD-1 antibodies including pembrolizumab, nivolumab, SHR-1210, and PDR001 and in which the epigenetic drugs are decitabine or 5-azacitidine/azacitidine, which are hypomethylating agents. It is also noted that azacitidine is another name for 5-azacytidine as evidenced by Kaminskas (abstract; Figure 1, page 177).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to administer the TIL as an adoptive cell therapy for the treatment of AML as disclosed by Wei in combination with a hypomethylating therapy and a PD-1/PD-L1 inhibitor, including a PD-1 inhibitor, as disclosed by Chen. An ordinarily skilled artisan would have been motivated to further administer a hypomethylating therapy as Chen teaches that such epigenetic therapies can improve antigen presentation, T cell trafficking and infiltration, and disrupt the immunosuppressive state. An ordinarily skilled artisan would have been motivated to administer an anti-PD-1/PD-L1 inhibitor in order to overcome tumor immune escape and T cell exhaustion. Additionally, Chen teaches that epigenetic therapy combined with immune checkpoint inhibitors can restore immune recognition and tumor elimination improving clinical responses and that there is potential synergy in the combination of immune checkpoint inhibitors and epigenetic agents. An ordinarily skilled artisan would have had a reasonable expectation of success as the trials disclosed by Chen demonstrate the combination of an hypomethylating agent in combination with an inhibitor of the PD-1/PD-L1 pathway had been considered for the treatment of AML, which is the same type of cancer being treated by Chen. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 blockade in AML.
Claims 3 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 1 above, and in further view of WO 2015/157636 A1 (Sarnaik, A.A., et al) 15 October 2015.
The combination of Wei and Chen teach the method of claim 1 as discussed in detail above.
As discussed above, Wei teaches that the autologous TIL are expanded ex vivo in a culture system.
The combination of Wei and Chen, however, do not disclose that the TIL are PD-1 inhibited or that the TIL are bioengineered or exposed to a PD-1 inhibitor.
WO’636 teaches a method for ex vivo expanding tumor infiltrating lymphocytes for use in adoptive cell therapy (abstract). The method involves culturing tumor fragments from the subject in a culture medium containing IL-2 and 41BB agonist in an amount effective to expand tumor-infiltrating lymphocytes with enriched tumor reactivity and specificity. The culture medium can further contain a checkpoint inhibitor, such as anti-PD-1 antibody, e.g., BMS 936558, anti-PD-L1 antibody, e.g., clone M1H1, anti-CTLA-4 antibody, e.g., Ipilimumab, MS, or any combination thereof (page 11, lines 1-7). WO’636 teaches that PD-1 blockade has been shown to facilitate anti-tumor T cell priming, increase T cell infiltration into tumors and anti-tumor effector function (page 38, lines 26-27). WO’636 further teaches that PD-1 blockade in vivo prior to TIL expansion from resected tumors enhances anti-tumor reactivity of expanded TIL (page 39, lines 4-8).
WO’636 teaches that ACT may be performed by (i) obtaining autologous lymphocytes from a mammal, (ii) culturing the autologous lymphocytes to produce expanded lymphocytes, and (ii) administering the expanded lymphocytes to the mammal. Preferably the lymphocytes are tumor-derived, i.e., they are TILs, and are isolated from the mammal to be treated, i.e., autologous transfer (page 9, lines 1720).
WO’636 also teaches that anti-cancer drugs that can be used in combination with the method and compositions disclosed include azacitidine and decitabine (page 24, lines 1-5, 8, and 13).
WO’636 further teaches that ACT is a very effective form of immunotherapy and involves the transfer of immune cells with antitumor activity into cancer patients. ACT is a treatment approach that involves the identification, in vitro, of lymphocytes with antitumor activity, the in vitro expansion of these cells to large numbers and their infusion into the cancer-bearing host. Lymphocytes used for adoptive transfer can be derived from the stroma of resected tumors, i.e., tumor infiltrating lymphocytes or TILs. They can also be derived from blood if they are genetically engineered to express antitumor T cell receptors (TCRs) or chimeric antigen receptors (CARs), enriched with mixed lymphocyte tumor cell cultures, or cloned using autologous antigen presenting cells and tumor derived peptides (page 22, lines 4-12).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wei and Chen to inhibit PD-1 on the expanded TIL, for instance by further including an anti-PD-1 antibody in the culture media, as taught by WO’636. It would have further been obvious to bioengineer the TIL, for instance through the engineered inclusion of a TCR or CAR based on the teachings of WO’636. An ordinarily skilled artisan would have been motivated to inhibit PD-1 on the expanded TIL as WO’636 teaches that PD-1 blockade can facilitate anti-tumor T cell priming, increase T cell infiltration into tumors and improve anti-tumor effector function and teaches the inclusion of anti-PD-1 antibodies in culture media during ex vivo expansion of TIL. It would have been obvious to further bioengineer the TIL, for instance through the inclusion of a TCR or CAR, as WO’636 demonstrates that the engineering of lymphocytes to express such receptors was known in the prior art. An ordinarily skilled artisan would have had a reasonable expectation of success because, like Wei, WO’636 is teaching methods of adoptive cell therapy for cancer treatment comprising the ex vivo culturing of autologous TIL. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 blockade in TIL obtained from AML patients.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 1 above, and in further view of WO 2015/157636 A1 (Sarnaik, A.A., et al) 15 October 2015, WO 2017/214190 A1 (Tang, X, et al) 14 Dec 2017, and Miyaura, C., et al (1981) 1α,25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells Biochemical and biophysical research communications 102(3); 937-943.
