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 .
Detailed Action
This action is in response to the papers filed April 13, 2026.
Claim Amendments
Applicant’s amendment to the claims filed 04/13/2026 is acknowledged.
Claims 1-25, 27-32, 35-38, 41-51 have been cancelled.
Claims 26, 40, 52-53, 55, 57-59, 61 and 64 are amended.
Claims 26, 33-34, 39-40, 52-64 are pending.
Claims 33-34, and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 26, 40, 52-64 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the application:
Applicant elected without traverse the invention of Group 1, drawn to methods of culturing CD8 T cells with a signal 3 cytokine, selection thereof, and administration thereof, in the reply filed 04/29/2024. See Requirement for Restriction/Election mailed 02/29/2024.
Claims 33-34, and 39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/29/2024.
Priority
The instant application 17/258,533 was filed on 01/07/2021. This application is a national stage of international application PCT/IB2019/055801 filed 07/08/2019, claiming priority based on U.S. Provisional Application No. 62/695,298 filed 07/09/2018.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 11/12/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Claim Interpretation
Page 4, line 22, specification defines “signal 3 cytokine” as referring to IL-12 and type I interferons, i.e., IFN-α and IFN-β.
Page 8, line 8, defines “CD8 T cell” as referring to “CD8+ T cell.”
Page 16, lines 16-19, define a “positive memory cell methylation marker” as referring to markers whose methylation status relative to the corresponding methylation status of the same marker of an appropriate control (e.g., naïve T cell) indicates increased T-cell activity compared to a naïve T cell.
Claim Objections
Claim 57 is objected to because of the following informalities:
In claim 57, the phrase “CD8 T+ cell” should be “CD8+ T cell” instead.
Appropriate correction is required.
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 26, 40, 52-64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending U.S. Application No. 16/467,358 (reference to claim listing filed 11/06/2025); in view of Curtsinger et al. (2010) “Inflammatory cytokines as a third signal for T cell activation” Current opinion in immunology, 22(3), 333-340.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the copending claims and secondary references. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection is repeated for the same reasons provided in the previous Office action.
The copending claims recite a method of producing a population of CAR-modified CD8+ T cells having increased T cell activity comprising:
measuring methylation levels of genomic loci of a first population of CD8+ T cells, wherein the genomic loci comprise Tcf7, T-bet and Eomes, and
separating a subset of the CAR-modified CD8+ T cells to obtain a second population of CAR-modified CD8+ T cells, wherein the second population of CAR modified CD8+ T cells comprises decreased methylation levels of the genomic loci comprising Tcf7, T-bet, and Eomes, thereby producing a population of CAR modified CD8+ T cells having increased T cell activity (claim 1);
wherein said genomic loci further comprise at least one of: IFNγ, granzyme K, granzyme B, Foxp1, CCR7, and Myc (claim 8);
wherein the second population of CD8+ T cells is administered to a subject (claim 12);
wherein an immune checkpoint blockade (ICB) therapy is further administered to the subject (claim 54).
Accordingly, the difference between the instantly claimed invention and that of the copending claims is a step of “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine to obtain modified CD8 T cells,” as instantly claimed in claim 26. Prior to the effective filing date of the instantly claimed invention, Curtsinger teaches that CD8+ naïve T cells require signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β), along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2), to make a productive response and avoid death and/or tolerance induction. TCR and costimulatory signals initiate proliferation of naïve cells, but the cells fail to develop optimal effector functions, survive poorly, and do not form a responsive memory population in the absence of signal 3. In vitro experiments have found that CD8+ naïve T cells expanded for 3 days in the presence of aAPC having Ag and B7-1 on the surface, but in the absence of signal 3 cytokine, resulted in cell death within a few days following transfer to mice. By contrast, if IL-12 is present during the in vitro stimulation, the cells continued to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells. See Abstract; pg. 333-334; Figure 1:
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Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the copending claims by further including a step of “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine to obtain modified CD8 T cells,” as taught by Curtsinger, with a reasonable expectation of success because stimulation of CD8+ naïve T cells require signal 3 cytokines to make a productive response and avoid death and/or tolerance induction, allowing the cells continued to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells.
