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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Status of Claims
Claims 1-3, 6, 7, 14 -19, 22-25 and 31 are currently pending. Claims 1-3, 6, 7, 14-19, 24 and 31 have been amended by Applicants’ amendment filed 05-05-2026. Claims 5, 8-13, 20, 21 and 26-28 have been canceled by Applicants’ amendment filed 05-05-2026. No claims have been added by Applicants’ amendment filed 05-05-2026.
Applicant's election of Group I, claims 1 and 4-22, directed to a method of preparing an enriched population of T cells having antigenic specificity for a target antigen; and Applicant’s election of Species as follows:
Species (A): one or more of the markers recited in claim 1a (claim 1a);
Species (A)(I): CD4+, CXCL13+, ITM2A+, KLRB1+, TIGIT+, LTB-, LYAR, RGCC-, and S100A10-
Species (B): the election of Species (B) is moot, directed to Group II;
Species (B)(I): the election of Species (B) is moot, directed to Group II;
Species (C): wherein the gene expression profile comprises CXCL13+ (claim 5); and
Species (D): wherein selecting the isolated T cells, which have a gene expression profile comprises carrying out one or more single cell dimensional reduction methods (claim 16), in the reply filed January 13, 2026 was previously acknowledged.
Claims 2, 3 and 23-28 and 31 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on January 13, 2026.
Claims 4, 6-15, and 17-21 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement is deemed proper and is, therefore, made FINAL.
The claims will be examined insofar as they read on the elected species.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 1, 16 and 22 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed September 16, 2022, is a 35 U.S.C. 371 national stage filing of International Application PCT/US2021/023240, filed March 19, 2021, which claims the benefit of US Provisional Patent Application 62992701, filed March 20, 2020.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 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 the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application 62992701, filed March 20, 2020, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 1 does not have support for; “a cancer-associated viral antigen” such as recited in claim 1, line 11. Therefore, the priority date for the presently claimed invention is March 19, 2021, the filing date of PCT/US2021/023240.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 1 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed May 5, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Double Patenting
The provisional rejection of claims 1, 16 and 22 is withdrawn on the ground of nonstatutory double patenting as being unpatentable over: claims 2-20 and 26 of copending US Patent Application No. 17/906524 because the instant claims recite different genes.
In view of the withdrawn provisional rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 16 and 22 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “the separated selected” such as recited in claim 1, line 8. There is insufficient antecedent basis for the term :the separated selected” in the claim because claim 1, lines 5 and 7 recite the terms “selecting” and “separating”. The Examiner suggests that Applicant amend the claim to recite, for example, “the selected and separated clonotypes”.
Claims 16 and 22 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 16 and 22 is maintained under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Sade-Feldman et al. (hereinafter “Sade-Feldman”) (US Patent Application Publication No. 20200147210, published May 14, 2020, PCT filed May 11, 2018).
Regarding claim 1, Sade-Feldman teaches that the subject matter disclosed herein is generally directed to CD8+ tumor infiltrating lymphocytes comprising gene signatures associated with response to immunotherapy treatment, wherein the subject matter is generally directed to methods and compositions for use of the gene signatures; as well as, gene signatures associated with response to checkpoint blockade therapy and immune cell subtypes characterized by said gene signatures; and methods of using said gene signatures and immune cell subtypes; and pharmaceutical compositions comprising populations of CD8+ TILs enriched for a specific subtype (interpreted as clonotypes having a gene expression profile; and CD8+, claim 1) (Abstract). Sade-Feldman teaches that the efficiency of checkpoint therapy depends on CD8+ T-cell recognition of neoantigens presented on human leukocyte antigen (HLA) class I by tumor cells (interpreting target antigens as neoantigens associated with a cancer-specific mutation, claim 1) (paragraph [0005]). Sade-Feldman teaches that mutations