The combination of Wei and Chen teach the method of claim 1 as discussed in detail above.
As discussed above, Wei teaches that the autologous TIL are expanded ex vivo in a culture system.
The combination of Wei and Chen, however, do not disclose that the TIL are PD-1 inhibited or that the TIL are bioengineered to express CYP27B1.
The teachings of WO’636 are as discussed in detail above.
WO’190 teaches engineered cells comprising a heterologous polynucleotide that encodes a 1α-hydroxylase protein and that, in some embodiments the 1α-hydroxylase protein is human cytochrome P450 family 27 subfamily B member 1 (CYP27B1) (abstract).
WO’190 teaches the engineering of dendritic cells and teaches that the cells are engineered for de novo synthesis of a supra-physiological and/or therapeutic dose of the active vitamin D metabolite 1,25[OH]2D, also referred to as calcitriol. In some embodiments, the de novo synthesis of a therapeutic calcitriol dose is achieved through overexpression of a 1α-hydroxylase that physiologically convers 25[OH]D (or calcidiol), the major vitamin D form in the blood circulation and the substrate for 1α-hydroxylase, into calcitriol. In some embodiments, the overexpression of 1α-hydroxylase is achieved through transduction of dendritic cells with a vector that expresses cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) gene (page 2, [0007]).
WO’190 teaches that “1α-hydroxylase” refers to 25-hydroxyvitamin D-1 alpha hydroxylase. 1α-hydroxylase is an enzyme that catalyzes the conversion of 250hydroxyvitamin D3 (25(OH)D) to 1,25-dihydroxyvtamin D3 (1,25(OH)2D). The gene that encodes 1α-hydroxylase is a human cytochrome P450 family 27 subfamily B member 1 (CYP27B1). Sequences for human CYP27B1 mRNA and 1α-hydroxylase are set forth in, for example NCBI GenBank Accession numbers NM_000785.3 and NP_000776.1, respectively (page 14, [0044]).
Miyaura teaches that it is well established that vitamin D3 undergoes two sequential hydroxylations in the liver and kidney before exerting its biological effect in enhancing intestinal calcium transport and bone mineral mobilization activities (page 937, paragraph 1). Of great interest is that some tumor cells possess a cytosol protein specifically bound to the resulting metabolite 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). It had been previously shown that murine myeloid leukemia cells (M1 cells) could be induced to differentiate into macrophages in vitro by physiological plasma concentrations of 1α,25(OH)2D3. The metabolite was at least 100 times more potent on a molar basis than dexamethasone, the most potent known stimulator, in suppressing cell growth and inducing differentiation (paragraph bridging pages 937 and 938). The study presented by Miyaura examined whether human myeloid leukemia cells are similarly induced to differentiate by 1α,25(OH)2D3. It is reported that 1α,25(OH)2D3 is capable of inducing differentiation of not only M1 cells, but also a human myeloid leukemia cell line (HL-60 cells) isolated from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia (page 938, paragraph 2).
Miyaura teaches that, when HL-60 cells were cultured with various concentrations of 1α,25(OH)2D3, cell growth was inhibited markedly in a dose- and time- dependent manner. The inhibition of cell growth was effected by as little as 10-9 M of 1α,25(OH)2D3 and at 10-8 M, the viable cell number decreased to 20% of the control (page 939, paragraph 1; Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wei and Chen to inhibit PD-1 on the expanded TIL, for instance by further including an anti-PD-1 antibody in the culture media, as taught by WO’636 and to further engineer the cell to overexpress CYP27B1 as taught by WO’190 based on the teachings of Miyaura.
An ordinarily skilled artisan would have been motivated to inhibit PD-1 on the expanded TIL as WO’636 teaches that PD-1 blockade can facilitate anti-tumor T cell priming, increase T cell infiltration into tumors and improve anti-tumor effector function and teaches the inclusion of anti-PD-1 antibodies in culture media during ex vivo expansion of TIL. An ordinarily skilled artisan would have had a reasonable expectation of success because, like Wei, WO’636 is teaching methods of adoptive cell therapy for cancer treatment comprising the ex vivo culturing of autologous TIL. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 blockade in TIL obtained from AML patients.
