Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1, 3-10, 12-14, 17-18, 24-26, 44-45 and 242-244 are pending.
Claim 14 is withdrawn.
Claims 1, 3-10, 12-13, 17-18, 24-26, 44-45 and 242-244 are examined on the merits herein.
Grounds of Rejection Withdrawn
Previous objection to claim 5 are withdrawn in view of claim amendment.
All previous rejections of claims 11, 30, and 31 are rendered moot by claim cancellation.
Previous rejection of claims 1, 3, 7, 17-18, 24-26, and 30 under 35 U.S.C. 102 is withdrawn in view of claim amendments.
Information Disclosure Statement
The information disclosure statement filed March 12, 2026 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. NPL reference 1, Oelke et al. is not attached.
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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.
Claims 1, 3-7, 17-18, 24-26, 44-45 and 242 are rejected under 35 U.S.C. 103 as being unpatentable over Klinger (PLoS One. 2013 Sep 19;8(9):e74231; IDS entered April 8, 2022) as evidenced by Wolfl (Blood. 2007 Jul 1;110(1):201-10; PTO-892) and Lu (WO 2018/183485 A1; IDS entered April 8, 2022) as evidenced by Balasubramanian (Biochem Soc Trans, 2022 Apr 29, 50(2):825-837; cited in OA 09/12/2025).
Regarding claims 1, 17, and 26, Klinger teaches a combined novel sequencing method that can identify individual clonotypes based on unique TCR rearrangement, with existing immune assays to characterize antigen specific T cell responses (abstract). Klinger further teaches use of pentamers to identify TCRs that bind to CMV pp65 protein (same as pre-determined type of antigen; instant step (a)(i)) and validation of the clonotypes identified by identical clonotype identification from sequencing cells that upregulated activation marker expression (instant step (a)(ii)) after incubation with an identical peptide (abstract). Klinger further teaches that 8 clonotypes were identified using a pentamer reagent derived from the CMV pp65 protein and the same 8 clonotypes were also identified following sequencing of cells that upregulated an activation marker following incubation with an identical peptide derived from pp65 (instant step (b)) (abstract).
Regarding claim 3, Klinger teaches use of PBMCs cultured in the presence of peptides to identify antigen specific T cells (subjects and samples).
Regarding the T cells being derived from healthy donors and claim 3: Klinger teaches the procedures for obtaining viable antigen-specific T cells based on acquisition of the cell surface markers CD137/ 107 (for CD8 antigen-specific T cells) following brief in vitro incubation with peptides have been described in detail elsewhere including: Wolfl (reference 21). As evidenced by Wolfl, in vitro priming of naïve T cells from healthy donors to Wilms tumor antigen 1 (WT1), using two overlapping pentadecamers that were identified as immunogenic, and further analysis of the HLA restriction element, provided an efficient and sensitive in vitro approach to rapidly identify and isolate antigen specific CD8+ T cells (abstract).
Regarding claims 7, 10 and 18, Klinger teaches a method combining sorting and sequencing to directly identify T cells specific to an antigen by sorting cells with a pentamer reagent containing pp65495 peptide bound to an MHC molecule (meeting the limitation of claim 7 step (a), claim 10 step (a), and claim 18) and then identifying pp65495 CD8 T cells by sequencing the TCRbeta repertoire of cells that were sorted based on pentamer binding (pentamer +) (pg 3, col 2, para 2). Klinger further teaches stimulation of PBMCs with the pp65495 peptide for 18 hours followed by flow cytometry based on the activation marker CD137 expression (which meets the limitation of claim 7 step (b) and claim 10 step (b); expression of an activation marker is evidence that the activation agent is immunogenic), then identifying the TCR beta clonotypes (page 4, col 1, para 2). Klinger further teaches comparison of the specific clonotypes identified by the pentamer and CD137 assay, and that all 8 clonotypes identified in the pentamer assay were also identified in the CD137 assay (meeting limitation of claim 7 and claim 10 step (c)) (page 4, col 2, para 3; Figure 4A).
Regarding claims 24-25, Klinger teaches that the peptide MHC complex used an MHC class I pentamer (page 3, col 1, para 1).
Regarding claim 242, Klinger teaches that next-generation sequencing enables the characterization of the immune repertoire diversity at the level of a single cell (introduction).
Klinger does not teach that the PBMC are derived from healthy donors, activating functional T cells by contacting the T cells with a plurality of cells that present the first predetermined type of antigen; the presenting cells being Class I or class II p-MHC; that the peptide is a neoantigen derived from a tumor; or full sequencing of the TCR including the alpha and beta chain.
Regarding claims 1 and 5-6, Lu teaches that the TCR has antigenic specificity for a cancer antigen/ neoantigen (para 0038).
As evidenced by Balasubramanian, MHC-I and MHC-II proteins are key components of the antigen presentation machinery responsible for neoantigen presentation to CD8+ and CD4+ T lymphocytes (abstract).
Regarding claim 3, Lu teaches that the host cells are peripheral blood
mononuclear cells (PBMC) that include T cells that can be of any developmental stage, including naïve T cells (para 0094).