For these reasons, instant claim 26 would have been prima facie obvious over the copending claims and secondary references.
Regarding instant claim 40, the copending claims recite the second population of CD8+ T cells is administered to a subject (claim 12).
Regarding instant claim 54, Curtsinger teaches incubation occurs in vitro. See, e.g., Signal 3 cytokine requirements for CD8 T cell responses on pages 333-334.
Regarding instant claim 56, Curtsinger teaches the signal 3 cytokine is a type I interferon or IL-12. See, e.g., Abstract.
Regarding instant claims 57-58, Curtsinger teaches a step of activating the at least one naïve CD8 T cell. The signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β) are provided along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2) to active T cells. See, e.g., pages 333-334; Abstract. Anti-CD28 monoclonal antibodies (mAbs) for T cell stimulation are also described. See, e.g., pg. 336, left column.
Regarding instant claim 61, copending claim 1 recites that the CD8+ T cells are modified with a chimeric antigen receptor (CAR) prior to the measurement step.
Regarding instant claims 62-63, the copending claims do not recite that the subject or T cells are human. However, prior to the effective filing date of the instantly claimed invention, CAR-T cell therapy comprising administration of human T cells to human subject was known in the art (Official Notice taken, if necessary). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of the copending claims by using human T cells with a reasonable expectation of success because the copending claims are directed to CAR-T therapy, and thus one of ordinary of ordinary skill in the art would have used human T cells to provide said therapy to human subjects in need thereof. Since humans possess a risk of developing cancer, including lymphoma, a leukemia, non-small cell lung carcinoma (NSCLC), head and neck cancer, skin cancer, melanoma, or squamous cell carcinoma (SCC), the limitations of claim 63 are also met.
Regarding instant claim 64, the copending claims recite an immune checkpoint blockade (ICB) therapy is further administered to the subject (claim 54).
The instant claims further recite that the incubation step results in a memory or Tscm cell phenotype comprising expression of CD95 and CD122 markers (claims 52-53); an effector-associated epigenetic program comprising demethylation of one or more of granzyme K, granzyme B, and perforin 1 locus (claim 55); an increase in cytokine production, increase in the formation of intracellular granules, increase in the loading of granules with effector agents, and/or an increase in the transport and exocytosis of effector agents (claim 59), wherein the effector agents are granzymes, perforins, and/or granulysins (claim 60).
MPEP 2111.04 instructs that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In this case, the claims 52-53, 55, 59-60 recite functional properties and intended results of performing the claimed incubation step (i.e., “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine”). Since the claimed incubation step is taught by Curtsinger, the recited functional properties and intended results of claims 52-53, 55, 59-60 would naturally flow from the incubation step taught by Curtsinger.
Moreover, Curtsinger teaches that the modified CD8 T cell exhibit a memory phenotype, including both central (Tcm) and effector (Tem) memory phenotypes (pg. 334, left column); produce IFNγ (pg. 333, right column), and exhibit altered expression of genes included many whose products are involved in effector functions (granzymes, IFNγ, FasL), proliferation and costimulation (CD25, Ox-40, 4-1BB), survival (serine protease inhibitor 6, Bcl-3), trafficking and migration, and differentiation, including T-bet, eomesodermin and Blimp-1 (pg. 336, left column). Curtsinger concludes that signal 3 cytokines act, at least partly, by promoting chromatin remodeling to maintain transcription of numerous genes needed for differentiation and effector functions; epigenetic memory of chromatin remodeling contributes to the more rapid and robust response of memory cells upon rechallenge, and it appears likely that at least some of this remodeling occurs in response to the signal 3 cytokine during the early phase of Ag recognition and differentiation. See Conclusions on page 338. In addition, the copending claims recite decreased methylation levels of granzyme K and granzyme B (claim 8). Accordingly, the cited references teach similar functional properties as claimed.
For these reasons, the recited functional properties and intended results of claims 52-53, 55, 59-60 are not found to patentably distinguish the instantly claimed invention from the copending claims and secondary references.