An ordinarily skilled artisan would have been motivated to engineer the TIL to overexpress CYP27B1 as taught by WO’190 because WO’190 teaches that overexpression of 1α-hydroxylase, achieved through transduction of a vector that expresses the CYP27B1 gene, physiologically converts 25(OH)D to the active D metabolite 1,25(OH)2D, which Miyaura demonstrates is capable of inducing differentiation in acute myeloid leukemia cells resulting in marked inhibition of cell growth in a dose and time dependent manner. An ordinarily skilled artisan would have had a reasonable expectation of success because Miyaura teaches the use of 1,25(OH)2D in the treatment of an AML cancer, which is the same type of cancer disclosed by the combination of Wei and Chen and WO’190 teaches that the overexpression of CYP27B1 is an alternative method of treating with 1,25(OH)2D. Additionally, WO’636 demonstrates that the genetic engineering of lymphocytes was known and practiced in the prior art demonstrating a reasonable expectation of success in genetically modifying the TIL.
Claims 7-10, 12 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as evidenced by Kaminskas, E., et al (2005) FDA Drug approval summary: Azacitidine (5-azacytidine, VidazaTM) for injectable suspension The Oncologist 10; 176-182.
The teachings of Wei are as discussed in detail above.
In the studies performed by Wei, bone marrow and peripheral blood samples were taken from patients with AML (page 3188, left column, patient samples). Bone marrow mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC) were enriched by density gradient centrifugation using Ficoll-Hypaque. Cells were then labeled with CD3 microbeads for cell selection according to the manufacturer’s protocol. CD3+ cells were considered AML TIL, whereas CD3- cells were considered autologous AML cells. Wei teaches that the BMMC and PBMC were then expanded in culture (page 3188, Enrichment and expansion of TIL).
Wei further teaches that the expandability of AML TIL in 10 bone marrow samples were tested and compared to that of circulating lymphocytes from 10 peripheral blood samples collected from the patient cohort in a 14-day co-culture system using irradiated feeder cells of unrelated PBMC supplemented with anti-CD3, IL-2, IL-7, and IL-15. Bone marrow group yielded a mean ± SD of 8.7x109 ± 1.0x109 cells being similar to 7.1x109 ± 0.8 x109 derived from the peripheral blood group. The folds of increase in cell numbers of 875 ± 102 were noted among bone marrow samples being comparable to 713 ± 80 of the circulating lymphocytes in peripheral blood samples (page 3189, right column, paragraph 2). Based on these teachings, Wei teaches an expansion of up to 977-fold (875+102), which meets the instant claim 12 limitation of about a 1000-fold increase relative to the starting number which was derived from a sample from the subject.
While Wei does not exemplify the administration of the cultured TILs back to the subject, Wei teaches that the TIL from AML patients exhibit profound anti-AML reactivity and cytotoxicity and are expandable in cultures, which might translate to ACT for AML in the future (page 3194, left column, conclusion). Wei also teaches that the TIL are active against autologous AML cells. Wei further teaches that ACT with TIL has been practiced in the prior art in the treatment of other cancers, such as metastatic melanoma and metastatic cholangiocarcinoma.
The teachings of Chen and Kaminskas are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to administer the cultured TILs back to the subject after expansion based on the teachings of Wei. It would have further been obvious to administer the TIL as an adoptive cell therapy in combination with a hypomethylating therapy, including 5-azacytidine, and a PD-1/PD-L1 inhibitor, including a PD-1 inhibitor, as disclosed by Chen.
An ordinarily skilled artisan would have been motivated to administer the expanded TIL back to the subject as Wei suggests their use in ACT regimens and demonstrates that the expanded TIL exhibit autologous anti-AML reactivity, Thus, an ordinarily skilled artisan would have had a reasonable expectation of success. Furthermore, Wei demonstrates that such methods of ACT using TIL had been practiced in the prior art in methods of treating other cancers.
An ordinarily skilled artisan would have been motivated to further administer a hypomethylating therapy, including 5-azacytidine, as Chen teaches that such epigenetic therapies can improve antigen presentation, T cell trafficking and infiltration, and disrupt the immunosuppressive state. An ordinarily skilled artisan would have been motivated to administer an anti-PD-1/PD-L1 inhibitor in order to overcome tumor immune escape and T cell exhaustion. Additionally, Chen teaches that epigenetic therapy combined with immune checkpoint inhibitors can restore immune recognition and tumor elimination improving clinical responses and that there is potential synergy in the combination of immune checkpoint inhibitors and epigenetic agents. An ordinarily skilled artisan would have had a reasonable expectation of success as the trials disclosed by Chen demonstrate the combination of an hypomethylating agent in combination with an inhibitor of the PD-1/PD-L1 pathway had been considered for the treatment of AML, which is the same type of cancer being treated by Chen. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 blockade in AML.
Claims 11 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 7 above, and in further view of WO 2018/075664 A1 (Moriarity, B., et al) 26 April 2018.
