DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 54-61 and 63-73 are pending. Claims 55 and 72-73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 54, 56-61, and 63-71 are currently under examination.
Response to Amendment
The Amendment filed 9/10/25 has been entered. Claims 54 and 56-71 are pending. Applicant’s amendments to claims 54, 56-61, and 63-71 have overcome the objections and 101 rejections previously set forth in the Non-Final Office Action mailed 6/13/25.
Response to Arguments
Applicant’s arguments, see pages 8-16, filed 9/10/25, with respect to the rejections of claims 54, 56-61, and 63-71 under 35 USC 103 have been fully considered and are found unpersuasive, and the rejections documented in the Non-Final mailed on 6/13/25 have been revised to address the claim amendments filed 9/10/25. More detailed responses to Applicant’s arguments are provided at the end of each maintained rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 54, 56-61, and 63-71 remains/are rejected under 35 U.S.C. 103 as being unpatentable over Kuchroo et al. (2017; FOR citation N in PTO-892 filed on 4/8/25; WO 2017/069958) in view of Quezada et al. (2019; FOR citation O in PTO-892 filed on 4/8/25; WO 2019/008375 A1).
This rejection is revised/updated in response to claim amendments filed 9/10/25.
(i) Kuchroo et al. teaches “methods and compositions… based, in part, on the discovery of target gene(s) that are involved in T cell dysfunction, including but not limited to, T cell exhaustion and T cell non-responsiveness” (page 4, paragraph 0013). Kuchroo et al. teaches limitations relevant to claims 54, 57-61, 64, and 66-71.
Relevant to claim 54, Kuchroo et al. teaches “a method of determining the presence of T cells exhibiting an exhausted phenotype, the method comprising detecting, in a sample comprising T cells, a level of expression, activity and/or function of one or more genes or expression products thereof selected from the target genes listing in Table 1, Table 2 or any combination thereof” (page 12, paragraph 0076). Kuchroo et al. further teaches that Table 1 contains “Genes that modulate T cell function/dysfunction” (page 44, Table 1 caption). Within Table 1, Kuchroo et al. includes TIGIT and TIM3 (page 45). Kuchroo et al. teaches that bladder cancers are included within their proposed embodiments (page 120, paragraph 00352).
These teachings read on claim 54 (a) profiling gene expression in a T cell population from a biological sample from the subject, wherein the gene expression profiling comprises genes associated with T-cell specialization and/or T-cell exhaustion; (b) generating a cell composition profile of the T cell population based on the gene expression profiling… wherein the subject has or is suspected of having bladder cancer.
Further relevant to claim 54, Kuchroo et al. page 70, paragraph 00223 teaches “For example, a signature for use in the disclosed detection methods can include a combination of genes either Table 1, Table 2, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, or Table 13.” Relevant Kuchroo et al. genes include ABCB1 (Table 13c), CXCL13 (Table 11d), GZMB (Table 11a), IL2RA (Table 11c), SLAMF7 (Table 1), STMN1 (Table 13e), TIGIT (Table 1), TUBA1B (Table 13e), GZMK (Table 13a), PDCD1 (Table 13b), and TIM3 (Table 1).
This teaching reads on claim 54 and the gene signature biomarker comprises [biomarkers], or any combination of any thereof.
Relevant to claim 57, Kuchroo et al. Table 16 “Transcriptional Gene Signature” (pages 209-210) and Table 18 differentially expressed genes (page 224-227) read on claim 57 the gene signature biomarker comprises one or more of the following parameters… the one or more genes whose expression is upregulated in the… CD4+ T cells.
Relevant to claim 58, Kuchroo et al. page 68, paragraph 00221 teaches “As used herein a signature may encompass any gene or genes, or protein or proteins, whose expression profile or whose occurrence is associated with a specific cell type, subtype, or cell state of a specific cell type or subtype within a population of cells.” Kuchroo et al. page 69, paragraph 00223 teaches “The signature according to certain embodiments of the present invention may comprise or consist of one or more genes and/or proteins, such as for instance 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 59, or 50 or more.”
These teachings read on claim 58 the gene signature biomarker comprises at least 2, at least 3, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50 genes.
Relevant to claim 59, Kuchroo et al. page 70, paragraph 00223 teaches “For example, a signature for use in the disclosed detection methods can include a combination of genes either Table 1, Table 2, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, or Table 13.” Relevant Kuchroo et al. genes include ABCB1 (Table 13c), IL2RA (Table 11c), SLAMF7 (Table 1), STMN1 (Table 13e), (Table 13a), PDCD1 (Table 13b), and TIM3 (Table 1).