Response to arguments: Applicant’s remarks filed 04/13/2026 have been carefully considered, but are not found persuasive.
Applicant argues that it would be unclear whether Curtsinger’s T cell population possess increased expansion potential when exposed to ICB therapy, as recited in claim 1 of the copending application. The argument continues by asserting that Curtsinger would require constraining the T cell population to naïve T cells when the copending application’s claims may start with any T cell population. Page 5-6 of remarks.
The argument is not persuasive because claim 1 of the copending application positively recites that the increased expansion potential during ICB therapy is a result of sorting based on genomic methylation levels. Accordingly, since the T cells would be sorted in the manner recited in the claims of the copending application, the T cells would possess the increased expansion potential during ICB therapy, as claimed. Further, the argument that the Curtsinger would necessitate constraining the claims of the copending application to naïve T cells is not persuasive because the claims of the copending application claims may start with any T cell population, including Curtsinger’s naïve T cells. Also, when IL-12 is present during the in vitro stimulation, the cells were found to continue to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells.
Applicant argues that neither Curtsinger or the claims of the copending application disclose measuring the DNA methylation profile of modified CD8 T cells. Pages 6-7 of remarks.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, the claims of the copending application recite measuring the DNA methylation profile of CD8 T cells, and Curtsinger teaches modifying T cells by exposure to a signal 3 cytokine.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 26, 40, 52-64 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/104909 A2 to Youngblood et al.; in view of Curtsinger et al. (2010) “Inflammatory cytokines as a third signal for T cell activation” Current opinion in immunology, 22(3), 333-340.
This rejection is repeated for the same reasons provided in the previous Office action. Youngblood teaches a method comprising measuring the methylation status of specific memory cell methylation markers and using the markers to identify and separate population of CD8 T cells having desired T cell activity (pg. 3, ll. 1-10; claim 18), wherein the methylation markers include IFNγ, granzyme K (GzmK), granzyme B (GzmB), Prf1, T-bet, Tcf7, Myc, T-bet, eomesodermin (Eomes), Foxp1, CCR7, and/or CD62L (pg. 6, ll. 19-25).
Accordingly, the difference between the instantly claimed invention and that of Youngblood is a step of “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine to obtain modified CD8 T cells,” as instantly claimed in claim 26. Prior to the effective filing date of the instantly claimed invention, Curtsinger teaches that CD8+ naïve T cells require signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β), along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2), to make a productive response and avoid death and/or tolerance induction. TCR and costimulatory signals initiate proliferation of naïve cells, but the cells fail to develop optimal effector functions, survive poorly, and do not form a responsive memory population in the absence of signal 3. In vitro experiments have found that CD8+ naïve T cells expanded for 3 days in the presence of aAPC having Ag and B7-1 on the surface, but in the absence of signal 3 cytokine, resulted in cell death within a few days following transfer to mice. By contrast, if IL-12 is present during the in vitro stimulation, the cells continued to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells. See Abstract; pg. 333-334; Figure 1, reproduced above.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Youngblood by further including a step of “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine to obtain modified CD8 T cells,” as taught by Curtsinger, with a reasonable expectation of success because stimulation of CD8+ naïve T cells require signal 3 cytokines to make a productive response and avoid death and/or tolerance induction, allowing the cells continued to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells.
For these reasons, instant claim 26 would have been prima facie obvious over the prior art.
Regarding claim 40, Youngblood teaches that the CD8+ T cells are administered to a subject. See, e.g., pg. 12, ll. 4-16.
Regarding claim 54, Curtsinger teaches incubation occurs in vitro. See, e.g., Signal 3 cytokine requirements for CD8 T cell responses on pages 333-334.
Regarding claim 56, Curtsinger teaches the signal 3 cytokine is a type I interferon or IL-12. See, e.g., Abstract.
Regarding claims 57-58, Youngblood teaches a step of activating comprising anti-CD3/CD28 antibodies. See, e.g., pg. 42, ll. 21-25; pg. 47, ll. 1-11. Curtsinger teaches a step of activating the at least one naïve CD8 T cell. The signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β) are provided along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2) to active T cells. See, e.g., pages 333-334; Abstract. Anti-CD28 monoclonal antibodies (mAbs) for T cell stimulation are also described. See, e.g., pg. 336, left column.