The combination of Wei and Chen teach the method of claim 7 as discussed in detail above.
The combination of Wei and Chen, however, does not disclose that the TILs comprise CCR7+CD95- and/or CD62L+CD45RA+ T cells as recited in claim 11 or that the isolated TILs are engineered to reduce expression or function of a PD-1 gene as recited in claim 17.
WO’664 teaches that the adoptive transfer of tumor infiltrating lymphocytes (TIL) has achieved considerable success in mediating durable regression of metastatic melanoma. In spite of these successes, the use of TIL therapy in other settings has been challenging. This is likely due to the suppressive effects exerted by the tumor microenvironment and T-cell intrinsic impairments in receptor signaling and acquisition of effector functions. Monoclonal antibody based immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte associated protein (CTLA-4) function can sometimes relieve T-cell extrinsic suppressive effects (page 1, [0001]).
WO’664 teaches that the cells can have one or more disrupted genes. For example, the expression of a checkpoint gene, such as PD-1, can be disrupted (page 15, [0087]).
WO’664 teaches methods in which a CRISPR system is used to knock out an endogenous gene, such as PD-1, in a tumor-reactive TIL (page 26 [0128]; page 78, example 3).
WO’664 further teaches that in some cases the cell is a stem memory cell, TSCM, comprised of CD45RO-, CCR7+, CD45RA+, CD62L+, CD27+, CD28+, and IL-5Ra+ and show numerous functional attributes distinctive of stem memory cells (page 20, [0108]).
WO’664 further teaches that the methods disclosed can be used to treat cancer including acute myeloid leukemia (page 14, [0081]; page 8, [0017]). WO’664 teaches that the method comprises obtaining TIL, identifying reactive TIL, and disrupting an endogenous gene or portion thereof with CRISPR nuclease (page 8, [0017]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by the combination of Wei and Chen to use TILs comprising stem memory T cells (TSCM) that express CD45RA+ and CD62L+ as disclosed by WO’664. It would have further been obvious to engineer the TILs to reduce expression of the PD-1 gene as taught by WO’664. It would have been obvious to have the TILs comprise TSCM cells as WO’664 demonstrates the use of such cells as TILs for adoptive cell therapy and also teaches that the cells have functional attributes distinctive of stem memory cells. An ordinarily skilled artisan would have been motivated to knockdown PD-1 as WO’664 teaches that PD-1 is an immune checkpoint that can lead to suppressive effects on TIL exerted by the tumor microenvironment and demonstrates methods of knocking down PD-1 in TIL for adoptive cell therapy. An ordinarily skilled artisan would have had a reasonable expectation of success because, like Wei, WO’664 is teaching methods for adoptive transfer of TILs for the treatment of cancers including AML. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 disruption in TIL obtained from AML patients.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 7 above, and in further view of WO 2015/157636 A1 (Sarnaik, A.A., et al) 15 October 2015.
The combination of Wei and Chen teaches the method of claim 7 as discussed in detail above.
As discussed above, Wei teaches that the TIL are expanded ex vivo in a culture system.
The combination of Wei and Chen, however, does not disclose that the step of culturing the isolated TILs comprise exposing the isolated TILs to a PD-1 inhibitor, such as a PD-1 antibody.
The teachings of WO’636 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wei and Chen to further expose the isolated TIL to a PD-1 inhibitor, for instance an anti-PD-1 antibody, by including the anti-PD-1 antibody in the culture media as taught by WO’636. An ordinarily skilled artisan would have been motivated to inhibit PD-1 on the expanded TIL as WO’636 teaches that PD-1 blockade can facilitate anti-tumor T cell priming, increase T cell infiltration into tumors and improve anti-tumor effector function and teaches the inclusion of anti-PD-1 antibodies in culture media during ex vivo expansion of TIL. An ordinarily skilled artisan would have had a reasonable expectation of success because, like Wei, WO’636 is teaching methods of adoptive cell therapy for cancer treatment comprising the ex vivo culturing of autologous TIL. Additionally, Wei teaches that the TIL from AML bone marrow patients highly expressed PD-1 further demonstrating the relevance of PD-1 blockade in TIL obtained from AML patients.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 7 above, and in further view of Prieto, P.A., et al (2010) Enrichment of CD8+ cells from melanoma tumor infiltrating lymphocyte cultures reveals tumor reactivity for use in adoptive cell therapy J. Immunother 33(5); 547-556.
The combination of Wei and Chen teaches the method of claim 7 as discussed in detail above.
Wei further teaches the immunophenotypes of the ex vivo expanded TIL and aPBL from AML patients in table 2 on page 3191, in which it is shown that, after expansion, there is a higher number of CD8+ CD3+ TIL in both cultures of TIL and aPBL from AML patients.
The combination of Wei and Chen, however, does not disclose the initial phenotypes in order to establish that the ratio of CD8+ T cells was increased during culturing.
