Office Action Predictor
Last updated: April 16, 2026
Application No. 17/906,524

METHODS OF ISOLATING T CELLS AND T-CELL RECEPTORS FROM PERIPHERAL BLOOD BY SINGLE-CELL ANALYSIS FOR IMMUNOTHERAPY

Non-Final OA §101§102§103§112§DP
Filed
Sep 16, 2022
Examiner
DRISCOLL, MAUREEN VARINA
Art Unit
1644
Tech Center
1600 — Biotechnology & Organic Chemistry
Assignee
The United States Of America,As Represented By The Secretary,Department Of Health And Human Services
OA Round
1 (Non-Final)
67%
Grant Probability
Favorable
1-2
OA Rounds
3y 5m
To Grant
99%
With Interview

Examiner Intelligence

Grants 67% — above average
67%
Career Allow Rate
44 granted / 66 resolved
+6.7% vs TC avg
Strong +34% interview lift
Without
With
+34.3%
Interview Lift
resolved cases with interview
Typical timeline
3y 5m
Avg Prosecution
40 currently pending
Career history
106
Total Applications
across all art units

Statute-Specific Performance

§101
3.1%
-36.9% vs TC avg
§103
29.5%
-10.5% vs TC avg
§102
10.9%
-29.1% vs TC avg
§112
31.7%
-8.3% vs TC avg
Black line = Tech Center average estimate • Based on career data from 66 resolved cases

Office Action

§101 §102 §103 §112 §DP
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 Claim Status Applicant’s arguments and remarks filed August 26, 2025 have been received and entered. Claims 3-18 and 22 have been amended. Claims 24-25 have been canceled. Claim 26 has been added. Claims 1-23 and 26 are pending and under consideration. Election/Restrictions Applicant's election with traverse of Group I, encompassing claims 1-20, in the reply filed on August 25, 2025 is acknowledged. The traversal is on the ground(s) that at leas t Group IV (claim 26) depends from and requires all the features of claim 1, wherein the T cells are isolated from a blood sample of a patient. Applicant’s arguments (pg. 2-4) were considered and deemed persuasive. Therefore, the restriction requirement between Group I and IV is hereby withdrawn. Group II (claim 21) and Group III (claims 22-23) also require all the features of claim 1. As such, the restriction requirement between Group II and Group III is also withdrawn. Further, Applicant’s species election with traverse of RNA and the expression profile comprising all of the genes recited in part (c) of claim 1 in the reply filed on August 25, 2025 is acknowledged. However, after further consideration, all species have been examined. Priority Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US2021/023225 filed March 1 9 , 202 1 , which claims the benefit of U.S. Provisional Application 62/992,715 filed March 30, 2020. However, Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date as follows: The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc. , 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). The disclosure s of the prior-filed applications fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application. The instant claims are drawn to a method for preparing an enriched population of T cells having antigenic specificity for a target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises the genes recited in claim 1 part (a) – claim 1 part (o). However, the expression profiles as recited in claim 1 part (c) – part (o) do not appear in the March 20, 2020 provisional application. Moreover, the following specific genes recited in Applicant’s elected gene expression profile of claim 1 part (c) are not found in any part of the disclosure of the provisional application: ALOX5AP +, CDC25B+, CHN1+, CLECL1+, CYTOR+, GATA3+, HLA- DRB5+, ITM2A+, LIME1+, MYO1G+, P2RY8+, PASK+, RBPJ+, S1OOA11+, TPM4+, TRADD+, UBXN11+, CCR7-, CYTIP-, EEF1G-, GZMH-, IMPDH2-, LINC02446-, LYAR-, MYC-, NKG7-, NUCB2-, PITPNC1-, PLAC8-, and TCF7- . The first occurrence of the gene expression profiles recited in claim 1 part (c) – claim 1 part (o) is in PCT/US2021/023225 filed March 19, 2021. Therefore, the PCT/US2021/023225 filing date of March 19, 2021 will be used for the purpose of applying prior art for claims 1- 13, 16- 17, 22-23, and 26. Claims 14-15 and 18-21 are entitled to the benefit of the Provisional Application 62/992,715 filing date of March 20, 2020. Should Applicant disagree with the examiner’s factual determination as to the disclosure of the particular subject matter , Applicant may point out the particular places within the prior application that disclose s the aforementioned limitations . Information Disclosure Statement s The information disclosure statements (IDSs) submitted on September 16 , 202 2, December 31, 2024, and August 26 , 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Claim Interpretation Claim 26 is drawn to a method of treating and preventing cancer or a viral condition in a mammal by administering an enriched population of T cells having antigenic specificity for a target antigen recited in claim 1. The plain meaning of the word “prevention” implies up to 100% prevention of cancer, which has yet to be achieved. However, t he instant specification defines the term "prevent" as well as words stemming therefrom, do not necessarily imply 100% or complete treatment or prevention. Rather, there are varying degrees of treatment or prevention of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the inventive methods can provide any amount of any level of treatment or prevention of a condition in a mammal. Furthermore, the treatment or prevention provided by the inventive method can include treatment or prevention of one or more signs or symptoms of the condition being treated or prevented. For example, treatment or prevention can include promoting the regression of a tumor. Also, for purposes herein, "prevention" can encompass delaying the onset of the condition, or a symptom, sign, or recurrence thereof [0097] . Accordingly, the word “prevention ” is interpreted as defined in the instant specification. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b ) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. Claim 12 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Claim 12 recites “selecting isolated T cells which have a gene expression profile comprises carrying out epitopes by sequencing analysis”. It is unclear what “carrying out epitopes by sequencing analysis” is referring to, or how an expression profile can comprise this step. As such, the claim does not make sense. The specification provides no clarification, as it only recites the same indefinite language. Appropriate correction is required. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 21-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. The claim s recite isolated TCRs, an isolated population of T cells, and a pharmaceutical composition comprising said T cells . This judicial exception is not integrated into a practical application because the claim s are directed to natural biological materials isolated from blood . The claim s do not include additional elements that are sufficient to amount to significantly more than the judicial exception . The TCRs and T cell populations as claimed are naturally occurring products found in the blood which have the specific gene signature profiles as listed in the instant claims . The TCRs and T cells can be isolated directly from PBMC using the claimed expression profiles, and therefore the clai med invention appears to be a product that is not markedly different in structure from naturally occurring products. Without any evidence to the contrary, the isolated TCRs and T cell populations would not be markedly different from the ir naturally occurring counterparts. Further, b ecause there is no difference in the characteristics (structural, functional, or otherwise) between the claimed and naturally occurring T cell populations , a pharmaceutical composition comprising any of the isolated T cell populations does not have markedly different characteristics from what exists in nature. See, e.g., MPEP § 2106, Ass’n for Molecular Pathology v. Myriad Genetics, Inc. , 569 U.S. 576, 591-94, 106 USPQ2d 1972, 1979-81 (2013); Roche Molecular System, Inc. v. CEPHEID , 905 F.3d 1363, 1371, 128 USPQ2d 1221, 1227 (Fed. Cir. 2018). Accordingly, the claims are directed to a judicial exception. Because the claim does not include any additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter under 35 U.S.C §101. Claim Rejections - 35 USC § 102 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis ( i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale , or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. Claim s 1 , 3, 5, 7, and 22-23 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Gros et al. ( US 10,716,809 ) (“ Gros ”) . This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises CD8+ and one or more of CD45RO+, CD45RA-, HLA-DR+, CD39+, and PD-1+ , further comprising HAVCR2+ (TIM3+) , wherein the method does not require identifying any HLA molecules expressed by the patient . Gros discloses a method of obtaining a cell population enriched for tumor-reactive T cells, the method comprising: (a) obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood; (b) specifically