Regarding instant claim 61, Youngblood teaches that the CD8+ T cells are modified with a chimeric antigen receptor (CAR). See, e.g., pg. 12, ll. 4-16.
Regarding instant claims 62-63, Youngblood teaches that the T cells and subject are human. See, e.g., pg. 11, ll. 27-30; pg. 12, ll. 4-16; pg. 22, ll. 19-20. Since humans possess a risk of developing cancer, including lymphoma, a leukemia, non-small cell lung carcinoma (NSCLC), head and neck cancer, skin cancer, melanoma, or squamous cell carcinoma (SCC), the limitations of claim 63 are also met. In addition, Youngblood teaches that the subject has a lymphoma, a leukemia, non-small cell lung carcinoma (NSCLC), head and neck cancer, skin cancer, melanoma, or squamous cell carcinoma (SCC). See, e.g., claim 16.
Regarding instant claim 64, Youngblood an immune checkpoint blockade (ICB) therapy is further administered to the subject. See, e.g., pg. 12, ll. 4-16; claim 17.
The claims further recite that the incubation step results in a memory or Tscm cell phenotype comprising expression of CD95 and CD122 markers (claims 52-53); an effector-associated epigenetic program comprising demethylation of one or more of granzyme K, granzyme B, and perforin 1 locus (claim 55); an increase in cytokine production, increase in the formation of intracellular granules, increase in the loading of granules with effector agents, and/or an increase in the transport and exocytosis of effector agents (claim 59), wherein the effector agents are granzymes, perforins, and/or granulysins (claim 60).
MPEP 2111.04 instructs that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In this case, the claims 52-53, 55, 59-60 recite functional properties and intended results of performing the claimed incubation step (i.e., “incubating naïve CD8 T cells obtained from a mammal in the presence of a signal 3 cytokine”). Since the claimed incubation step is taught by Curtsinger, the recited functional properties and intended results of claims 52-53, 55, 59-60 would naturally flow from the incubation step taught by Curtsinger.
Moreover, Curtsinger teaches that the modified CD8 T cell exhibit a memory phenotype, including both central (Tcm) and effector (Tem) memory phenotypes (pg. 334, left column); produce IFNγ (pg. 333, right column), and exhibit altered expression of genes included many whose products are involved in effector functions (granzymes, IFNγ, FasL), proliferation and costimulation (CD25, Ox-40, 4-1BB), survival (serine protease inhibitor 6, Bcl-3), trafficking and migration, and differentiation, including T-bet, eomesodermin and Blimp-1 (pg. 336, left column). Curtsinger concludes that signal 3 cytokines act, at least partly, by promoting chromatin remodeling to maintain transcription of numerous genes needed for differentiation and effector functions; epigenetic memory of chromatin remodeling contributes to the more rapid and robust response of memory cells upon rechallenge, and it appears likely that at least some of this remodeling occurs in response to the signal 3 cytokine during the early phase of Ag recognition and differentiation. See Conclusions on page 338. In addition, Youngblood teaches that the cells exhibit a Tscm phenotype and express CD95 (pg. 41, 47), demethylation of one or more genomic loci (pg. 41). and an increase in cytokine production (pg. 7). Accordingly, the cited references teach similar functional properties as claimed.
For these reasons, the recited functional properties and intended results of claims 52-53, 55, 59-60 are not found to patentably distinguish the instantly claimed invention from the prior art.
Response to arguments: Applicant’s remarks filed 04/13/2026 have been carefully considered, but are not found persuasive.
Applicant argues that the Youngblood disclosure is not prior art under the exception under 35 U.S.C. 102(b)(1)(A) and 35 U.S.C. 102(b)(2)(C) because the Youngblood disclosure was made 1 year or less before the effective filing date of the instant application, and the Youngblood disclosure was made by the inventor of the present application and cited patent application, Benjamin Youngblood. The argument continues by asserting the subject matter of the Youngblood patent application and the claimed invention of the instant application was owned by the same person not later than the effective filing date of the claimed invention. Pages 7-8 of remarks.