These teachings read on claim 59 the gene signature biomarker comprises: [biomarkers], or any combination of any thereof; or [biomarkers], or any combination of any thereof.
Relevant to claim 60, Kuchroo et al. teaches “The signatures of the present invention may be discovered by analysis of expression profiles of single-cells within a population of cells from isolated samples (e.g. blood samples)” (page 69, paragraph 00222). Kuchroo et al. teaches “Not being bound by a theory, the signature genes can be used to deconvolute the cells present in a tumor based on comparing them to data from bulk analysis of a tumor sample” (page 72, paragraph 00231).
These teachings read on claim 60 the biological sample comprises bladder cancer cells and/or peripheral blood mononuclear cells (PBMCs).
Relevant to claim 61, Kuchroo et al. teaches “Treatment of Chronic Immune Conditions” (page 120, paragraphs 00349-00350 and 00352). Embodiments include metastatic and non-metastatic bladder cancer. These teachings read on claim 61 the bladder cancer is selected from the group consisting of… metastatic bladder cancer, non-metastatic bladder cancer…
Relevant to claim 64, Kuchroo et al. teaches detection of gene expression of ABCB1 (Table 13c) and SLAMF7 (Table 1). These teachings read on claim 64 the one or more genes is selected from the group consisting of ABCB1… SLAMF7.
Relevant to claim 66, Kuchroo et al. teaches detection of gene expression of GZMK (Table 13a), GZMB (Table 11a), PDCD1 (Table 13b), and TIM3 (Table 1). These teachings read on claim 66 the one or more genes is selected from the group consisting of GZMK, GZMB,… PDCD1, and TIM3.
Relevant to claim 67, Kuchroo et al. teaches detection of gene expression within CD4+ T cells (Table 10a) and detection of GZMK (Table 13a), PDCD1 (Table 13b), and TIM3 (Table 1). These teachings read on claim 67 the one or more genes comprise a combination selected from the group consisting of:… (c) CD4, GZMK, PDCD1, and TIM3.
Relevant to claim 68, Kuchroo et al. teaches obtaining gene signatures from Foxp3- CD4 T cells (page 214, paragraph 00612) and observing differential expression of CCR7 (Table 18). These teachings read on claim 68 the one or more genes further comprises FOXP3 and CCR7 whose expressions are undetectable.
Relevant to claim 69, Kuchroo et al. Table 13 teaches CD8+ upregulation of GZMK and PDCD1. These teachings read on claim 69 the one or more genes upregulated in the cytotoxic CD8+ T cells is selected from the group consisting of… GZMK… PDCD1….
Relevant to claim 70, Kuchroo et al. teaches “Exhausted T cells also generally express PD-1 and TIM-3” (page 41, paragraph 00183). Kuchroo et al. Table 13 teaches CD8+ upregulation of GZMK and PDCD1. Together, these teachings read on claim 70 the one or more genes comprises a combination selected from the group consisting of:… (d) CD8, GZMK, PDCD1, and TIM3…
Relevant to claim 71, Kuchroo et al. teaches differential expression of CCR7 (Table 18), reading on claim 71 the one or more genes further comprises CCR7, whose expression is undetectable.
(ii) Kuchroo et al. is silent to specifics regarding gene signature biomarker expression upregulation in CD4+ T cells and unchanged expression in CD8+ T cells, recited in claims 54 and 63, and predictions of anti-PD-L1 therapy responsiveness recited in claim 54. However, these limitations were known in the prior art and taught by Quezada et al. Quezada et al. teaches a “Method for identifying responders to cancer treatment” (Title). Quezada et al. teaches limitations relevant to claims 54, 56-57, 63, and 65.
Relevant to claims 54, 56-57, 63, and 65, Quezada et al. teaches that “As used herein, ‘regulatory T cells’ (‘Treg’) refer to a lineage of CD4+ T lymphocytes specialized in controlling anti-tumour immunity, autoimmunity, allergy and infection. Typically, they regulate the activities of T cell populations, but they can also influence certain innate immune system cell types” (page 23, lines 25-28). The “Treg” cells of Quezada et al. “may directly kill target cells such as effector T cells and APCs through perforin- or granzyme B-dependent pathways” (page 23, lines 36-37). Quezada et al. also teaches that “Treg depletion by ADCC [antibody-dependent cell-mediated cytotoxicity] or ADCP [antibody-dependent cell-mediated phagocytosis] relies on higher expression of relevant target molecules on tumour-infiltrating Tregs relative to tumour-infiltrating… CD8 effector T cells” (page 26, lines 20-21). Quezada et al. includes TIGIT and TIM3 within examples of inhibitory immune checkpoint proteins (page 20, lines 15-16).
