8049DETAILED 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 .
Election/Restrictions
Applicants’ election without traverse of Group II (claims 1, 7-8, 13, 15, 20, 23, 25, 39, 43, 49, 51-52, 55-57, 69, 79-80, 86-88, 94, 102, 104, 106-107, 109, 118-119, 127, 138-139, and 142) with respect to the restriction requirement in the reply filed on 07/11/2025 is acknowledged.
Applicants’ elections without traverse of the method of claim 1 (i.e., a method of producing a composition of tumor-reactive T cells in the presence of one or more modulatory cytokines selected from recombinant IL-23, recombinant IL-25, recombinant IL-27, or recombinant IL-35) with respect to species election (b) and a T cell adjuvant that is an immune checkpoint inhibitor with respect to species election (c) in the reply filed on 07/11/2025 is acknowledged.
Claims 1 and 7 read on the elected species of invention and are examined on the merits herein.
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2020/062439 (filed 11/25/2020). Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application Nos. 63/070,823 (filed 08/26/2020) and 62/941,628 (filed 11/27/2019).
Claim Objections
Claim 1 is objected to because of the following informalities: line 23 contains a typographical error, reciting, “…wherein one or more of steps (a)-(e) are carried out in the presence of one or more modulatory cytokines are selected from recombinant IL-23…”.
Appropriate correction is required.
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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Zacharakis, et al. (Nat Med. 2018), in view of L.X. Wang, et al. (J Transl Med. 2004).
Zacharakis, et al. teaches adoptive transfer of mutant-protein-specific tumor-infiltrating lymphocytes (TILs) in conjunction with IL-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer for >22 months (Abstract).
L.X. Wang, et al. teaches adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells (Title).
Regarding claim 1:
Briefly, Zacharakis, et al. teaches a method wherein a metastatic right breast subcutaneous lesion from a patient was resected and processed for identification of nonsynonymous somatic mutations in the tumor and for the generation of TILs (“Methods: Clinical history.”; pg. 731; Fig. 2d). Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were used for neoantigen identification (“Methods: Whole-exome sequencing (WES), RNA sequencing (RNA-seq) and determination of mutation clustering.”; pg. 731). Autologous dendritic cells (APCs) were incubated with 10 µg/ml of an individual peptide or peptide pools (10μg/ml of each peptide) for 2 h or overnight; following pulsing, the APCs were centrifuged, resuspended in fresh medium without cytokines and used immediately in coculture assays (“Methods: RNA transfection and peptide-pulsing of autologous antigen-presenting cells.”; pg. 731). TILs were derived from culturing small pieces of the patient’s tumor in high-dose IL-2 (pg. 724; col. 1, par. 1). T cells were incubated with peptide-pulsed dendritic cells; TILs were rested in complete medium with or without IL-2 for several hours to several days before coculture (“Methods: Coculture assays.”; pg. 732). Following the identification of neoantigen-reactive TILs, TIL cultures were selected for treatment and expanded into high numbers using a rapid expansion protocol using IL-2 (“Methods: TIL generation.”; pg. 731). Autologous TILs were administered to the patient via intravenous infusion (“Methods: Treatment and analysis of response.”; pg. 731).
The step in the method of Zacharakis, et al. where TILs were derived by culturing pieces of the patient’s tumor in IL-2 (pg. 724; col. 1, par. 1) reads on steps (a)-(b) of claim 1; the step where autologous dendritic cells were pulsed with peptide or peptide pools for 2 h or overnight followed by collection and use for coculture essays (“Methods”; pg. 731) reads on step (c) of claim 1. The step where neoantigen-reactive TILs were selected and expanded using IL-2 before collection for administration to the patient (“Methods”; pg. 731) reads on steps (d)-(f) of claim 1.
Zacharakis, et al. doesn’t teach one or more of steps (a)-(e) as carried out in the presence of one or more modulatory cytokines selected from IL-23, IL-25, IL-27, or IL-35, as required by the remaining limitation recited in claim 1.