This is not persuasive because the arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). The Office has provided a mechanism for filing an affidavit or declaration (under 37 CFR 1.130) to establish that a disclosure is not prior art under AIA 35 U.S.C. 102(a) due to an exception in AIA 35 U.S.C. 102(b). See MPEP § 717. In the situations in which it is not apparent from the grace period disclosure itself or the patent application specification that the disclosure is an inventor-originated disclosure, the applicant may establish that the AIA 35 U.S.C. 102(b)(1)(A) exception applies by way of an affidavit or declaration under 37 CFR 1.130(a). MPEP § 2155.01 discusses the use of affidavits or declarations to show that a disclosure was an inventor-originated disclosure made during the grace period.
In this case, the Youngblood disclosure (WO 2018/104909 A1) lists an additional inventor, Hazem Ghoneim, whose name is not included in the inventorship of the present application. As instructed by MPEP 2153.01(a), when the application names fewer joint inventors than a publication (e.g., the application names as joint inventors A and B, and the publication names as authors A, B and C), it would not be readily apparent from the publication that it is an inventor-originated disclosure and the publication would be treated as prior art under AIA 35 U.S.C. 102(a)(1) unless there is evidence of record that an exception under AIA 35 U.S.C. 102(b)(1) applies. Accordingly, since there is a lack of evidence of record that an exception under AIA 35 U.S.C. 102(b)(1) applies, the Youngblood disclosure (WO 2018/104909 A1) is not excepted as prior and the rejection is maintained.
Claims 26, 40, 52-64 are rejected under 35 U.S.C. 103 as being unpatentable over Curtsinger et al. (2010) “Inflammatory cytokines as a third signal for T cell activation” Current opinion in immunology, 22(3), 333-340; in view of Satoh et al. (2012) "The development of IL-17/IFN-γ-double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter" European journal of immunology, 42(9), 2329-2342; and Abdelsamed et al. (10 May 2017) “Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis” Journal of Experimental Medicine, 214(6), 1593-1606.
This rejection is newly applied, necessitated by amendment.
Curtsinger teaches that CD8+ naïve T cells require signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β), along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2), to make a productive response and avoid death and/or tolerance induction. TCR and costimulatory signals initiate proliferation of naïve cells, but the cells fail to develop optimal effector functions, survive poorly, and do not form a responsive memory population in the absence of signal 3. In vitro experiments have found that CD8+ naïve T cells expanded for 3 days in the presence of aAPC having Ag and B7-1 on the surface, but in the absence of signal 3 cytokine, resulted in cell death within a few days following transfer to mice. By contrast, if IL-12 is present during the in vitro stimulation, the cells continued to expand for several days following transfer, and, following a characteristic contraction phase, the surviving cell population persisted long-term displaying a memory phenotype, including both central (Tcm) and effector (Tem) memory cells. . See Abstract; pg. 333-334; Figure 1, reproduced above. Curtsinger further teaches that the modified CD8 T cell exhibits a memory phenotype, including both central (Tcm) and effector (Tem) memory phenotypes (pg. 334, left column); produce IFNγ (pg. 333, right column), and exhibit altered expression of genes included many whose products are involved in effector functions (granzymes, IFNγ, FasL), proliferation and costimulation (CD25, Ox-40, 4-1BB), survival (serine protease inhibitor 6, Bcl-3), trafficking and migration, and differentiation, including T-bet, eomesodermin and Blimp-1 (pg. 336, left column). Curtsinger concludes that signal 3 cytokines act, at least partly, by promoting chromatin remodeling to maintain transcription of numerous genes needed for differentiation and effector functions. Epigenetic memory of chromatin remodeling contributes to the more rapid and robust response of memory cells upon rechallenge, and it appears likely that at least some of this remodeling occurs in response to the signal 3 cytokine during the early phase of Ag recognition and differentiation. See Conclusions on page 338.