selecting CD 8 + T cells that also express PD-1 and/or TIM-3 from the bulk population; and ( c) separating the cells selected in (b) from unselected cells to obtain a cell population enriched for tumor reactive T cells [claim 1], wherein (b) comprises specifically selecting CD 8 + T cells that are TIM-3+/PD-1+ [claim 5] , wherein the cell population enriched for tumor-reactive T cells is obtained without screening for autologous tumor recognition [claim 6] . Gros further discloses combining the cell population enriched for tumor reactive T cells with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition comprising a cell population enriched for tumor-reactive T cells [claim 2]. T herefore, absent a showing of any difference, the methods disclosed by the prior art are deemed to anticipate the claimed methods. Claim s 1 , 4, and 8-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pauken et al. ( J Exp Med , 2021; 218(4):1- 31 ) (“Pauken ”). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises one or more of the genes recited in claim 1 part (a), wherein the blood sample is from a patient that has not been treated with T cell therapy, wherein selecting the isolated T cells which have a gene expression profile comprises detecting and measuring the presence or absence of protein(s) and RNA encoded by positively expressed gene(s) of the gene expression profile , wherein selecting the isolated T cells which have a gene expression profile comprises carrying out single cell transcriptome analysis with one or more single cell dimensional reduction methods and cellular indexing of transcriptomes analysis . Pauken discloses methods for single-cell RNA sequencing to develop marker panels for tracking and analysis of anti-tumor CD8+ T cells [Abstract]. Pauken used paired tumor and blood samples to identify and characterize tumor-matching (TM) blood CD8+ T cells that had shared TCR sequences with CD8+ T cells in MC38 tumors in mice or melanoma in patients. Pauken identified candidate surface markers that enrich for TM cells and validated three markers using CITE-seq in mice. Pauken found that combinations of these marker genes achieved improved performance compared with single markers at identifying TM cells [pg. 2, col. 1] . Pauken used a self-developed computational program to predict markers from the RNAseq data at the transcription and protein levels. Three of the predicted candidates, including Entpd1 encoding CD39, were evaluated by single cell RNA sequencing ( scRNAseq ) , measuring gene expression, TCR, and protein expression . As single markers, each protein successfully enriched for TM cells, however, using combinations improved on either or both the sensitivity and specificity over single markers [pg. 4, col. 1]. In addition, Pauken performed scRNAseq and TCR sequencing on four checkpoint treatment-naive advanced melanoma patients , finding CD8+ T cells had transcriptional signatures in blood consistent with naive-like, central memory-like, effector-like, and effector memory–like cells [pg. 6, col. 1] . Figure S4 depicts the transcriptional profile of CD8+ T cells in paired peripheral blood and melanoma samples, identifying several genes, including PDCD1, HAVCR2, and SELL that were positive for TM selection. Pauken further identified transcripts that significantly enriched for TM cells finding low expression LTB, CCR7, GYPC , FLT3LG as the best four markers for selecting TM cells across patients with different tumor burden and therapeutic states [pg. 9, col. 1]. Pauken used flow cytometry to sort CD8+ T cells prior to scRNA seq analysis. Data visualization of key markers was performed using uniform manifold approximation and projection (UMAP) visualization [pg. 15, col. 1]. The instant specification defines CITE-seq as Cellular Indexing of Transcriptomes and Epitopes by Sequencing analysis [0040]. S ingle cell dimensional reduction method s i nclude t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis and Uniform Manifold Approximation and Projection (UMAP) [0041] . T herefore, absent a showing of any difference, the methods disclosed by the prior art are deemed to anticipate the claimed methods. Claim s 1 , 15, 18 -19, 21, and 26 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Pasetto et al. ( WO 2017/048614; cited IDS 9/16/2022) (“ Pasetto ”) . This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises LAG3+, or CD8+ and one or more of CD45RO+, CD45RA-, HLA-DR+, CD39+, and PD-1+ . Further claimed is a method of isolating a T cell receptor (TCR), or an antigen-binding portion thereof, having antigenic specificity for a target antigen, the method comprising: preparing an enriched population of T cells having antigenic specificity for the target antige n; sorting the T cells in the enriched population into separate single T cell samples; sequencing TCR complementarity determining regions 3 (CDR3) in one or more of the separate single T cell samples; pairing an alpha chain variable region comprising a CDR3 with a beta chain variable region comprising a CDR3 encoded by the nucleic acid of the separate single T cell samples; introducing a nucleotide sequence encoding the paired alpha chain variable region and beta chain variable region into host cells and expressing the paired alpha chain variable region and beta chain variable region by the host cells; screening the host cells expressing the paired alpha chain variable region and beta chain variable region for antigenic specificity for the target antigen; and selecting the paired alpha chain variable region and beta chain variable region that have antigenic specificity for the target antigen, and introducing a nucleotide sequence encoding the isolated TCR, or the antigen-binding portion thereof, into peripheral blood mononuclear cells (PBMC) to obtain cells that express the TCR, or the antigen-binding portion thereof. The method can be used for treating or preventing a condition in a mammal, wherein the condition is cancer or a viral condition. Pasetto discloses a method of obtaining tumor-reactive T cells comprising: (a) obtaining a bulk population o f T cell clonotypes from a biological sample from a patient, wherein each T cell clonotype comprises a T cell receptor (TCR) comprising a CDR 1 b , CDR2 b , and CDR3 b and a CDR 1 a , CDR 2 a , and a CDR3 a ; (b) sequencing the CDR3 a and the CDR3 b of one or more T cell clonotypes obtained in (a) to provide a CDR3 a amino acid sequence and a CDR3 b amino acid sequence; (c) pairing a CDR3 a amino acid sequence of (b) with a CDR3 b amino acid sequence of (b ); (d) sequencing the CDR 1 a and the CDR 2 a of the alpha chain comprising the CDR3 a amino acid sequence of (c) and the CDR 1 b and the CDR 2 b of the beta chain comprising the CDR 1 b amino acid sequence of (c); (e) preparing one or more polynucleotide(s) encoding a TCR comprising the CDR 1 a , CDR 2 a , CDR3 a , CDR 1 b, CDR 2 b , and CDR3 b of (d); (f) introducing the one or more polynucleotide(s) of (e) into peripheral blood mononuclear cells (PBMCs) and expressing the TCR; (g) screening the PBMCs expressing the TCR for tumor reactivity; and (h) selecting the PBMCs of (g) that are tumor-reactive [claim 1], wherein (a) further comprises selecting T cells expressing one or more of PD-1, LAG-3, TIM-1, 4- 1 BB, and CD8 and separating the selected T cells from the bulk population [claim 2], wherein (a) comprises selecting T cells that co - express PD-1 and any one or more of CD3, CD4, CD8, TIM-3, and CD27 and separating the selected T cells from the bulk population [claim 3], wherein (a) comprises selecting T cells that co - express CD8 and PD-1 and separating the selected cells from the bulk population [claim 4], wherein (a) comprises selecting T cells that are CD8+PD-1+ [claim 5]. Pasetto further discloses that the biological sample is a tumor sample or a sample of peripheral blood [0026]. Therefore, absent a showing of any difference, the methods disclosed by the prior art are deemed to anticipate the claimed methods. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis ( i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness . This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claim s 1 , 6, and 17 are rejected under 35 U.S.C. 10 3 as being unpatentable over Cillo et al. ( Immunity , 2020; 52:183-199) (“ Cillo ”). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises one or more of the genes recited in claim 1, wherein isolating T cells from the blood sample of the patient comprises isolating CD4+ T cells from the blood sample , wherein the cancer-associated viral antigen is a human papillomavirus (HPV) antigen or an Epstein- Barr (EBV) virus antigen. Cillo teaches h ead and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Cillo assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV– and HPV+ HNSCC and healthy donors and identified a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer p rogression-free survival in HNSCC patients [Summary]. Clinically, patients afflicted with HPV+ HNSCC have better overall survival compared with