occur in individual cancers that can be used to detect cancer progression, such that these mutations can be used in conjunction with the responder and non-responder phenotypes described herein (corresponding to neoantigens encoding a cancer-specific mutation, claim 1) (paragraph [0137], lines 1-4). Sade-Feldman teaches that the present invention provides for a method of predicting cancer clinical outcome in a subject in need thereof comprising detecting in a sample obtained from the subject the ratio of immune cells enriched for expression of a gene signature according to any of claims 1 to 3 as compared to immune cells enriched for expression of a gene signature according to claims 4 or 5, wherein a ratio greater than one indicates sensitivity to an immunotherapy and an increased overall survival, and wherein a ratio less than one indicates resistance to an immunotherapy and a decreased overall survival (interpreted as enriching cells having antigenic specificity for a target antigen; and having a gene expression profile, claim 1) (paragraph [0015]). Sade-Feldman teaches that the method comprises detecting mutations associated with loss of antigen presentation in tumor cells obtained from the subject, which indicates resistance to an immunotherapy and a decreased overall survival (interpreted as a cancer-specific mutation, claim 1) (paragraph [0017]). Sade-Feldman teaches that the biomarkers of the present invention were discovered by analysis of expression profiles of single immune cells within populations of cells from freshly isolated tumors, thus allowing the discovery of novel gene signatures and immune cell subtypes that were previously unrecognized, wherein treatment of solid tumors has been revolutionized by immune checkpoint blockade therapies; yet even in melanoma, for which high response rates are observed, the majority of patients do not respond; and to identify key immunological components associated with success or failure of immunotherapy, such that 16,291 immune cells were profiled from 48 tumor samples of melanoma patients treated with checkpoint inhibitors, using single-cell transcriptomics, wherein samples were obtained from melanoma patients receiving checkpoint blockade therapy both before they received treatment and after they received treatment with a checkpoint inhibitor, such that a non-responder signature and a responder signature are identified in the CD8+ TILs (interpreted as isolating T cells from a tumor sample of a patient; and selecting and isolating T cell that have a gene expression profile; and having antigenic specificity, claim 1) (paragraph [0105], lines 1-20). Sade-Feldman teaches that unique exhaustion and memory/effector states of CD8+ T-cells associated with tumor regression were identified, and it was found that the expression of a single transcription factor, TCF7, in CD8+ T-cells was sufficient to predict clinical outcome in an independent cohort; and that by using immunofluorescence, it is shown that responders have more CD8+ TCF7+ T cells than CD8+ TCF7- T cells and vice versa, such that the detection of CD8+ TCF7+ T cells can be used to predict overall survival in cancer patients to delineate the epigenetic landscape and clonality of these T-cell states, and to demonstrate enhanced anti-tumor immunity by targeting a novel combination of factors identified in exhausted cells (interpreted as separating TCR clonotypes having an expression profile; which have specificity for the target antigen, claim 1) (paragraph [0105], lines 24-36). Sade-Feldman teaches that the invention provides for a method of detecting a checkpoint blockade (CPB) therapy responder gene signature comprising, detecting in CD8+ T cells obtained from a biological sample the expression of a gene signature comprising one or more genes or polypeptides including LTB and RGCC (interpreted as CD8+, LTB and RGCC, claim 1) (paragraph [0009]). Sade-Feldman teaches a method of detecting a checkpoint blockade (CPB) therapy responder gene signature comprising, detecting in CD45+ cells obtained from a biological sample the expression of a gene signature comprising one or more genes or polypeptides including LTB (interpreted as including LTB, claim 1) (paragraph [0008]). Sade-Feldman teaches a method of detecting a checkpoint blockade (CPB) therapy non-responder gene signature comprising, detecting in CD45+ cells obtained from a biological sample the expression of a gene signature comprising one or more genes or polypeptides including CXCL13, CD4, TIGIT (interpreted as including CXCL13, CD4, TIGIT, claims 1 and 5) (paragraph [0011]). Sade-Feldman teaches that “immune cells” include CD4+/CD8+ thymocytes, B-cells, etc. (interpreted as CD4+ and CD8+, claim 1) (paragraph [0141]). Sade-Feldman teaches in Figure 25B, a heatmap showing scaled expression values (log2(TPM+1)) of discriminative gene sets for each cluster defined in (A) including S100A10, CXCL13 and LTB (interpreted as including S100A10, CXCL13 and LTB, claim 1) (paragraph [0063], lines 5-8; and Figure 25B). Sade-Feldman teaches maker genes identified for the 6 different clusters, suggesting that these markers indeed highlight distinct biological functions (Table 10), wherein Table 10 includes the markers: CXCL13, LTB, TIGIT, and LYAR (interpreted as including CXCL13, LTB, TIGIT, and LYAR, claims 1 and 5) (paragraph [0642], lines 53-55; and pgs. 130-131, Table 10). Sade-Feldman teaches that unsupervised clustering of cells was initially performed on 16,291 cells that passed quality control, based on the ~ 4,000 most variable genes across all cells, where Table 2C includes genes CXCL13 and ITM2A (interpreted as selecting and separating TCR clonotypes; and the expression profile includes ITM2A and CXCL13, claim 1) (paragraph [0636], lines 2-4 and 13; and Table 2C). Sade-Feldman teaches that dg T-cells are enriched in CD4/CD8 double negative (DN) T cells (Fig. 17); and that V61 T-cells have a high expression of inhibitory receptors and V62 T-cells have a higher expression of KLRB1 and other genes (interpreted as CD4, CD8 and KLRB1, claim 1) (paragraph [0629]). Sade-Feldman teaches the markers ITM2A, CXCL13, CD4, LTB, and KLRB1 in Table 2D (interpreted as ITM2A, CXCL13, CD4, LTB, and KLRB1 elected species, claim 1) (pgs. 181, 183 and 184; Tables 2D and 2E). Sade-Feldman teaches in claim 4e, and Tables 9 & 10, AFAP1IL2 (interpreted as AFAPIl2, claim 1) (claim 4e, and pg. 213, Table 9; pg. 219, Table 10). Sade-Feldman teaches that the efficiency of checkpoint therapy depends on CD8+ T-cell recognition of neoantigens presented on human leukocyte antigen (HLA) class I by tumor cells (interpreting CD8+ cells recognizing neoantigens, claim 1) (paragraph [0005]). Sade-Feldman teaches that tumor antigens can also be subject specific (e.g., subject specific neoantigens; see, e.g., U.S. Pat. No. 9,115,402; and international patent application publication numbers WO2016100977Al, WO201416SS74A2, WO20150S5233Al, and WO2015095S11A2) (interpreting antigens to include neoantigens, claim 1) (paragraph [0298], last 6 lines). Sade-Feldman teaches that Figure 16 shows TCR analysis in the single T cells, wherein the left panel shows clonal expansion as determined by the same TCR being detected in the same patient in different time points, and the right panel shows clonal enrichment as determined by the same TCR being detected in the same patient in single time points (interpreting clonal cells as TCR clonotypes enriched for the target antigen, claim 1) (paragraph [0054]; and Figure 16). Figure 16 is shown below:
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Sade-Feldman teaches that aspects of the invention involve the adoptive transfer of immune system cells, such as T cells, specific for selected antigens, such as tumor associated antigens or tumor specific neoantigens (see, e.g., Maus et al., 2014, Adoptive Immunotherapy for Cancer or Viruses, Annual Review of Immunology, Vol. 32: 189-225; Rosenberg and Restifo, 2015, Adoptive cell transfer as personalized immunotherapy for human cancer, Science Vol. 348 no. 6230 pp. 62-68; Restifo et al., 2015, Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12(4): 269-281; and Jenson and Riddell, 2014, Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev. 257(1): 127-144; and Rajasagi et al., 2014, Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014 Jul. 17; 124(3):453-62) (interpreted as selecting TCR clonotypes specific for selected antigens; having an expression profile; and interpreting the target antigen to be a neoantigen, claim 1) (paragraph [0309]). Sade-Feldman teaches in Figure 48, coupling TCR clonality with T-cell states, wherein Figure 48A illustrates tSNE plot delineating the six clusters and persistent TCRs (black triangle), such that the fraction of persistent TCRs in each cluster out of total persistent TCRs is shown on the right; and in Figure 48B, tSNE plot delineating the six clusters and enriched TCRs (black triangle), wherein the fraction of enriched TCRs in each cluster out of total enriched TCRs is shown on the right (interpreting clonal cells as TCR clonotypes enriched for the target antigen; and tSNE as a single cell dimensional reduction method, claims 1 and 16) (paragraph [0090], lines 1-8; and Figure 48A-B). Sade-Feldman teaches that modified clonal cell lines can be derived within 2-3 weeks (interpreted as selecting the TCR clonotypes, claim 1) (paragraph [0543], last two lines). Sade-Feldman teaches that the relationship