Accordingly, Curtsinger provides a method of modulating the activity of naïve CD8+ T cells obtained from a mammal, the method comprising a step of incubating the naïve CD8+ T cells in the presence of a signal 3 cytokine to obtain modified CD8+ T cells possessing enhanced activity. Curtsinger further recognizes that the modified CD8 T cells exhibit a memory phenotype, including both central (Tcm) and effector (Tem) memory phenotypes, and the signal 3 cytokines likely act, at least partly, through epigenetic changes and chromatin remodeling of numerous genes needed for differentiation and effector functions.
However, Curtsinger does not teach steps of measuring the methylation profile of the T cells; and separating a subset of the T cells comprising at least one positive memory cell methylation marker (claim 26), wherein the at least one positive memory cell methylation marker comprises CCR7, CD62L, T-bet, Eomes, Foxp1, IFNγ, granzyme K, granzyme B, or perforin 1 (claim 51).
Satoh is relevant prior art for disclosing a method of activating naïve CD8+ T cells with an antigenic peptide (OVA257–264 peptide), followed by incubation of the activated CD8+ T cells in media containing IL-12. See page 2339, Generation of CD8+ T-cell subsets. Satoh teaches that IL-12 treatment results in epigenetic modifications of the Ifng (IFNγ) promoter region that results in induced IFN-y production (pg. 2330, Epigenetic remodeling of IL-12-converted Tc17 cells). Figure 3A shows an increased degree of methylated histone 3 lysine 4 residues (H3K4me), which is a permissive modification, and a decreased degree of tri-methylation of histone 3 lysine 27 residues (H3K27me3), which is a repressive modification, relative to control Tc17 cells. Accordingly, Satoh recognizes that IL-12 treatment results in IFN-γ production and epigenetic changes of the Ifng (IFNγ) locus.
Satoh further teaches the steps of measuring the methylation profile (H3K4me and H3K27me3) of the CD8+ T cells (Figures 3A-B, 4D), and separating T cell subsets based on production of IFN-γ (pg. 2333, Modifications in the Il17a and Ifng loci of Tc17/IFN-γ cells; Figure 4). Satoh further recognizes that the IL-12 modified T cells comprise the positive methylation markers of IFN-γ and T-bet (Tbx21). See, e.g., Figure 3. Accordingly, Satoh’s separated IFNγ+ T cells comprise at least the positive methylation marker of T-bet (Tbx21).
In addition, Abdelsamed is relevant prior art for performing whole-genome bisulfite sequencing (WGBS) to measure the DNA methylation profiles delineating CD8+ T cell differentiation states: naïve T cell > stem cell memory T (Tscm) cell > central memory T (Tcm) cell > effector memory T (Tem) cell. See, e.g., Abstract; pg. 1594, right column. Abdelsamed further found the following differentially methylated regions (DMRs): IFNγ, CCR7, CD62L (SELL), T-bet (Tbx21), eomesodermin (Eomes), granzyme K (GzmK), granzyme B (GzmB), and perforin 1 (Prf1). See, e.g., pages 1594-1596, and Figure 1. Abdelsamed further teaches separating the memory T cells from naïve T cells, by CD45RA+ cell depletion, and infusing said separated cells into a subject. See, e.g., pg. 1599, 1601; and Figure 5.
Accordingly, Abdelsamed recognizes that the differentiated, memory CD8+ T cell subsets exhibit the positive methylation markers, including IFNγ, CCR7, CD62L (SELL), T-bet (Tbx21), eomesodermin (Eomes), granzyme K (GzmK), granzyme B (GzmB), and perforin 1 (Prf1), relative to naïve T cells, and Abdelsamed separated memory T cells comprising said positive methylation markers by CD45RA+ cell depletion, as claimed in claim 26.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Curtsinger by further including steps of measuring the DNA methylation profile of the modified CD8+ T cells, and separating a subset of the modified CD8+ T cell comprising at least one positive memory cell methylation marker selected from CCR7, CD62L, T-bet, Eomes, granzyme K, granzyme B and perforin 1, in view of Satoh and Abdelsamed, with a reasonable expectation of success because the IL12-modified CD8+ T cells of Curtsinger exhibit a memory phenotype, including Tcm and Tem phenotypes, by epigenetic changes and chromatin remodeling of numerous genes related to differentiation and effector functions, and positive memory cell methylation markers (IFNγ, CCR7, CD62L, T-bet, Eomes, granzyme K, granzyme B and perforin 1) were previously identified by Satoh and Abdelsamed to delineate the memory T cell subsets from naïve T cells.