These teachings read on claim 54 (c) determining presence of a gene signature biomarker in the T cell population based at least in part upon the gene expression profiling and the cell composition profile, wherein the gene signature biomarker comprises one or more genes whose expression is specifically upregulated in cytotoxic CD4+ T cells while remaining unchanged in CD8+T cells; claim 56 the cell composition profile comprises following T cell subpopulations:… regulatory CD4+ T cells… proliferating cytotoxic CD4+ T cells, and non-proliferating cytotoxic CD4+ T cells; claim 57 (iii)… regulatory CD4+ T cells; (iv)… cytotoxic CD4+ T cells; and (v)… proliferative cytotoxic CD4+ T cells; claim 63 the expression of the one or more genes is upregulated in the proliferating CD4+ T cells and/or the non-proliferating CD4+ T cells while remaining substantially unchanged in the CD8+ T cells; and claim 65 the one or more genes is upregulated in the cytotoxic CD4+ T cells.
Relevant to claim 54, Kuchroo et al. teaches that “The present invention relates to a method for identifying a subject with cancer who is suitable for treatment with an IgG1 antibody or IgG2 antibody targeting an immune checkpoint molecule, and to methods of treatment of such subjects” (Abstract). Quezada et al. specifies that “Immune checkpoint molecules may also refer to proteins which bind to other immune checkpoint proteins which modulate the immune response in an inhibitory or activatory manner. Such proteins include but are not limited to PD-L1…” (page 20, lines 18-20). Quezada et al. discloses that “As used herein, the term ‘suitable for treatment’ may refer to a subject who is more likely to respond to treatment with an immune checkpoint intervention, or who is a candidate for treatment with an immune checkpoint intervention. A subject suitable for treatment may be more likely to respond to said treatment than a subject who is determined not to be suitable using the present invention” (page 13, lines 18-22). Quezada et al. further teaches that “Inhibitors of immune checkpoint protein, referring to any protein that can interfere with the signalling and/or protein-protein interactions mediated by an immune checkpoint protein, are known in the art” (page 20, lines 23-25).
These teachings read on claim 54 A method for (i) identifying a subject having an increased responsiveness to a therapy comprising a Programmed Death Ligand 1 (PD-L1) antagonist or (ii) selecting a subject amenable to the therapy comprising the PD-L1 antagonist, the method comprising:… (d) (i) identifying the subject as having the increased responsiveness to the therapy comprising the PD-L1 antagonist, relative to a subject lacking the gene signature biomarker, if the gene signature biomarker is present in the biological sample, or (ii) selecting the subject as amenable to the therapy comprising the PD-L1 antagonist if the gene signature biomarker is present in the biological sample.
(iii) Although Kuchroo et al. does not explicitly teach combining their T-cell exhaustion gene panel with the methodologies of Quezada et al., it would have been prima facie obvious to the skilled artisan. Kuchroo et al. and Quezada et al. are analogous disclosures in the field of detecting gene expression within T cells.
The skilled artisan would be motivated to combine the analogous art. Kuchroo et al. teaches that “Dysfunctional or exhausted T cells arise in chronic diseases including chronic viral infections and cancer, and express high levels of co-inhibitory receptors” (Abstract). Kuchroo et al. further teaches that “exhausted T cells are poor mediators of viral and/or tumor clearance” (page 2, paragraph 0006). Thus, the skilled artisan would be motivated to combine the Kuchroo et al. T cell exhaustion panel with the Quezada et al. methodologies in order to better refine therapeutic intervention via the methods of Quezada et al. Equipped with a gene signature biomarker, the skilled artisan would be motivated to apply the predictive treatment methodologies of Quezada et al. and improve cancer therapies.
The skilled artisan would have a reasonable expectation of success based on the disclosures of Kuchroo et al. in view of Quezada et al.
Applicant’s Arguments
Applicant argues that “Quezada does not teach or suggest the use of a PD-1 antibody based on the gene expression of a biomarker but rather off of a polymorphism that directly relates to the PD-1 or PD-L1 antibody itself” (Remarks 9/10/25, page 9, last paragraph).