However, L.X. Wang, et al. teaches that CD4+ T cell anti-tumor function is mediated through cross-presentation of specific tumor-antigens by tumor associated APCs, and CD4+ cells cultured with IL-23 produced greater levels of INF-γ that would augment antigen presentation (pg. 10; col. 2, par. 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Zacharakis, et al. by including the use of IL-23 for culturing the TILs, as taught by L.X. Wang, et al. This conclusion of obviousness is based on the ‘teachings, suggestion, or motivation rationale’; one would be motivated to do so for the increased IFN-γ production to augment antigen presentation, as disclosed by L.X. Wang, et al. Further, as Zacharakis, et al. teaches the infused TILs were predominantly CD4+ (pg. 726; col. 1, par. 2), one skilled in the art would have more than a reasonable expectation of success.
Therefore, the embodiments of claim 1 are thus rendered obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Zacharakis, et al. (Nat Med. 2018), in view of L.X. Wang, et al. (J Transl Med. 2004), further in view of C. Wang, et al. (Cancer Immunol Res. 2014).
The teachings of Zacharakis, et al. and L.X. Wang, et al. are set forth above.
C. Wang, et al. teaches the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody (Abstract).
Regarding claim 1: It is set forth above the method of claim 1 is rendered obvious over Zacharakis, et al. in view of L.X. Wang, et al. Neither Zacharakis, et al. nor L.X. Wang, et al. teach steps (b), (c), or (e) as carried out in the presence of an immunosuppressive blocking agent or a T cell adjuvant, wherein the T cell adjuvant is an immune checkpoint inhibitor, as required by the limitation recited in claim 7.
Briefly, C. Wang, et al. teaches in an allogeneic mixed lymphocyte reaction assay, PD-1 blockade with nivolumab systematically resulted in a titratable enhancement of IFN-γ release, and in some donor T-cell/dendritic cell pairs, enhanced T-cell proliferation was observed (Fig. 2A; pg. 849; col. 2, par. 2). As Tregs also express PD-1, nivolumab was assessed in an allogeneic mixed lymphocyte reaction assay in which Tregs suppressed the proliferation and cytokine secretion of purified CD4+CD25- responder T cells, which were stimulated by allogeneic dendritic cells; nivolumab completely restored proliferation and partially restored IFN-γ release by the alloreactive T cells (Fig. 2D; pg. 851; col. 1, par. 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method rendered obvious over Zacharakis, et al. in view of L.X. Wang by culturing the T cells in the presence of nivolumab for one or more of steps (b), (c), or (e), as taught by C. Wang, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the enhancement of IFN-γ release, as well as rescue of any reduced proliferation or cytokine secretion in CD4+ responder T cells suppressed by Tregs, as taught by C. Wang, et al. Further, as C. Wang, et al. teaches the use of nivolumab for in vitro assays using primary human T cells, one skilled in the art would have more than a reasonable expectation of success in using nivolumab in the ex vivo expansion of patient-derived T cells.
Therefore, the embodiments of claim 7 are thus rendered obvious.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Tran, et al. (Science. 2014), in view of L.X. Wang, et al. (J Transl Med. 2004).
Tran, et al. teaches CD4+ T cell response against a mutated antigen can be harnessed to mediate regression of a metastatic epithelial cancer (Abstract).
The teachings of L.X. Wang, et al. are set forth above.
Regarding claim 1: Tran, et al. teaches lung metastases from patient 3737 were resected and used as a source for whole-exomic sequencing and generation of T cells for treatment, wherein whole-exomic sequencing revealed 26 nonsynonymous mutations (pg. 641; col. 3, par. 1). To test whether the patient’s tumor infiltrating lymphocytes (TIL) recognized any of these mutations, a minigene approach was used; for each mutation a minigene construct was designed, and multiple minigenes were synthesized in tandem to generate tandem minigene (TMG) constructs used as templates for the generation of in vitro transcribed (IVT) RNA (pg. 641; col. 3, par. 1). Each of these IVT TMG RNAs was then individually transfected into autologous antigen-presenting cells, followed by a coculture with TIL to determine whether any of the processed and presented mutated antigens were recognized by TIL; reactivity predominated in the CD4+ T cell population to a mutated antigen present in TMG-1 but not TMG-2 or -3 (pg. 642; col. 1). To determine which of the nine mutations in TMG-1 was being recognized by 3737-TIL, nine additional TMG-1 constructs were synthesized, each one containing a reversion of one of the mutations back to the wild-type sequence; reactivity of 3737-TIL to TMG-1 was abrogated only when the erbb2 interacting protein (ERBB2IP) mutation was reverted back to the wild-type sequence, indicating that the TIL specifically recognized the ERBB2IPE805G mutation (Fig. 1C; pg. 642; cols. 1-2). Clonality of the mutated ERBB2IP-specific CD4+ T cells was characterized by sorting after antigen-specific activation, after which cells were bulk-expanded and cloned by limiting dilution (pg. 642; col. 2). The patient underwent adoptive transfer of 42.4 billion TIL containing CD4+ ERBB2IP mutation-reactive T cells followed by four doses of interleukin (IL)–2 to enhance T cell proliferation and function (pg. 642; col. 3).