For these reasons, claim 26 would have been prima facie obvious over the prior art.
Regarding claim 40, Curtsinger teaches adoptive transfer of T cells. See, e.g., page 334. Abdelsamed teaches infusing the memory T cells into a subject. See, e.g., pg. 1599, 1601; and Figure 5.
Regarding claim 54, Curtsinger teaches incubation occurs in vitro. See, e.g., Signal 3 cytokine requirements for CD8 T cell responses on pages 333-334.
Regarding claim 56, Curtsinger teaches the signal 3 cytokine is a type I interferon or IL-12. See, e.g., Abstract.
Regarding claims 57-58, Curtsinger teaches a step of activating the at least one naïve CD8 T cell. The signal 3 cytokines (IL-12, Type I IFN, i.e., IFNα/β) are provided along with TCR signal (signal 1, Ag) and costimulatory signal (signal 2, including IL-2) to active T cells. See, e.g., pages 333-334; Abstract. Anti-CD28 monoclonal antibodies (mAbs) for T cell stimulation are also described. See, e.g., pg. 336, left column. Satoh teaches a step of activating T cells with antigenic peptides (OVA257-264) and anti-CD8/CD28 antibodies. See, e.g., pg. 2339-2340. Abdelsamed teaches activating T cells with anti-CD8/CD28 antibodies. See, e.g., pg. 1597, and Figure 2.
Regarding claim 61, Satoh teaches that the T cells comprise a heterologous T-cell receptor (TCR). See, e.g., page 2330. Curtsinger also teaches OT-I CD8 T cells (e.g., pg. 334), which comprise a heterologous TCR.
Regarding claims 62-63, Abdelsamed teaches that the subject and T cells are human. See, e.g., page 1599, 1601; and Figure 5. Since humans possess a risk of developing cancer, including lymphoma, a leukemia, non-small cell lung carcinoma (NSCLC), head and neck cancer, skin cancer, melanoma, or squamous cell carcinoma (SCC), the limitations of claim 63 are also met.
Regarding claim 64, the claim recites that the subject is administered an immune checkpoint blockade (ICB) therapy. Curtsinger, Satoh and Abdelsamed do not teach ICB therapy. However, prior to the effective filing date of the instantly claimed invention, ICB therapy was known in the art to enhance T cell therapy by preventing checkpoint molecule triggered exhaustion (Official Notice taken, if necessary). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Curtsinger, Satoh and Abdelsamed, combined, by further including a step of administering ICB therapy to the subject, as previously known in the art, with a reasonable expectation of success because ICB therapy enhances T cell therapy by preventing checkpoint molecule triggered exhaustion.
The claims further recite that the incubation step results in a memory or Tscm cell phenotype comprising expression of CD95 and CD122 markers (claims 52-53); an effector-associated epigenetic program comprising demethylation of one or more of granzyme K, granzyme B, and perforin 1 locus (claim 55); an increase in cytokine production, increase in the formation of intracellular granules, increase in the loading of granules with effector agents, and/or an increase in the transport and exocytosis of effector agents (claim 59), wherein the effector agents are granzymes, perforins, and/or granulysins (claim 60).
MPEP 2111.04 instructs that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. In this case, the claims 52-53, 55, 59-60 recite functional properties and intended results of performing the claimed incubation step of naïve CD8+ T cells and signal 3 cytokines. Since the claimed incubation step is taught by Curtsinger, the recited functional properties and intended results of claims 52-53, 55, 59-60 would naturally flow from the incubation step taught by Curtsinger.