between the clinical response, cell states and T-cell clonality was interrogated, wherein Applicants reconstructed T-cell receptor (TCR) sequences from the transcriptomic data using the MiXCR tool for all identified CD8+ T-cells; and defined 4 patterns of TCR clonality based on the CDR3 sequence identified in both a and b chains (Figure 28A): (1) Persistent TCRs that were detected in pre- and post-therapy samples from the same patient; (2) enriched-TCRs detected in multiple T-cells at a single time point; (3) singlets-TCRs found in only one T-cell at one time point, and (4) common TCRs that were shared across patients (interpreted as TCR clonotypes, claim 1) (paragraph [0647]; and Figure 28A). Figure 28A is shown below:
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Sade-Feldman teaches that a signature is characterized as being specific for a particular immune cell or immune cell (sub)population if it is upregulated or only present, detected or detectable in that particular immune cell or immune cell (sub)population, or alternatively is downregulated or only absent, or undetectable in that particular immune cell or immune cell (sub)population, such that a signature consists of one or more differentially expressed genes/proteins or differential epigenetic elements when comparing different cells or cell (sub )populations, including comparing different immune cell or immune cell (sub)populations, as well as comparing immune cell or immune cell (sub)populations with non-immune cell or non-immune cell (sub)populations, where it is to be understood that "differentially expressed" genes/proteins include genes/proteins which are up- or down-regulated as well as genes/proteins which are turned on or off (interpreted as upregulated and downregulated genes, claim 1) (paragraph [0130]).
Regarding claim 16, Sade-Feldman teaches in Figure 48, coupling TCR clonality with T-cell states, wherein Figure 48A illustrates tSNE plot delineating the six clusters and persistent TCRs (black triangle), such that the fraction of persistent TCRs in each cluster out of total persistent TCRs is shown on the right; and in Figure 48B, tSNE plot delineating the six clusters and enriched TCRs (black triangle), wherein the fraction of enriched TCRs in each cluster out of total enriched TCRs is shown on the right (interpreting clonal cells as TCR clonotypes including clonotype enrichment; and tSNE as a single cell dimensional reduction method, claims 1 and 16) (paragraph [0090], lines 1-8; and Figure 48A-B). Sade-Feldman teaches that about 4000 genes were selected and the results were robust to this threshold, wherein dimension reduction is performed such that the genes with the most variance are used to further cluster the cells (e.g., tSNE analysis) (interpreting tSNE as a single cell dimensional reduction method; and selecting, claims 1 and 16) (paragraph [0611]).
Regarding claim 22, Sade-Feldman teaches that aspects of the invention involve the adoptive transfer of immune system cells, such as T cells, specific for selected antigens, such as tumor associated antigens or tumor specific neoantigens (see, e.g., Maus et al., 2014, Adoptive Immunotherapy for Cancer or Viruses, Annual Review of Immunology, Vol. 32: 189-225; and Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014 Jul. 17; 124(3):453-62) (interpreted to include cancer-associated viral antigens, claim 22) (paragraph [0309]). Sade-Feldman teaches that an antigen (such as a tumor antigen) to be targeted in adoptive cell therapy (such as particularly CAR or TCR T-cell therapy) of a disease (such as particularly of tumor or cancer) can be selected from a group including Human papillomavirus (HPV) including HPV E6 and HPV E7 (interpreted as the cancer-associated viral antigen is an HPV antigen, claim 22) (paragraph [0310], lines 1-5 and 29-30). Sade-Feldman teaches that HPV E6 and/or HPV E7 can be targeted in cervical cancer or head and neck cancer (interpreted as the cancer-associated viral antigen is an HPV antigen, claim 22) (paragraph [0315], lines 6 and 24-25).
Sade-Feldman meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s arguments filed May 5, 2026 have been fully considered but they are not persuasive. Please see the Examiner’s response below wherein Applicant’s arguments are directed to both rejections.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 16 and 22 is maintained under 35 U.S.C. 103 as being unpatentable over Sade-Feldman et al. (hereinafter “Sade-Feldman”) (US Patent Application Publication No. 20200147210, published May 14, 2020, PCT filed May 11, 2018) in view of Fotin-Mleczek et. al. (hereinafter “Fotin-Mleczek”) (US Patent No. 11078247, issued August 3, 2021; WO2017/191274, filed May 4, 2017).