As Tran, et al. discloses resected tumors were minced into fragments and placed in wells comprising culture media and IL-2 (“Supplementary Materials and Methods”; pg. 2), the step where Tran, et al. teaches lung metastases from patient 3737 were resected and used for the generation of T cells for treatment (pg. 641; col. 3, par. 1) reads on steps (a)-(b) of claim 1; the step where IVT TMG RNAs, based on whole-exomic sequencing of patient 3737’s resected tumor, were transfected into autologous antigen-presenting cells followed by a coculture with TIL (pg. 642; col. 1) reads on step (c) of claim 1. Tran, et al. teaches the bulk-expansion of mutated ERBB2IP-specific CD4+ T cells (pg. 642; col. 2), wherein sorted T cells were expanded in culture media comprising IL-2 (“Supplementary Materials and Methods”; pg. 4); this reads on step (e) of claim 1. The step where Tran, et al. teaches the patient underwent adoptive transfer of the expanded T cells (pg. 642; col. 3) necessarily reads on step (f) of claim 1.
Tran, et al. doesn’t teach one or more of steps (a)-(e) as carried out in the presence of one or more modulatory cytokines selected from IL-23, IL-25, IL-27, or IL-35, as required by the remaining limitation recited in claim 1.
However, L.X. Wang, et al. teaches that CD4+ T cell anti-tumor function is mediated through cross-presentation of specific tumor-antigens by tumor associated APCs, and CD4+ cells cultured with IL-23 produced greater levels of INF-γ that would augment antigen presentation (pg. 10; col. 2, par. 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of Tran, et al. by including the use of IL-23 for culturing the TILs, as taught by L.X. Wang, et al. This conclusion of obviousness is based on the ‘teachings, suggestion, or motivation rationale’; one would be motivated to do so for the increased IFN-γ production to augment antigen presentation, as disclosed by L.X. Wang, et al. Further, as Tran, et al. teaches the infused T cells as mutated ERBB2IP-specific CD4+ T cells (pg. 642; col. 2), one skilled in the art would have more than a reasonable expectation of success.
Therefore, the embodiments of claim 1 are thus rendered obvious.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Tran, et al. (Science. 2014), in view of L.X. Wang, et al. (J Transl Med. 2004), further in view of C. Wang, et al. (Cancer Immunol Res. 2014).
The teachings of Tran, et al., L.X. Wang, et al., and C. Wang, et al. are set forth above.
Regarding claim 1: It is set forth above the method of claim 1 is rendered obvious over Tran, et al. in view of L.X. Wang, et al. Neither Tran, et al. nor L.X. Wang, et al. teach steps (b), (c), or (e) as carried out in the presence of an immunosuppressive blocking agent or a T cell adjuvant, wherein the T cell adjuvant is an immune checkpoint inhibitor, as required by the limitation recited in claim 7.