Regarding claims 4 and 44-45, Lu teaches a method of isolating paired T cell receptor (TCR) alpha and beta chain sequences comprising (a) isolating, from a biological sample, T cells having antigenic specificity for a mutated amino acid sequence (isolating antigen specific T cells requires binding meeting instant claim 4 step (a)); (b) co-culturing the isolated T cells with antigen presenting cells (APCs) that present the mutated amino acid sequence so that the T cells express one or more T cell activation markers (instant claim 4 step (b)); (c) sorting the co-cultured T cells; (d) isolating mRNA from each separate T cell; (e) sequencing the mRNA; (f) aligning the sequence with known sequences of T cell activation markers; (g) aligning sequences to a reference TCR sequence database to identify TCR alpha and beta chain sequences (meeting instant claims 44-45) (claim 1).
Lu further teaches that TCRs that specifically recognize cancer antigens may be difficult to identify and/ or isolate from a patient and therefore there is a need to improve methods of obtaining cancer-reactive TCRs (para 0004). Lu further teaches that these methods provide an advantage of reducing time and cost of identifying a TCR that has antigenic specificity for a cancer antigen after a biological sample is removed from a patient, which can also identify the cancer antigen and the sequence of the TCR that recognizes that cancer antigen (para 0038).
Regarding claim 242, Lu teaches a method of identifying neoantigen-specific TCR sequences from single-cell RNA sequencing (RNA-seq) data (Fig 2; para 0116).
It would be obvious to one of ordinary skill in the art before the effective filing date of the instant application to use APCs to present the peptide: MHC complex as taught by Lu to the method of selecting a population of antigen specific T cells as taught by Klinger. The ordinary artisan would be motivated to do so because Lu and Klinger are analogous arts both selecting for T cells with antigen specific TCRs and functional activation. Further, Klinger teaches a method of identifying antigen specific T cells by both peptide-MHC binding and activation marker expression with a known peptide antigen, while Lu teaches that TCRs that specifically recognize cancer antigens may be difficult to identify and/ or isolate from a patient but the method isolating TCR alpha and beta chains using APCs provides an advantage of reducing time and cost of identifying a TCR that has antigenic specificity for a cancer antigen after a biological sample is removed from a patient, which can also identify the cancer antigen and the sequence of the TCR that recognizes that cancer antigen. Therefore, Lu teaches the ordinary artisan how to isolate cancer neoantigens utilizing APC presentation and sequence the antigen specific TCRs generated therefrom with decreased time and cost, and Klinger teaches identification of antigen specific TCRs by peptide binding or sorting and identification of TCR clonotypes, so the ordinary artisan has a reasonable expectation of success to utilize APCs to present neoantigens to T cells and select the TCRs that bind and are activated therefrom.
Claims 8-9 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Klinger (PLoS One. 2013 Sep 19;8(9):e74231; IDS entered April 8, 2022) as evidenced by Wolfl (Blood. 2007 Jul 1;110(1):201-10; PTO-892) and (WO 2018/183485 A1; IDS entered April 8, 2022) as evidenced by Balasubramanian (Biochem Soc Trans, 2022 Apr 29, 50(2):825-837; cited in OA 09/12/2025) as applied to claims 1, 3-7, 10, 17-18, 24-26, 44-45, and 242 above, and further in view of Simon (Front Immunol. 2018 Aug 30;9:1962; cited in OA 09/12/2025).
The teachings of Klinger and Lu regarding claims 1, 3-7, 10, 17-18, 24-26, 44-45 and 242 are detailed above.
Regarding claims 8-9, Lu teaches a method of isolating paired T cell receptor (TCR) alpha and beta chain sequences comprising (a) isolating, from a biological sample, T cells having antigenic specificity for a mutated amino acid sequence (isolating antigen specific T cells requires binding meeting instant step (a)); (b) co-culturing the isolated T cells with antigen presenting cells (APCs) that present the mutated amino acid sequence so that the T cells express one or more T cell activation markers (instant step (c)); (c) sorting the co-cultured T cells; (d) isolating mRNA from each separate T cell; (e) sequencing the mRNA; (f) aligning the sequence with known sequences of T cell activation markers; (g) aligning sequences to a reference TCR sequence database to identify TCR alpha and beta chain sequences (claim 1).
Klinger and Lu do not teach expanding the isolated T cell after antigen binding.
Regarding claims 8-9, Simon teaches use of PBMC isolated from HLA-A2 metastatic melanoma patients that were stimulated with Melan-A peptide or MELOA-1 peptide and IL-2, then FACS sorted with the HLA-peptide tetramer and an anti-CD8 antibody (this reads on step (a) of the instant claims), then expanded with PHA and IL-2 for 14 days (this reads on step (b) of the instant claims) (Materials and methods). Simon further teaches that purity of the expanded cells was assessed by double staining with the relevant HLA-peptide tetramer and anti-CD8 antibody (this reads on step (d) of the instant claims) (page 2, col 2, para 2). Simon further teaches high throughput TCR sequencing method to fully characterize the Melan-A peptide or MELOA-1 peptide specific T cell populations (page 2, col 2, para 2). Simon further teaches use of this method as a clinical grade procedure for selection and amplification of polyclonal CD8 T cells specific for two shared and widely expressed melanoma antigens to be used for adoptive cell transfer as a treatment for cancer and that analysis of the TCR repertoire is useful for immunotherapeutic approach follow up in patients (abstract) with the aim to improve immunotherapeutic treatments (page 14, col 1, para 3).