patients with HPV– disease [Introduction, pg. 185, col. 1]. Cillo compared the transcriptional landscape of CD4+ T cells between HPV - and HPV+ HNSCC . Figure 3 depicts the analysis of 45,640 CD4+ T cells recovered from combined patient samples, with 41,889 conventional CD4+ T cells ( T conv ) and 3,751 Treg cells. Analysis of the CD4 + Treg cells identified six distinct clusters including HPV+ PBMC and HPV-PBMC clusters, with t he majority (89%) of CD4+ Treg cells d erived from HPV+ and HPV- TILs (Fig. 3G) . The combined sample set was used for g ene set enrichment which revealed IFN a - r esponsive clusters associated with IFN-induced antiviral activity (2 and 4) , including IFITM1 , IFIT1, IFIT3, and ISG20 , and clusters enriched for TNF signaling (3 and 6) , including TNFRSF18 (GITR), TNFRSF9 (CD137, 4-1BB), and TNFRSF4 (OX40) [pg. 188, col. 1]. The teachings of Cillo differ from the instant claimed invention in that even though a gene signature was identified that would allow for the isolation of an enriched population of CD4+ T cells with antigenic specificity for HPV antigens in H NSCC patient samples, the samples used for the gene enrichment were m ixed sample types that included TIL samples in addition to PBMC. Given that Cillo enriched CD4+ Tregs with genes correlated with antiviral activity , a skilled artisan would have a reasonable expectation of success in selecting one or more of those genes to be included in a gene expression profile to enrich for CD4+ T cells with specificity against HPV antigens. Therefore, the instant invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made. Claim s 1 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Cillo et al. ( Immunity , 2020; 52:183-199) (“ Cillo ”), as applied to claims 1, 6, and 17 above, and in further view of Zhong et al. ( Onco Targets Ther , 20 15 ; 8 :183 1 -1 833 ) (“ Zhong ” ). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises one or more genes recited in claim 1 part (j) and CD127-. The teachings of Cillo are set forth above. Cillo does not teach the expression profile comprises C127-. Zhong teaches that Tregs and the PD-1/PD-L1 pathway play important roles in lung cancer pathogenesis. Zhong examined PD-1 expression on Tregs, and compared these results with established clinical indicators of lung cancer. These analyses revealed significant expression of PD-1 on Tregs in lung cancer, which may be used to inform clinical diagnoses [pg. 1831] . Zhong isolated CD4+ CD25+ CD127low Tregs from peripheral blood mononuclear cells of 22 primary lung cancer patients and 25 healthy donors. Lung cancer patients had a nearly 2-fold increase in the number of circulating Tregs . PD-1 expression also increased in the lung cancer patient population. Given that Cillo teaches gene signatures of CD4+ Tregs that are involved in HPV-associated H NSCC in mixed samples, the skilled artisan would be motivated to isolate Tregs from PBMC by selecting for CD4+CD5+CD127- cells as evidenced by Zhong. This expression profile can be further used in combination with one or more antiviral genes identified by Cillo to enrich for CD4+ Tregs with specificity against one or more HPV antigens with a reasonable expectation of success. As such, the instant invention was prima facie obvious in view of the combined prior art references. Claims 1 and 1 8 -20 are rejected under 35 U.S.C. 103 as being unpatentable over Pasetto et al. (WO 2017/048614; cited IDS 9/16/2022) (“ Pasetto ”). The instant claims are drawn to a method o f preparing an enriched population of T cells having antigenic specificity for a target antigen, the method comprising: isolating T cells from a blood sample of a patient; selecting the isolated T cells which have a gene expression profile; and separating the selected T cells from the unselected cells, wherein the separated selected T cells provide an enriched population of T cells having antigenic specificity for the target antigen, wherein the target antigen is a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, and the gene expression profile comprises LAG3+, or CD8+ and one or more of CD45RO+, CD45RA-, HLA-DR+, CD39+, and PD-1+ . Further claimed is a method of isolating a T cell receptor (TCR), or an antigen-binding portion thereof, having antigenic specificity for a target antigen, the method comprising: preparing an enriched population of T cells having antigenic specificity for the target antige n; sorting the T cells in the enriched population into separate single T cell samples; sequencing TCR