Briefly, C. Wang, et al. teaches in an allogeneic mixed lymphocyte reaction assay, PD-1 blockade with nivolumab systematically resulted in a titratable enhancement of IFN-γ release, and in some donor T-cell/dendritic cell pairs, enhanced T-cell proliferation was observed (Fig. 2A; pg. 849; col. 2, par. 2). As Tregs also express PD-1, nivolumab was assessed in an allogeneic mixed lymphocyte reaction assay in which Tregs suppressed the proliferation and cytokine secretion of purified CD4+CD25- responder T cells, which were stimulated by allogeneic dendritic cells; nivolumab completely restored proliferation and partially restored IFN-γ release by the alloreactive T cells (Fig. 2D; pg. 851; col. 1, par. 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method rendered obvious over Tran, et al. in view of L.X. Wang by culturing the T cells in the presence of nivolumab for one or more of steps (b), (c), or (e), as taught by C. Wang, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the enhancement of IFN-γ release, as well as the rescue of any reduced proliferation or cytokine secretion in CD4+ responder T cells suppressed by Tregs, as taught by C. Wang, et al. Further, as C. Wang, et al. teaches the use of nivolumab for in vitro assays using primary human T cells, one skilled in the art would have more than a reasonable expectation of success in using nivolumab in the ex vivo expansion of patient-derived T cells.
Therefore, the embodiments of claim 7 are thus rendered obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/599,446 (reference application), in view of L.X. Wang, et al. (J Transl Med. 2004).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of L.X. Wang, et al. are set forth above.
Regarding claims 1, 7:
Claim 1 of copending Application No. 17/599,446 teaches a method for manufacturing tumor-reactive T cells, the method comprising:
(1) culturing T cells by a process that comprises:
(a) incubating a population of cells comprising T cells from a biological sample obtained from a subject that has a tumor with a first T cell stimulatory agent(s) under conditions to stimulate expansion of T cells of the population to produce a population of stimulated T cells;
(b) co-culturing the population of stimulated T cells in the presence of antigen presenting cells (APCs) under conditions in which the APCs have been induced to present one or more peptides from a tumor-associated antigen from the subject, thereby generating a population containing T cells comprising tumor reactive T cells;
(d)[sic] enriching from the co-culture the population of tumor reactive T cells reactive to the one or more peptides, wherein said tumor-reactive T cells comprise an endogenous TCR that is reactive to a tumor-associated antigen, thereby producing a population of T cells enriched for tumor-reactive T cells; and
(d) incubating the population of T cells enriched in tumor reactive T cells with a second T cell stimulatory agent(s) under conditions to stimulate expansion of T cells in the population; and
wherein one or more steps of the culturing is carried out in the presence of at least one of a T cell adjuvant that is an apoptosis inhibitor that inhibits caspase activation or activity, a costimulatory agonist, or a checkpoint inhibitor; and
(2) harvesting cells produced by the method to produce a composition of expanded T cells enriched in tumor reactive T cells.
Following the above discussion, Step (1)(a) of copending claim 1 reads on step (a) of instant claim 1, as well as the performing a first expansion of T cells with a first T cell stimulatory agent(s) that stimulates expansion of T cells, to produce a second population of T cells limitation recited in step (b) of instant claim 1.
Steps (1)(b)-(d)[sic] of copending claim 1 reads on steps (c)-(d) of instant claim 1.
Step (d) of copending claim 1 reads on the performing a second expansion by culturing the fourth population enriched in the tumor-reactive T cells with a second T cell stimulatory agent(s) that stimulates expansion of T cells, to produce a fifth population of T cells limitation recited in step (e) of instant claim 1.
Step (2) of copending claim 1 reads on step (f) of instant claim 1.
The wherein one or more steps of the culturing is carried out in the presence of at least one of a T cell adjuvant that is a checkpoint inhibitor limitation recited in copending claim 1 reads on the wherein one or more of steps (b), (c), or (e) is carried out in the presence of an immunosuppressive blocking agent or a T cell adjuvant, wherein the T cell adjuvant is an immune checkpoint inhibitor limitation recited in instant claim 7.
Claim 1 of copending Application No. 17/599,446 does not explicitly teach the T cell stimulatory agent(s) as one or more of IL-2, IL-15, IL-7, and IL-21, as required by the remaining limitations recited in steps (b) and (e) of instant claim 1, nor does it teach one or more of steps (a)-(e) as carried out in the presence of one or more modulatory cytokines selected from IL-23, IL-25, IL-27, or IL-35, as required by the final limitation recited in claim 1.