Moreover, Curtsinger teaches that the modified CD8 T cell exhibit a memory phenotype, including both central (Tcm) and effector (Tem) memory phenotypes (pg. 334, left column); produce IFNγ (pg. 333, right column), and exhibit altered expression of genes included many whose products are involved in effector functions (granzymes, IFNγ, FasL), proliferation and costimulation (CD25, Ox-40, 4-1BB), survival (serine protease inhibitor 6, Bcl-3), trafficking and migration, and differentiation, including T-bet, eomesodermin and Blimp-1 (pg. 336, left column). Curtsinger concludes that signal 3 cytokines act, at least partly, by promoting chromatin remodeling to maintain transcription of numerous genes needed for differentiation and effector functions; epigenetic memory of chromatin remodeling contributes to the more rapid and robust response of memory cells upon rechallenge, and it appears likely that at least some of this remodeling occurs in response to the signal 3 cytokine during the early phase of Ag recognition and differentiation. See Conclusions on page 338. In addition, Abdelsamed teaches that the cells exhibit a memory (Tscm) cell phenotype comprising expression of CD95 and CD122 markers (e.g., pg. 1593), and an effector-associated epigenetic program comprising demethylation of one or more of granzyme K, granzyme B, and perforin 1 locus (e.g., pg. 1596, Figure 1). Accordingly, the cited references teach similar functional properties as claimed.
For these reasons, the recited functional properties and intended results of claims 52-53, 55, 59-60 are not found to patentably distinguish the instantly claimed invention from the prior art.
Response to arguments: Applicant’s remarks filed 04/13/2026 have been carefully considered, but are not found persuasive.
Applicant argues there is no motivation to combine the cited references. In particular, Applicant asserts one of ordinary skill in the art would not have known whether Curtsinger’s T cell population comprise at least one of the recited positive memory cell methylation markers. Regarding the secondary references, the argument alleges that Satoh’s histone methylation is distinct from the claimed DNA methylation, and there is no evidence that Curtsinger’s IL-12 treated T cell population and Abdesamed’s T cell population are the same or would be synergistic. The argument concludes that the claimed invention is useful for enriching a T cell population useful for fighting cancer. Pages 11-12 of remarks.
The argument is not persuasive because the IL12-modified CD8+ T cells of Curtsinger exhibit a memory phenotype, including Tcm and Tem phenotypes, by epigenetic changes and chromatin remodeling of numerous genes related to differentiation and effector functions, and positive memory cell methylation markers (IFNγ, CCR7, CD62L, T-bet, Eomes, granzyme K, granzyme B and perforin 1) were previously identified by Satoh and Abdelsamed to delineate the memory T cell subsets from naïve T cells. Further, Abdelsamed teaches measuring DNA methylation, specifically, as claimed. Also, Curtsinger’s teachings pertain to differentiated, memory CD8+ T cell subsets, and the DNA methylation markers found in Abdesamed pertains to differentiated, memory CD8+ T cell subsets. Regarding adoptive T cell therapy for fighting cancer, such utility is not claimed, and, further, Curtsinger recognizes signal 3 cytokines support in vivo T cell responses to peptide and protein antigens (Abstract).
Applicant further argues that none of the references, individually, teach separating a subset of modified CD8+ T cells, wherein the subset comprises at least one positive memory cell DNA methylation marker. Pages 12-13 of remarks.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, Abdesamed teaches separating a subset of CD8 T cells comprising at least one positive memory cell DNA methylation marker, and Curtsinger teaches modifying T cells by exposure to a signal 3 cytokine.
Applicant further argues that the rejection relies on improper hindsight, and there is no explanation why one of ordinary skill in the art would have combined the cited references. Pages 13-14 of remarks.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the IL12-modified CD8+ T cells of Curtsinger exhibit a memory phenotype, including Tcm and Tem phenotypes, by epigenetic changes and chromatin remodeling of numerous genes related to differentiation and effector functions, and positive memory cell methylation markers (IFNγ, CCR7, CD62L, T-bet, Eomes, granzyme K, granzyme B and perforin 1) were previously identified by Satoh and Abdelsamed to delineate the memory T cell subsets from naïve T cells. The rejection does not include knowledge gleaned only from the applicant's disclosure, and, therefore, there is no improper hindsight reasoning.
Conclusion
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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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631
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