complementarity determining regions 3 (CDR3) in one or more of the separate single T cell samples; pairing an alpha chain variable region comprising a CDR3 with a beta chain variable region comprising a CDR3 encoded by the nucleic acid of the separate single T cell samples; introducing a nucleotide sequence encoding the paired alpha chain variable region and beta chain variable region into host cells and expressing the paired alpha chain variable region and beta chain variable region by the host cells; screening the host cells expressing the paired alpha chain variable region and beta chain variable region for antigenic specificity for the target antigen; and selecting the paired alpha chain variable region and beta chain variable region that have antigenic specificity for the target antigen, and introducing a nucleotide sequence encoding the isolated TCR, or the antigen-binding portion thereof, into peripheral blood mononuclear cells (PBMC) to obtain cells that express the TCR, or the antigen-binding portion thereof , further comprising expanding the numbers of PBMC that express the TCR, or the antigen-binding portion thereof. The teachings of Pasetto have been set forth above. In addition, Pasetto teaches that the method further comprises expanding the numbers of PBMCs that are tumor reactive in vitro [0076]. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made. Allowable Subject Matter Claim 2 objected to as being dependent upon a rejected independent claim, but would be allowable if rewritten in independent form including all of the limitations of the independent claim. The following is a statement of reasons for the indication of allowable subject matter: Claim 2 is drawn to a method of preparing an enriched population of T cells having antigenic specificity to the all neoantigens in the gene expression profiles recited in part s (a) – (o) . There is no prior art that teaches or suggests a gene expression profile with the gene annotation as recited in claim 2 parts (a) – (o) . It should be noted gene and protein names are used interchangeably in the art in regard to gene expression profiles, as is the use of both hi/low and (+) positive/(-) indicators of expression. However, the gene expression profiles were only searched as recited in claim 2. The closest prior art, U.S. Patent No. 10,716,809 is directed to isolation of T cell neoantigens, however, does not teach or suggest the exact gene expression profiles as recited in claim 2. Nonstatutory Double Patenting Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822. 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 . Claim s 1 , 3, 5, 7, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,716,809 . Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the same method of preparing an enriched population of T cells having antigenic specificity for a neoantigen encoded by a cancer antigen with a gene expression profile comp rising one or more genes recited in claim 1. Thus, the instant claims are anticipated by the claims of the issued patent. Claim s 1 , 4, and 8-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,716,809, in further view of Pauken et al. ( J Exp Med , 2021; 218(4):1-31) (“Pauken”). Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the same method of preparing an enriched population of T cells having antigenic specificity for a neoantigen encoded by a cancer antigen with a gene expression profile comprising one or more genes recited in claim 1. The instant claims differ from the claims in the issued patent in that they do not recite methods for obtaining a gene expression profile using single-cell RNA sequencing and analysis methods.. The teachings of Pauken have been set forth above. Specifically, Pauken teaches methods for single-cell RNA sequencing to develop marker panels for tracking and analysis of anti-tumor CD8+ T cells using flow cytometry to sort CD8+ T cells prior to scRNA seq analysis and data visualization of key markers performed using uniform manifold approximation and projection (UMAP) visualization . As such, the instant claimed invention is an obvious modification of the issued claims in view of Pauken. Claim s 1 , 6, and 16-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,716,809, in further view of Cillo et al. ( Immunity , 2020; 52:183-199) (“ Cillo ”), and in further view of Zhong et al. ( Onco Targets Ther , 2015; 8 :1831-1833) (“Zhong”). Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the same method of preparing an enriched population of T cells having antigenic specificity for a neoantigen encoded by a cancer antigen with a gene expression profile comprising one or more genes recited in claim 1. The instant claims differ from the claims in the issued patent in that they do not recite that the neoantigen is one or more genes selected from claim 1 part (j), further comprising CD127-, or that it is a viral antigen from HPV or EBV. The teachings of Cillo and Zhong are set forth above. Specifically, Cillo teaches gene signatures of CD4+ Tregs that are involved in HPV-associated HNSCC in mixed samples. Zhong teaches Tregs can be isolated from PBMC of lung cancer patients by selecting for CD4+CD5+CD127. Genes taught by Cillo and Zhong can be combined in an expression profile to enrich for CD4+ Tregs with specificity against one or more HPV antigens with a reasonable expectation of success. As such, the instant claimed invention is an obvious modification of the issued claims in view of Cillo and Zhong. Claim s 1 , 15, 18-21, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 10,716,809, in further view of Pasetto et al. (WO 2017/048614; cited IDS 9/16/2022) (“ Pasetto ”) . Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the same method of preparing an enriched population of T cells having antigenic specificity for a neoantigen encoded by a cancer antigen with a gene expression profile comprising one or more genes recited in claim 1. The instant claims differ from the claims in the issued patent in that they do not recite methods for isolating T cell receptors. The teachings of Pasetto have been set forth above. Specifically, Pasetto teaches a method of obtaining tumor-reactive T cells comprising obtaining a bulk population o f T cell receptor s from a sample of peripheral blood, and s electing T cells expressing that are CD8+PD-1+ . As such, the instant claimed invention is an obvious modification of the issued claims in view of Pasetto . C laims 1 , 3 -23 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 and 31 of copending Application No. 17 / 912 , 315 . Although the claims at issue are not identical, they are not patentably distinct from each other because they teach the same method of preparing an enriched population of T cells and TCRs using one or more gene expression profiles recited in the instant claims. Thus, the instant claims are anticipated by the claims of the copending application . This is a provisional nonstatutory double patenting rejection. Similarly, c laims 1 , 3 -23 and 26 are ( provisionally ) rejected on the ground of nonstatutory double patenting as being unpatentable over claims in the following patent and applications. Although the claims at issue are not identical, they are not patentably distinct from each other because they are anticipated by the claims of the issued patent or copending applications , or deemed obvious by the claims of the issued patent or copending applications in view of Pauken, Cillo , Zhong, and/or Pasetto . U.S. Patent No. 11 , 629 , 334 – Claims 1-4, 9, and 12-15 18/147,786 – Claims 1, 4-5, 10-11, and 14-15 18/ 174,928 – Claims 2-4, 8-9, and 12-16 In the interest of compact prosecution, Applicant is invited to indicate whether or not the differences between the instant and copending claims are obvious, as they read on methods for isolating T cells and/or TCRs specific for neoantigens as recited in the instant claims. These are provisional nonstatutory double patenting rejections. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Enter examiner's name" \* MERGEFORMAT MAUREEN DRISCOLL whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-0730 . The examiner can normally be reached FILLIN "Work schedule?" \* MERGEFORMAT Monday through Friday . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Daniel Kolker can be reached on FILLIN "SPE Phone?" \* MERGEFORMAT (571) 272-3181 . The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at ( 866 ) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call ( 800 ) 786-9199 (IN USA OR CANADA) or ( 571 ) 272-1000. /MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644 /DANIEL E KOLKER/ Supervisory Patent Examiner, Art Unit 1644
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Prosecution Timeline

Sep 16, 2022
Application Filed
Dec 16, 2025
Non-Final Rejection — §101, §102, §103
Mar 20, 2026
Response Filed

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1-2
Expected OA Rounds
67%
Grant Probability
99%
With Interview (+34.3%)
3y 5m
Median Time to Grant
Low
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