However, L.X. Wang, et al. teaches CD4+ cells were activated with anti-CD3 mAb for 48h and cultured in the presence of IL-7 and IL-23, after which T cells were adoptively transferred to mice with 3-day subcutaneous (Figure 4B) or 3-day intracranial (Figure 4C) tumors, wherein a dose of 3×107 cells cultured in the presence of IL-23 was curative (pg. 7; cols. 1-2; Figs. 4B-C). Further, CD4+ T cell anti-tumor function is mediated through cross-presentation of specific tumor-antigens by tumor associated APCs, and CD4+ cells cultured with IL-23 produced greater levels of INF-γ that would augment antigen presentation (pg. 10; col. 2, par. 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending claim 1 by using IL-7 as the T cell stimulatory agent and including the use of IL-23 for culturing the T cells, as taught by L.X. Wang, et al. This conclusion of obviousness is based on the ‘teachings, suggestion, or motivation rationale’. The use of IL-7 as a T cell stimulatory agent is known in the art, as evidenced by L.X. Wang, et al.; thus one skilled in the art would have more than a reasonable expectation of success in its use as a T cell stimulatory agent. A person of ordinary skill in the art would be motivated to use IL-23 for the increased IFN-γ production to augment antigen presentation, as disclosed by L.X. Wang, et al; further, as the same disclosure teaches its use in expansion of T cells isolated from the tumors of mice (pg. 2; col. 2, par. 3), one skilled in the art would have more than a reasonable expectation of success in its use in a method for producing tumor-reactive T cells derived from a biological sample from a subject that has a tumor.
Therefore, the embodiments of claims 1 and 7 are thus rendered obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 and 7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/431,692 (reference application), in view of L.X. Wang, et al. (J Transl Med. 2004), further in view of C. Wang, et al. (Cancer Immunol Res. 2014).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of L.X. Wang, et al. and C. Wang, et al. are set forth above.
Regarding claim 1:
Claim 1 of copending Application No. 17/431,692 teaches a method for manufacturing T cells for use in a therapeutic cell composition, wherein the T cells express a T cell receptor (TCR) that recognizes an antigen on the surface of a target cell, the method comprising:
a. processing a biological sample containing a population of T lymphocyte cells obtained from a donor subject that has a tumor to produce a first population of T lymphocyte cells;
b. stimulating the first population with one or more first T-cell stimulating agents of lymphocytes under conditions for expansion of the T cells in the population to produce a second population of activated T cells;
c. co-culturing the second population of T cells in the presence of antigen presenting cells (APCs) that present one or more non-native peptide on a major histocompatibility complex (MHC), said one or more non-native peptides are peptides corresponding to nonsynonymous somatic mutations associated with the tumor of the subject, to produce a third population of cells containing T cells reactive to the peptides presented on the APCs comprising endogenous T cell receptors reactive to mutation encoding peptides of the tumor;
d. selecting, from the third population of cells, the population of T cells containing the endogenous TCRs that are reactive to the peptides presented on the APCs based on T cells positive for one or more upregulation markers expressed on reactive or activated T cells to produce a fourth population containing the selected T cells; and
e. expanding the fourth population of selected cells in the presence of one or more second T-cell stimulating agents of lymphocytes under conditions to expand the T cells in the population to produce a composition of expanded T cells for use as a therapeutic cell composition.
Following the above discussion, the method for manufacturing T cells for use in a therapeutic cell composition, wherein the T cells express a TCR that recognizes an antigen on the surface of a target cell limitation recited in copending claim 1 reads on the method of producing a composition of tumor-reactive cells limitation recited in instant claim 1.
Step (a) of copending claim 1 reads on step (a) of instant claim 1.
Step (b) of copending claim 1 reads on the performing a first expansion of T cells with a first T cell stimulatory agent(s) that stimulates expansion of T cells, to produce a second population of T cells limitation recited in step (b) of instant claim 1. Copending claim 13 recites wherein the one or more first T cell stimulating agents are selected from one or more of an anti-CD3 antibody; an anti-CD28 antibody; or a recombinant cytokine selected from among IL-2, IL-7, IL-15 and IL-21; this reads on the remaining limitation recited in step (b) of instant claim 1.
Step (c) of copending claim 1 reads on step (c) of instant claim 1.
Step (d) of copending claim 1 reads on step (d) of instant claim 1.