Regarding claims 12-13, Simon further teaches activation of T cells by both Melan-A or MELOA-1 peptides with validation by mRNA expression of activation markers and that analysis of the TCR repertoires revealed unique TCRs for each peptide (figure 3).
It would be obvious to one of ordinary skill in the art before the effective filing date of the instant application to use more than one peptide and expand the antigen specific T cells as taught by Simon in the method of selecting a population of antigen specific T cells using APCs to present the peptide: MHC complex as taught by Klinger and Lu. The ordinary artisan would be motivated to do so because Klinger, Lu and Simon are analogous arts directed to isolation of antigen specific T cells and the sequencing of the TCRs. Klinger teaches a method of identifying antigen specific T cells by both peptide-MHC binding and activation marker expression with a known peptide antigen, while Lu teaches that TCRs that specifically recognize cancer antigens may be difficult to identify and/ or isolate from a patient but the method isolating TCR alpha and beta chains using APCs provides an advantage of reducing time and cost of identifying a TCR that has antigenic specificity for a cancer antigen after a biological sample is removed from a patient, which can also identify the cancer antigen and the sequence of the TCR that recognizes that cancer antigen. Simon teaches use of this method as a clinical grade procedure for selection and amplification of polyclonal CD8 T cells specific for two shared and widely expressed melanoma antigens to be used for adoptive cell transfer as a treatment for cancer and that analysis of the TCR repertoire is useful for immunotherapeutic approach follow up in patients. Therefore, Lu teaches the ordinary artisan how to isolate cancer neoantigens utilizing APC presentation, then isolation of antigen specific TCRs and sequencing the antigen specific TCRs generated therefrom with decreased time and cost, Klinger teaches identification of antigen specific TCRs by peptide binding or sorting and identification of TCR clonotypes, Simon teaches use of multiple antigenic peptides, isolation and expansion of antigen specific T cells for adoptive cell therapy and monitoring TCR repertoire to assist in patient follow up during therapy to improve treatment. The ordinary artisan would have a reasonable expectation of success to select antigen specific T cells based on binding and/ or functional activation to multiple antigenic peptides presented by APCs, expand the selected cells and sequence the TCRs.
Claims 243-244 are rejected under 35 U.S.C. 103 as being unpatentable over Klinger (PLoS One. 2013 Sep 19;8(9):e74231; IDS entered April 8, 2022) as evidenced by Wolfl (Blood. 2007 Jul 1;110(1):201-10; PTO-892) and (WO 2018/183485 A1; IDS entered April 8, 2022) as evidenced by Balasubramanian (Biochem Soc Trans, 2022 Apr 29, 50(2):825-837; cited in OA 09/12/2025) as applied to claims 1, 3-7, 10, 17-18, 24-26, 44-45, and 242 above, and further in view of Ciceri (The Lancet Oncology, 2009; 10, 489-500; PTO-892).
The teachings of Klinger and Lu regarding claims 1, 3-7, 10, 17-18, 24-26, 44-45 and 242 are detailed above.
Klinger and Lu do not teach wherein the one or more healthy donors are at lest partially HLA matched to a subject or the specific HLA.
Regarding claim 243, Ciceri teaches that HLA antigens that differ between donor and recipient can lead to severe graft-versus-host disease (GVHD) and the T-cell depletion needed to prevent this reaction leads to profound and prolonged post-transplant immunodeficiency and high mortality (introduction). Ciceri further teaches the infusion of donor lymphocytes genetically engineered to express the TK suicide gene led to immune reconstitution, potentially increasing safety and feasibility of this transplant method (discussion, para 1) with results that are at least equivalent to the outcome of transplants reported for transplantation with cells from other alternative donors and HLA-matched sibling donors (discussion para 2). Ciceri further teaches the strong graft-versus-leukemia activity of TK-cells has already been shown in matched transplants (discussion, para 6).
Regarding claim 244, Ciceri teaches that haplotype mismatching was defined as disparity for two or more antigens encoded by HLA-A, HLA-B, or DRB1 loci (patients).
It would be obvious to one of ordinary skill in the art before the effective filing date of the instant application to use HLA matched leukocytes from the donor to a subject as taught by Ciceri in the method of selecting a population of antigen specific T cells using APCs to present the peptide: MHC complex as taught by Klinger and Lu. The ordinary artisan would be motivated to do so because Ciceri teaches that HLA antigens that differ between donor and recipient can lead to severe graft-versus-host disease (GVHD). Ciceri further teaches the strong graft-versus-leukemia activity of TK-cells has already been shown in matched transplants. Therefore the ordinary artisan has a reasonable expectation of success to establish a population of antigen specific T cells using APCs to present the peptide: MHC complex that are HLA-matched to a subject to avoid GVHD for potential adoptive cell therapy.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1 and all dependent claims thereof have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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