Prieto teaches that the successful application of TIL ACT therapy requires the selection of unique tumor-reactive lymphocyte cultures for each patient. To simplify the methods of TIL generation and extend TIL based immunotherapy to additional patients, methods were developed to use unselected, minimally cultured (“young”) TIL. Young TIL cultures contain a variable number of CD8+, CD4+, and CD3-CD56+ natural killer cells. Prieto provides a retrospective investigation of the roles of these subsets in clinical outcomes of patients treated with TIL derived from selected microcultures. The analysis demonstrated a suggestive but not significant association between the number of CD8+ cells administered and tumor regression. Therefore, Prieto investigated the feasibility of selecting CD8+ cells from young TIL cultures for ACT therapy and developed an optimized CD8+ enrichment method. It was observed that CD8+ enrichment of some TIL cultures revealed in vitro tumor recognition that was not evident in bulk culture and an improved in vitro tumor recognition in other TIL cultures. In addition, the enriched CD8+ young TIL expanded more reliably and predictably in rapid expansions than the bulk TIL. Thus, optimized CD8+ selection combines the benefits of antigen-selected TIL and young TIL for generation of lymphocyte cultures for ACT (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wei and Chen by further incorporating the optimized selection methods of Prieto to increase the ratio of CD8+ TILs in the culture. An ordinarily skilled artisan would have been motivated to increase the ratio of CD8+ TILs as Prieto teaches that such enrichment increases tumor recognition and regression and expands more reliably and predictably. An ordinarily skilled artisan would have had a reasonable expectation of success as Prieto is teaching methods of expanding isolated TIL for use in ACT for the treatment of cancer.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 7 above, and in further view of WO 2017/214190 A1 (Tang, X, et al) 14 Dec 2017, Miyaura, C., et al (1981) 1α,25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells Biochemical and biophysical research communications 102(3); 937-943, and Forget, M.A., et al (2017) A novel method to generate and expand clinical-grade, genetically modified, tumor-infiltrating lymphocytes Frontiers in Immunology 8(908); 1-8.
The combination of Wei and Chen teaches the method of claim 7 as discussed in detail above.
The combination of Wei and Chen, however, does not disclose that the method further comprises the bioengineering of the isolated TIL to increase expression of function of a CYP27B1 gene.
The teachings of WO’190 and Miyaura are as discussed above.
Forget teaches that following clinical success achieved with the first generation of adoptive cell therapy using in vitro expanded TIL, the second and third generations of TIL ACT are evolving towards the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 109 to 1011 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable for the GMP environment. Forget teaches the development and optimization of a method for the efficient production of large numbers of GMP-grade, gene modified TIL for the treatment of patients with ACT using CXCR2 as a gene of interest for method development. The optimized procedure is currently being used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the combination of Wei and Chen by engineering the TIL to increase expression of CYP27B1 as taught by WO’190 based on the teachings of Miyaura and as further supported by Forget. An ordinarily skilled artisan would have been motivated to engineer the cell to increase expression of CYP27B1 as taught by WO’190 because WO’190 teaches that overexpression of 1α-hydroxylase, achieved through transduction of a vector that expresses the CYP27B1 gene, physiologically converts 25(OH)D to the active D metabolite 1,25(OH)2D, which Miyaura demonstrates is capable of inducing differentiation in acute myeloid leukemia cells resulting in marked inhibition of cell growth in a dose and time dependent manner. An ordinarily skilled artisan would have had a reasonable expectation of success because Miyaura teaches the use of 1,25(OH)2D in the treatment of an AML cancer, which is the same type of cancer disclosed by the combination of Wei and Chen and WO’190 teaches that the overexpression of CYP27B1 is an alternative method expressing 1,25(OH)2D. The genetic modification of TIL is further supported by Forget, which demonstrates that methods were known and available in the prior art for the genetic engineering of TIL.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Wei, L., et al (2019) Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia Cancer management and research 11; 3187-3196 in view of Chen, X., et al (2020) Epigenetic strategies synergize with PD-L1-PD-1 targeted cancer immunotherapies to enhance antitumor responses Acta Pharmaceutica Sinica B 10(5); 723-733 as applied to claim 7 above, and in further view of Kerkar, S.P. (2013) “Model T” cells: a time-tested vehicle for gene therapy Frontiers in immunology 4(304); 1-7.
The combination of Wei and Chen teaches the method of claim 7 as discussed in detail above.
The combination of Wei and Chen, however, does not disclose that the method further comprises bioengineering the isolated TILs to increase expression or function of one or more of CD3, CCR7, CD62L, CD45RA, CD95, CD127, CD27, and CD28.