Step (e) of copending claim 1 reads on the performing a second expansion by culturing the fourth population enriched in the tumor-reactive T cells with a second T cell stimulatory agent(s) that stimulates expansion of T cells, to produce a fifth population of T cells limitation recited in step (e) of instant claim 1. Copending claim 18 recites wherein the one or more second T cell stimulating agents are selected from one or more of an anti-CD3 antibody; an anti-CD28 antibody; or a recombinant cytokine selected from among IL-2, IL-7, IL-15 and IL-21; this reads on the remaining limitation recited in step (e) of instant claim 1.
It is noted for the record that while step (e) of copending claim 1 only recites a fourth population of cells, step (e) comprises expanding said fourth population in the presence of a T cell stimulating agent, thereby necessarily producing a population of cells that reads on the fifth population recited in steps (e) and (f) of instant claim 1.
Copending claim 77 recites the method of claim 1 as further comprising harvesting the fourth population of cells produced by the method; this reads on step (f) of instant claim 1.
Copending Application No. 17/599,446 does not teach one or more of steps (a)-(e) as carried out in the presence of one or more modulatory cytokines selected from IL-23, IL-25, IL-27, or IL-35, as required by the final limitation recited in claim 1.
However, L.X. Wang, et al. teaches that CD4+ T cell anti-tumor function is mediated through cross-presentation of specific tumor-antigens by tumor associated APCs, and CD4+ cells cultured with IL-23 produced greater levels of INF-γ that would augment antigen presentation (pg. 10; col. 2, par. 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending Application No. 17/599,446 by including the use of IL-23 for culturing the T cells, as taught by L.X. Wang, et al. This conclusion of obviousness is based on the ‘teachings, suggestion, or motivation rationale’; one would be motivated to do so for the increased IFN-γ production to augment antigen presentation, as disclosed by L.X. Wang, et al. Further, as L.X. Wang, et al. teaches the use of IL-23 in the expansion of T cells isolated from the tumors of mice (pg. 2; col. 2, par. 3), one skilled in the art would have more than a reasonable expectation of success in its use in a method for producing tumor-reactive T cells derived from a biological sample from a subject that has a tumor.
Therefore, the embodiments of claim 1 are thus rendered obvious.
Regarding claim 7: Following the above discussion, copending Application No. 17/599,446 does not teach steps (b), (c), or (e) as carried out in the presence of an immunosuppressive blocking agent or a T cell adjuvant, wherein the T cell adjuvant is an immune checkpoint inhibitor, as required by the limitation recited in claim 7.
Briefly, C. Wang, et al. teaches in an allogeneic mixed lymphocyte reaction assay, PD-1 blockade with nivolumab systematically resulted in a titratable enhancement of IFN-γ release, and in some donor T-cell/dendritic cell pairs, enhanced T-cell proliferation was observed (Fig. 2A; pg. 849; col. 2, par. 2). As Tregs also express PD-1, nivolumab was assessed in an allogeneic mixed lymphocyte reaction assay in which Tregs suppressed the proliferation and cytokine secretion of purified CD4+CD25- responder T cells, which were stimulated by allogeneic dendritic cells; nivolumab completely restored proliferation and partially restored IFN-γ release by the alloreactive T cells (Fig. 2D; pg. 851; col. 1, par. 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method rendered obvious over Tran, et al. in view of L.X. Wang by culturing the T cells in the presence of nivolumab for one or more of steps (b), (c), or (e), as taught by C. Wang, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the enhancement of IFN-γ release, as well as the rescue of any reduced proliferation or cytokine secretion in CD4+ responder T cells suppressed by Tregs, as taught by C. Wang, et al. Further, as C. Wang, et al. teaches the use of nivolumab for in vitro assays using primary human T cells, one skilled in the art would have more than a reasonable expectation of success in using nivolumab in the ex vivo expansion of patient-derived T cells.
Therefore, the embodiments of claim 7 are thus rendered obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/822,767 (reference application), in view of Zacharakis, et al. (Nat Med. 2018) and L.X. Wang, et al. (J Transl Med. 2004).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of Zacharakis, et al. and L.X. Wang, et al. are set forth above.