The teachings of Sade-Feldman as applied to claims 1,16, and 22 are described supra.
Sade-Feldman does not specifically exemplify one or more of ASB2, HMOX1, and PDLIM4 (claim 1, in part).
Regarding claim 1 (in part), Fotin-Mleczek teaches RNA encoding a therapeutic protein including RNA suitable for use as a medicament; and the use of the RNA, compositions or kits as disclosed herein for increasing the expression of said encoded protein, in particular in gene therapy (Abstract). Fotin-Mleczek teaches that a "therapeutic protein" as defined herein is typically a peptide or a protein, which is beneficial for the treatment or prophylaxis of any inherited or acquired disease or which improves the condition of an individual, wherein therapeutic proteins play a key role in the design of new therapeutic agents that could modify and repair genetic deficiencies, destroy cancer cells or pathogen infected cells, treat or prevent immune system disorders, or treat or prevent metabolic or endocrine disorders, among other functions (interpreted for the treatment of cancer or infections including papillomavirus infections (col 15, lines 12-20; and col 767, line 5). Fotin-Mleczek teaches that the term "therapeutic protein" refers to any one of the peptides or proteins described herein, and more preferably to any one of the peptides or proteins specified in Table 1 herein, wherein the at least one coding sequence of the RNA according to the invention thus preferably encodes a peptide or protein provided in Table 1, or a fragment or variant thereof (col 16, lines 55-63). Fotin-Mleczek teaches in Table 1, ASB2, HMOX1 and PDLIM4 (col 20, line 5; col 30, line 30; and col 38, line 24).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of treating cancer and/or infections using therapeutic peptides and/or proteins as exemplified by Fotin-Mleczek, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of using gene signatures associated with response to checkpoint blockade therapy and immune cell subtypes characterized by the gene signatures including the analysis and profiling of biomarkers obtained from isolated tumors including CXCL13, ITM2A, TIGIT, LTB, LYAR, RGCC and S100A10 as disclosed by Sade-Feldman, to include the expression of RNA encoding a therapeutic peptides and/or proteins; and/or compositions comprising therapeutic peptides and/or proteins including ASB2, HMOX1 and/or PDLIM4 as exemplified by Fotin-Mleczek with a reasonable expectation of success in using gene signatures to differentiate patients that are checkpoint blockade therapy responders or non-responders, to determine associations with tumor growth, and/or to determine clinical outcome; as well as, using expanded immune cell populations expressing the therapeutic peptides and/or proteins for the treatment of various cancers and/or viral infections.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s arguments filed May 5, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) regarding both the 35 USC 102 rejection and the 35 USC 103 rejection, Sade-Feldman fails to teach a method of preparing an enriched population of TCR clonotypes having antigenic specificity for a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, comprising selecting TCR clonotypes which have a gene expression profile comprising (a) (i) one or both of CD4+ and CD8+ and (ii) all of CXCL13+, ITM2A+, KLRB1+, TIGIT+, LTB-, LYAR-, RGCC-, and SlO0A10-, as defined by the amended claims (Applicant Remarks, pg. 11, entire page); and (b) paragraph [0051] indicates that the superscript following the gene designation indicates either up-regulation or down-regulation in the tumor sample from the patient; and Sade-Feldman does not teach that upregulation of each of CXCL13, ITM2A, KLRB1, and TIGIT combined with downregulation of each of LTB, LYAR, RGCC, and S100A10 selects TCR clonotypes having antigenic specificity for a neoantigen encoded by a cancer-specific mutation (Applicant Remarks, pg. 12, entire page).
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. 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). Additionally, MPEP § 2112.01(I) states that,
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that Sade-Feldman fails to teach a method of preparing an enriched population of TCR clonotypes having antigenic specificity for a neoantigen encoded by a cancer-specific mutation, a cancer antigen, or a cancer-associated viral antigen, comprising selecting TCR clonotypes which have a gene expression profile comprising (a) (i) one or both of CD4+ and CD8+ and (ii) all of CXCL13+, ITM2A+, KLRB1+, TIGIT+, LTB-, LYAR-, RGCC-, and SlO0A10-, as defined by the amended claims, is not found persuasive. As an initial matter, Applicant did not distinctly and specifically point out the supposed errors in the Examiner’s action as required by 37 CFR 1.111(b). Instead, Applicant refers to the entirety of instant claim 1 (please see the teachings of Sade-Feldman for the steps as recited in instant claim 1). Thus, the claims remain rejected for the reasons already of record.