Kerkar teaches that T lymphocytes first carried foreign genes safely into humans over two decades ago. Since these pioneering studies, scientific techniques to better understand the genomic landscape of cells has directly led to more sophisticated appreciation of the diversity, functional complexity, and therapeutic potential of T cells. Through the use of mouse models, we now know the function of the many genes that are critical for T cells to recognize foreign, mutated, or self-antigens and the factors responsible for the lineage diversification of T cells that lead to inhibitory or stimulatory immune responses. This knowledge, combined with well-established modalities to introduce genes into T cells allows for the design of effector and memory CD8 and CD4 T lymphocytes specific for tumor-antigens. Kerkar provides a review of strategies for designing the ideal T cell by introducing genes including co-stimulatory/inhibitor surface molecules (abstract).
Kerkar teaches that generating a specific and productive T cell response requires not only appropriate signaling through the TCR but an additional secondary co-stimulatory signal. The most well studied co-stimulatory molecule is CD28, a disulfide linked homodimer that is constitutively expressed on naïve T cells. CD28 engagement with CD80 and CD86 on antigen presenting cells enables T cells to differentiate and become functionally active. However, after initial antigen encounter and under altered cytokine conditions, T cells can lose or decrease their expression of CD28 leading to replicative senescence and functional anergy. The lack of CD28 signaling can also result in an impaired memory response and activity of induced cell death. One strategy to circumvent these physiological restraints is to constitutively overexpress CD28 in T cells (page 3, right column, paragraph 3).
Kerkar teaches other potentially therapeutic gene therapies in T cells including co-stimulatory molecules including CD27 (page 2, Figure 1).
Kerkar also teaches that T lymphocytes represent the ideal vehicle for carrying therapeutic genes into humans. They are easily obtained through peripheral blood draws or apheresis procedures and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to retroviral introduction of ectopic genes. Today, the adoptive transfer of tumor infiltrating lymphocytes combined with total-body irradiation, lymphodepleting chemotherapy, and high-dose IL-2 achieve response rates as high as 70% in patients with metastatic melanoma. The rapid development of gene therapy in this field promises to vastly improve current cellular therapies and opens the door to treat cancers of various histologies and wider arrays of disease (page 1, right column, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method disclosed by the combination of Wei and Chen by engineering the TIL to constitutively express CD28 as taught by Kerkar. It would have been obvious to engineer the TILs to constitutively express CD28 as Kerkar teaches that T cells can lose or decrease expression of CD28 after initial antigen encounter leading to replicative senescence, functional anergy, and death. Additionally, Kerkar teaches that generating a specific and productive T cell response requires signaling through the TCR and also a secondary co-stimulatory molecule, such as CD28. An ordinarily skilled artisan would have had a reasonable expectation of success as Kerkar is teaching methods of designing ideal T cells by gene introduction and teaches that the cells can be accomplished with well-established modalities for gene introduction. Additionally, Kerkar is teaching such modification for use in gene therapies for adoptive cell therapy for the treatment of cancers.
Response to Arguments
Applicant’s response, filed 04/08/2026 has been fully considered in so far as it applies to the rejections of the instant office action, but were not persuasive.
Applicant’s arguments pertain to each of the references cited individually and what each of the references fail to teach rather than the combination of applied references. MPEP 2145 (IV) states “One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).”
With regards to the rejection of claims 1-2 and 6 under 35 USC 103, applicant argues that Wei examines the possibility of using TILs from AML patients in autologous therapy. Applicant further argues that Wei does not offer a method of treatment only suggests that TIL can be isolated, expanded, and could possibly be used in adoptive cell therapy. Applicant argues that Wei does not teach administration or their method of use in adoptive cell therapy. Applicant further argues that Wei provides no suggestion or motivation to modify or combine the TILs of the study with any additional treatments since they demonstrate that the AML TILs demonstrated profound anti-leukemia activity.
These arguments are not persuasive. Although Wei does not exemplify administration of the TILs in AML patients, the standard of obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required. See MPEP 2143.02 (I), which states that “conclusive proof of efficacy is not required to show a reasonable expectation of success…the expectation of success need only be reasonable, not absolute.” As discussed in detail in the rejection, Wei demonstrate the presence of AML TIL and also demonstrates that they are able to specifically recognize autologous AML cells. Wei also teaches that enrichment of expanded AML reactive TIL is feasible and might translate to ACT for AML in the future. Wei also teaches reports in literature in which ACT therapy using autologous TIL was promising in patients, demonstrating that administration of TIL had been practiced in ACT methods for cancer treatment.
With regards to applicant’s arguments that Wei does not suggest or motivate the combination of the TILs with additional treatments since the TILs are shown to have profound anti-leukemic activity, it is first noted that explicit motivation in the art is not required in order to establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art. That said, motivation from Chen is cited in the rejection for the further administration of a hypomethylating agent and an anti-PD1/PDL1 pathway inhibitor. Specifically, Chen teaches that the combination can restore immune recognition and tumor elimination improving clinical responses and teaches that the hypomethylating agent and anti-PD1/PDL1 inhibitor can improve antigen presentation, T cell trafficking and infiltration, while disrupting the immunosuppressive state.