Regarding claim 1: Copending Application No. 17/822,767 teaches a method for manufacturing tumor-reactive T cells, the method comprising:
(a) contacting cells from an input sample comprising CD4+ and CD8+ T cells with antibodies that bind to PD-1 and CD39, wherein the input sample is a single cell suspension processed by homogenization and/or enzymatic digestion of one or more tumor fragments from a resected tumor of a subject;
(b) selecting cells surface positive for PD-1 and CD39 to obtain selected cells from the sample;
(c) expanding the selected cells under conditions to produce a population of expanded Т cells, the expanding comprising:
(i) seeding the selected cells into a first culture vessel and expanding the seeded cells with one or more T-cell stimulating agents of lymphocytes in a first expansion for 7 to 21 days, wherein the one or more T-cell stimulating agents comprises an anti-CD3 antibody and a recombinant cytokine selected from the group consisting of IL-2, IL7, IL-15 and IL-21 or combinations thereof, wherein the concentration of recombinant IL-2 is from 100 IU/mL to 6000 IU/mL, the concentration of IL-7 is from 100 IU/mL to 2000 IU/mL, the concentration of IL-15 is from 100 IU/mL to 1000 IU/mL, and the concentration of IL-21 is from 0.5 IU/mL to 20 IU/mL; and
(ii) seeding cells that have been expanded by the first expansion into a second culture vessel and expanding the seeded cells with one or more T-cell stimulating agents of lymphocytes in a second expansion for 7 to 21 days, wherein the one or more T-cell stimulating agents comprises an anti-CD3 antibody and a recombinant cytokine selected from the group consisting of IL-2, IL-7, IL-15 and IL-21 or combinations thereof, wherein the concentration of recombinant IL-2 is from 100 IU/mL to 6000 IU/mL, the concentration of IL-7 is from 100 IU/mL to 2000 IU/mL, the concentration of IL-15 is from 100 IU/mL to 1000 IU/mL, and the concentration of IL-21 is from 0.5 IU/mL to 20 IU/mL;
(d) harvesting the population of expanded T cells, wherein the number of harvested cells is sufficient to provide a therapeutically effective dose of greater than 1x108 CD3+ T cells or viable cells thereof, and
(e) formulating the harvested population of expanded T cells as a therapeutic composition for administration to the subject.
Following the above discussion, the method for manufacturing tumor-reactive T cells of copending Application No. 17/822,767 reads on the method of producing a composition of tumor-reactive T cells limitation recited in instant claim 1.
Steps (a)-(b) of copending claim 156 reads on step (a) of instant claim 1.
Step (c)(i) of copending claim 156 reads on step (b) of instant claim 1.
Step (c)(ii) of copending claim 156 reads on step (e) of instant claim 1.
Step (d) of copending claim 156 reads on step (f) of instant claim 1.
Regarding antigen presenting cells exposed to or contacted with neoantigenic peptide(s):
Copending Application No. 17/822,767 does not teach steps (c) or (d) of instant claim 1; i.e., incubating the second population of T cells with antigen presenting cells exposed to or contacted with neoantigenic peptide(s) comprising subject-specific, tumor-specific mutation(s).
Briefly, Zacharakis, et al. teaches a method wherein a metastatic right breast subcutaneous lesion from a patient was resected and processed for identification of nonsynonymous somatic mutations in the tumor and for the generation of TILs (“Methods: Clinical history.”; pg. 731; Fig. 2d). Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were used for neoantigen identification (“Methods: Whole-exome sequencing (WES), RNA sequencing (RNA-seq) and determination of mutation clustering.”; pg. 731). Autologous dendritic cells (APCs) were incubated with 10 µg/ml of an individual peptide or peptide pools (10μg/ml of each peptide) for 2 h or overnight; following pulsing, the APCs were centrifuged, resuspended in fresh medium without cytokines and used immediately in coculture assays (“Methods: RNA transfection and peptide-pulsing of autologous antigen-presenting cells.”; pg. 731). TILs were derived from culturing small pieces of the patient’s tumor in high-dose IL-2 (pg. 724; col. 1, par. 1). T cells were incubated with peptide-pulsed dendritic cells; TILs were rested in complete medium with or without IL-2 for several hours to several days before coculture (“Methods: Coculture assays.”; pg. 732). Following the identification of neoantigen-reactive TILs, TIL cultures were selected for treatment and expanded into high numbers using a rapid expansion protocol using IL-2 (“Methods: TIL generation.”; pg. 731). Autologous TILs were administered to the patient via intravenous infusion (“Methods: Treatment and analysis of response.”; pg. 731).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending Application No. 17/822,767 to have included a step between (c)(i) and (c)(ii) wherein autologous dendritic cells incubated and pulsed with patient-specific, tumor-specific peptides were cocultured with the T cells, as taught by Zacharakis, et al. This conclusion of obviousness is based on the ‘teachings, suggestion, or motivation rationale’; one would be motivated to do so as Zacharakis, et al. discloses the patient has undergone complete durable regression of metastatic breast cancer (Abstract). Further, as Zacharakis, et al. teaches the infused TILs population as predominantly CD4+ (pg. 726; col. 1, par. 2) but also comprising CD8+ cells (Fig. 2a) and CD3+ cells expressing PD-1 (pg. 726; col. 1, par. 2), one skilled in the art would have more than a reasonable expectation of success.