To be clear, the Examiner contends that Sade-Feldman teaches all of the limitations as recited in claim 1. For example: Sade-Feldman teaches (in part):
Detecting in CD8+ T cells obtained from a biological sample the expression of a gene signature comprising one or more genes or polypeptides selected from the group including CXCL13, LTB, RGCC, ITM2A, LYAR, TGIT , KLRB1, and S100A10 (isolating and separating cells that have a gene expression profile, claim 1) (paragraphs [0009]; [0012]; [0629]; Tables 2C, 2D and 10; and Figure 25B).
Clustering of cells including by tSNE analysis was initially performed on 16,291 cells that passed quality control, based on the ~ 4,000 most variable genes across all cells (selecting and separating T cells, claim 1) (paragraphs [0041]; [0090]; and [0636]).
The efficiency of checkpoint therapy depends on CD8+ T-cell recognition of neoantigens presented on human leukocyte antigen (HLA) class I by tumor cells (CD8+ cells recognizing neoantigens; including cancer-associated antigens, claim 1) (paragraph [0005]).
Interrogating the relationship between the clinical response, cell states and T-cell clonality was interrogated for all identified CD8+ T-cells; and defining 4 patterns of TCR clonality based on the CDR3 sequence identified in both a and b chains (Figure 28A):
(a) Persistent TCRs that are detected in pre- / post-therapy samples from the same patient;
(b) Enriched-TCRs detected in multiple T-cells at a single time point;
(c) Singlets-TCRs found in only one T-cell at one time point, and
(d) Common TCRs that were shared across patients (TCR clonotypes, claim 1) (paragraph [0647]).
Thus, the claims remain rejected.
Regarding (b), Applicant’s assertion that Sade-Feldman does not teach that upregulation of each of CXCL13, ITM2A, KLRB1, and TIGIT combined with downregulation of each of LTB, LYAR, RGCC, and S100A10 selects TCR clonotypes having antigenic specificity for a neoantigen encoded by a cancer-specific mutation, is not found persuasive. As noted supra, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). As an initial matter:
Instant claim 1 does not teach the upregulation of some genes and the downregulation of other genes. Claim 1 provides an expression profile of target antigens.
Instant claim 1 does not recite detecting/measuring gene expression, and comparing each gene expression measurement to a specific reference (e.g., an untreated control, a healthy patient, a patient with stage 1 small cell lung cancer, etc.). Thus, claim 1 merely recites a list of genes included in the gene expression profile.
Moreover, claim 1 uses the term “comprising”, which is open-ended and does not exclude additional, unrecited elements or method steps, including wherein CXCL13, ITM2A, KLRB1, and TIGIT are down-regulated, and LTB, LYAR, RGCC and S100A10 are up-regulated.
To that end, Sade-Feldman teaches each of the genes as recited in instant claim 1 such that, for example, the term “CXCL13” encompasses both up-regulation and/or down-regulation of CXCL13 gene expression.
Sade-Feldman also teaches that a gene/protein signature refers to any set of up- and down-regulated genes that are representative of a cell type or subtype, wherein a gene signature as used herein, can also refer to any set of up- and down-regulated genes between different cells or cell (sub)populations derived from a gene-expression profile (differentially expressed genes) (paragraphs [0127]; and [0130]).
Claim 1 is very broadly recited, such that it does not recite any specific cell type; cancer type; tumor type; sample obtained; neoantigen; method of isolating, method of selecting; method of separating; method of analyzing; method of detecting, detector, etc.
It is noted that the particular cell; cancer, cancer stage, tumor, sample type and/or reference can affect whether the expression of a particular gene is measured as being up-regulated or down-regulated in a patient sample. A gene expression profile that requires each of CXCL13, ITM2A, KLRB1, and TIGIT to be up-regulated, and each of LTB, LYAR, RGCC and S100A10 to be down-regulated would likely limit the scope of claim 1 to apply to a small number of tumor samples and/or cancer types.
Sade-Feldman teaches all of the limitations of the claims. Thus, the claims remain rejected.
Conclusion
Claims 1, 16 and 22 remain rejected.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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