Applicant further argues that “currently amended claim 54 recites that the gene signature biomarker comprises [markers], or any combination of any thereof. The Office Action alleges that Kuchroo teaches some of these markers and provides the following list of markers taught in Kuchroo and which table they come from in Kuchroo… However, this demonstrates that Kuchroo and Quezada fail to teach the list of markers in claim 1. There are numerous markers not taught or suggested in either reference and the list that was provided by the Office Action demonstrates that the Office Action is picking and choosing from across multiple tables in Kuchroo to try to approximate the list of markers in claim 1 [typographical error for claim 54?]. As discussed in more detail below, there is no motivation to make the specific selections as made by the Office Action other than to try to replicate the list in the present claim” (Remarks 9/10/25, page 10, paragraphs 1-2).
Applicant further argues that “Applicant submits that the Office Action has failed to establish that the cited references, either alone or in combination, teach or suggest all of the claim limitation[s] of claim 54, that there would be no motivation to combine the cited references to arrive at the present claims, and there would be no reasonable expectation of success for the present claims based on the cited references” (Remarks 9/10/25, page 15, paragraph 5).
Response to Applicant’s Arguments
The Examiner disagrees with the assertion that the “Office Action is picking and choosing from across multiple tables in Kuchroo to try to approximate the list of markers” in claim 54 and that “there is no motivation to make the specific selections as made by the Office Action other than to try to replicate the list in the present claim.”
Applicant is reminded that the cited prior art reference must be read in its entirety, not merely selective portions. As set forth in MPEP 2141.02:
Ascertaining the differences between the prior art and the claims at issue requires interpreting the claim language, and considering both the invention and the prior art references as a whole… A prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention… However, ‘the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….’ In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004) (emphasis added)
To that end, “picking and choosing” genes from the Kuchroo et al. reference does not negate the prima facie obviousness analysis. Furthermore, multiple Kuchroo et al. genes can be found within the same table (e.g., Table 1 teaching of SLAMF7, TIGIT, and TIM3), indicating that the Examiner is not “picking and choosing”.
The applicant is further reminded that per MPEP 2111.03 regarding Transitional Phrases:
The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. (emphasis added)
Thus, the instant claim language is interpreted with this MPEP guidance, wherein the claim requires an open-ended gene signature biomarker comprising the recited markers “or any combination of any thereof”, indicating that the open-ended signature can include any combination of the recited markers, such as those referenced from Kuchroo et al.
The Examiner disagrees with the assertion that there is no motivation to combine the cited references. Per MPEP 2145(X)(C) regarding Lack of Suggestion To Combine References:
A teaching, suggestion, or motivation to combine references that is found in the prior art is an appropriate rationale for determining obviousness. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. However, it is just one of a number of valid rationales for doing so. The Court in KSR identified several exemplary rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. KSR, 550 U.S. at 415-21, 82 USPQ2d at 1395-97. See MPEP § 2141 and § 2143. (emphasis added)
The Non-Final Office Action established that Kuchroo et al. taught that their T cell exhaustion panel – which includes “any combination of any” of the claimed markers – is implicated in tumor clearance and cancers (see Non-Final 6/13/25, page 12, last paragraph continued to first paragraph of page 13). The Non-Final Office Action further established that both Kuchroo et al. and Quezada et al. are analogous disclosures within the instant field of detecting gene expression within T cells (see Non-Final 6/13/25, page 12, paragraph 3).
Therefore, when Quezada et al. teaches that “Blockade of the interaction between PD1 and one of its ligands, PD-L1, has been shown to enhance tumor-specific CD8+ T-cell immunity and may therefore be helpful in clearance of tumor cells by the immune system” (page 28, lines 11-13), the skilled artisan would find it obvious that the Kuchroo et al. T cell exhaustion panel implicated in tumor clearance would be analogous to the Quezada et al. invention. The skilled artisan would regard these teachings as motivations to combine the disclosures of Kuchroo et al. and Quezada et al.
Furthermore, although Quezada et al. makes their therapeutic determination based upon a polymorphism and not the instant biomarker panels, the skilled artisan would still find a reasonable expectation of success of combining the teachings of Kuchroo et al. and Quezada et al. based on the disclosures. Per MPEP 2143.02 Reasonable Expectation of Success Is Required:
As discussed above, reasonable expectation of success can be implicitly shown via the prior art teachings or as part of the obviousness analysis. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1376-77, 2023 USPQ2d 1100 (Fed. Cir. 2023) ("[W]e can reasonably discern that the Board considered and implicitly addressed reasonable expectation of success based on the arguments and evidence presented to the Board on motivation to combine."). (emphasis added)
The reasonable expectation of success is implicitly shown via the prior art teachings and as a part of the obviousness analysis.
Conclusion
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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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682