Applicant further argues that Wei does not teach selection parameters, modifying the TIL, inhibition or downregulation of the PD-1 gene, nor that such actions could improve the anti-tumor activity of the TIL.
While Wei does not teach these limitations, Wei is not required to teach these limitations. Claims 1, 2, and 6, which are rejected over Wei in view of Chen, do not require any specific selection parameters, modifying of TIL, or the inhibition or downregulation of the PD-1 gene.
With regards to Chen, applicant argues that Chen teaches anti-PD1/PDL1 therapies for various cancers including AML, but does not contemplate therapeutic challenges of AML. Applicant argues that Chen does not teach the isolation, expansion, enrichment, treatment, and administration of TIL for adoptive cell therapy. Applicant argues that Chen does not provide suggestion or motivation to apply anti-PD-L1/PD-1 antibodies to adoptive cell therapy and there is no teaching regarding administration of tumor infiltrating lymphocytes. Applicant argues that neither Wei nor Chen teach administration of TIL with a PD-1 inhibitor and a hypomethylating agent.
In response, it is first noted that neither Wei nor Chen alone are required to teach each and every limitation of the claimed methods alone as the rejection is not based on either of the references alone. Rather, the rejection is based on the combination of the references and what the references would have suggested to one of ordinary skill in the art. See MPEP 2145.
While Chen does not directly contemplate challenges in only AML, Chen teaches the benefits of epigenetic agents and immune checkpoint inhibitors in combination and their potential synergistic impact on anti-tumor immune response. Chen also demonstrates that treatment of AML with azacitidine in combination with the anti-PD-L1 antibody, avelumab, was in clinical trial, which indicates that the therapies were considered for use in AML. Although Chen does not directly teach the therapies in combination with TIL therapy, Chen demonstrates their impact on the immune system, for instance eliciting an immune response, increasing the presentation of tumor antigens, and regulating T cell trafficking and reactivation, all of which would be expected to benefit TIL therapy.
Applicant argues that Kaminskas is focused on 5-azacytidine alone as a therapeutic and doesn’t mention TILs or anti-PD1/PDL1 therapies.
Kaminskas is applied in the rejection as an evidentiary reference to demonstrate that the azacitidine disclosed by Chen is another name for 5-azacytidine. Kaminskas is not required to teach any other therapy or limitations of the claimed invention as they are taught by Wei and Chen.
Regarding the rejection of claims 3 and 4, and the reference WO’636, referenced in the response as “Sarnaik”, applicant argues that WO’636 studied breast cancer and, while AML is disclosed as a possible cancer, there is no motivation to specifically treat AML. Applicant argues that WO’636 discloses an extensive list of anti-cancer drugs that can be used in combination with the TIL including azactidine, but does not provide teaching or suggestion to select azactidine.
WO’636 is applied in the rejections of the instant claims to demonstrate that engineering of the TIL or exposure of the TIL taught by the combination of Wei and Chen to an anti-PD-1 inhibitor would have been obvious and is motivated by the prior art. The rejection relies on the combination of Wei, Chen, and WO’636, not WO’636 alone, and; therefore, WO’636 is not required to teach each and every limitation of the claimed invention or provide explicit motivation to select azactidine and AML as these limitations are supported by the other applied references.
Regarding the rejection of claim 4 and 5, and the reference WO’190 (referenced in the response as “Tang”), applicant argues that WO’190 does not provide teaching, suggestion or motivation to engineer TILs to express CYP27B1 or suggest any effects mediated by the enzyme. The instant application details advantages of vitamin D gene therapy in the treatment of leukemic cells such as enhancing differentiation of leukemic cancer cells and synergizing with 5-AZAA to eliminate majorities of viable blasts. Applicant cites Example 6 and Figs. 7A and 7B as detailing the effects of AZA and Vitamin D on bone structures in AML marrow.
In the rejections of the instant claims, the reference WO’190 is applied in combination with WO’636 and also Miyaura to demonstrate obviousness of engineering the cells to express CYP27B1. With regards to CYP27B1, WO’190 demonstrates the engineering of cells to overexpress the CYP27B1 gene through viral transduction and demonstrates that the enzyme convers 25(OH)D to the active D metabolite. Miyaura motivates this modification teaching that this metabolite is capable of inducing differentiation in AML cells resulting in marked inhibition of cell growth in a dose dependent manner. The rejection is further supported by WO’190 which demonstrates that methods of genetically engineering TIL were known in the art.