Regarding modulatory cytokines IL-23, IL-25, IL-27, or IL-35:
Neither copending Application No. 17/822,767 nor Zacharakis, et al. teach one or more of steps (a)-(e) as carried out in the presence of one or more modulatory cytokines selected from IL-23, IL-25, IL-27, or IL-35, as required by the remaining limitation recited in claim 1.
However, L.X. Wang, et al. teaches that CD4+ T cell anti-tumor function is mediated through cross-presentation of specific tumor-antigens by tumor associated APCs, and CD4+ cells cultured with IL-23 produced greater levels of INF-γ that would augment antigen presentation (pg. 10; col. 2, par. 2).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending Application No. 17/822,767 by including the use of IL-23 for culturing the CD4+ and CD8+ T cells, as taught by L.X. Wang, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so for the increased IFN-γ production to augment antigen presentation, as disclosed by L.X. Wang, et al. Further, as copending Application No. 17/822,767 teaches the T cell population as comprising CD4+ T cells, one skilled in the art would have more than a reasonable expectation of success.
Therefore, the embodiments of claim 1 are thus rendered obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 7 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 17/822,767 (reference application), in view of Zacharakis, et al. (Nat Med. 2018) and L.X. Wang, et al. (J Transl Med. 2004), further in view of C. Wang, et al. (Cancer Immunol Res. 2014).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of Zacharakis, et al., L.X. Wang, et al., and C. Wang, et al. are set forth above.
Regarding claim 1: It is set forth above copending Application No. 17/822,767 renders obvious the method of claim 1 in view of Zacharakis, et al. and L.X. Wang, et al.
Copending Application No. 17/822,767 does not teach steps (b), (c), or (e) as carried out in the presence of an immunosuppressive blocking agent or a T cell adjuvant, wherein the T cell adjuvant is an immune checkpoint inhibitor, as required by the limitation recited in claim 7.
Briefly, C. Wang, et al. teaches in an allogeneic mixed lymphocyte reaction assay, PD-1 blockade with nivolumab systematically resulted in a titratable enhancement of IFN-γ release, and in some donor T-cell/dendritic cell pairs, enhanced T-cell proliferation was observed (Fig. 2A; pg. 849; col. 2, par. 2). As Tregs also express PD-1, nivolumab was assessed in an allogeneic mixed lymphocyte reaction assay in which Tregs suppressed the proliferation and cytokine secretion of purified CD4+CD25- responder T cells, which were stimulated by allogeneic dendritic cells; nivolumab completely restored proliferation and partially restored IFN-γ release by the alloreactive T cells (Fig. 2D; pg. 851; col. 1, par. 1).
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the method of copending Application No. 17/822,767 by culturing the T cells in the presence of nivolumab for one or more of steps (b), (c), or (e), as taught by C. Wang, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’; one would have been motivated to do so for the enhancement of IFN-γ release, as well as rescue of any reduced proliferation or cytokine secretion in CD4+ responder T cells suppressed by Tregs, as taught by C. Wang, et al. Further, as C. Wang, et al. teaches the use of nivolumab for in vitro assays using primary human T cells, one skilled in the art would have more than a reasonable expectation of success in using nivolumab in the ex vivo expansion of patient-derived T cells.
Therefore, the embodiments of claim 7 are thus rendered obvious.
Conclusion
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633