Figures 7A and 7B, referenced by applicant in the response, show RNA-seq analysis of AML cells treated with single agent 1,25(OH)2D3 and AZA and their combination. Fig. 7A is the expression of human VDR (vitamin D receptor) and 7B is a the VDR expression and their combination confirmed by PCR experiments (page 4, [0015]). While these do demonstrate increases in VDR when the combination is used compared to single agents, the results are not commensurate in scope with the instantly claimed invention which is drawn to the treatment of AML using TIL in combination with any hypomethylating agent an inhibitor of PD-1. See MPEP 716.02(d). Additionally, it is noted that MPEP 716.02 states “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
With regards to Miyaura, applicant argues that the reference does not teach adoptive cell therapy, PD-1 signaling, use of a hypomethylating agent or engineering of T cells. Applicant argues that Miyaura teaches anti-tumor effect of exogenous vitamin D3, not the engineering of TIL to express CYP27B1 or that such expression would have the same result.
As discussed in detail above, Miyaura is applied in the rejection along with WO’190 and WO’636 and; therefore, is not required to teach each and every limitation of the claimed invention.
Regarding claims 7-10 and 12, applicant argues that the claims have been amended to recite that the subject is also administered effective amounts of an anti-PD1 and a hypomethylating agent and that these limitations are not taught by Wei.
In the rejections of the instant office action, the reference Chen is further cited with Wei to demonstrate obviousness in the addition of an anti-PD1 and a hypomethylating agent.
With regards to claims 11 and 17, and the reference WO’664 (referenced by applicant as “Moriarity”), applicant argues that WO’664 lists various cell types but does not recite the CCR7+CD95- and CD62L+CD45RA+ phenotypes, or make a connection of these phenotypes to naïve cell populations. Applicant argues that the instant application recognizes that CCR7+CD95- naïve T cells are needed to support quick expansion in vivo. Applicant argues that WO’664 is focused on solid tumors, not AML.
It is first noted that instant claim 11 does not require CCR7+CD95- cells as the claim uses the conjunction “and/or” and, under the “or” embodiments only requires one of CCR7+CD95- or CD62L+CD45RA+ phenotypes. As acknowledged by applicant in the response, WO’664 teaches stem memory cells comprising a CD45RO-, CCR7+, CD45RA+, CD62L+, CD27+, CD28+, and IL-Ra+ phenotype, which meets the limitation of the cells comprising a CD62L+CD45RA+ phenotype.
With regards to claims 13-14, applicant argues that independent claim 7 has been amended to recite that the subject is also administered effective amounts of an anti-PD1 and a hypomethylating agent and that these limitations are not taught by Wei and that the limitations are not supported by WO’636 (Sarnaik).
As discussed above, the rejections of the instant office action have been amended to further include the reference Chen to demonstrate obviousness in the addition of an anti-PD1 and a hypomethylating agent. WO’636 is not required to teach the limitations as they are supported by Wei and Chen.
With regards to claim 15, and the reference Prieto, applicant argues that Prieto studied metastatic melanoma, not AML and enriched for CD8+TIL while the instant application isolates and expands CD3+ T cells and differentiates them to enrich the percentage of CD8+ T cells relative to those in the native T cell sample.
As discussed in detail above, the rejections are based on the combination of applied references and; therefore, Prieto is not required to teach the treatment of AML as the patient population is taught by the combination of Wei and Chen. Furthermore, the instant claim does not require any specific method of enriching CD8+ T cells; only that in the step of culturing the percentage of CD8+ TILs is increased. Additionally, the claims use “comprising” language. The specification states that “including,” “having,” and the like are synonymous (page 7, [0029]). A definition which is consistent with MPEP 2111.03 I. which states that “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” As such, the claims encompass the methods of Prieto in which the CD8+ TIL are selected, isolated, and enriched.
Regarding claim 16, and the reference Forget, applicant argues that Forget does not teach or suggest modifying the TIL to express CYP27B1 or advantages thereof.
In the rejection of claim 16 in the instant office action, the references Wei, Chen, WO’190, and Miyaura are also applied. As discussed in detail above, and in the rejection, WO’190 demonstrates cells engineered to express CYP27B1 and Miyaura teaches the benefits of 1,25(OH)2D3 in the treatment of AML. The reference Forget is applied to demonstrate that genetic modification of TIL, as well as methods to accomplish such modification, were known and practiced in the prior art.
With regards to claim 18 and the reference Kerkar, applicant argues that Kerkar only recognizes that CD28 is constitutively expressed on naïve T cells, where the instant application recognizes that the expression of one or more of these genes can confer the TILs sternness and proliferative and functional capability as in naïve TIL. Applicant argues that Kerkar does not anticipate the instant claims or the results achieved.
As discussed in the rejection, Kerkar teaches that T cells can lose or decrease their expression of CD28 leading to replicative senescence and functional anergy. Kerkar also teaches that the lack of CD28 signaling can also result in impaired memory response and activity of induced cell death. Kerkar teaches that one strategy to circumvent the physiological restraints is to constitutively overexpress CD28 in the cells. Kerkar also teaches that T cells can be engineered. These teachings suggest the engineering of the cells to constitutively overexpress CD28. The instant claims require only one of the recited proteins and; therefore, the teachings of Kerkar meet the instant claim limitations.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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