DETAILED ACTION
The amendment filed on 11/13/2025 has been entered.
Claims 1, 4, 5 and 40 were amended in the claim set filed on 11/13/2025.
Applicant’s election without traverse of Group I, claims 1, 3-6, 14, 16, and 35-43 and species BAMBI, TMEM45B, MYL9 and GRHL3 in the reply filed on 03/21/2025 is acknowledged.
Claim 16 was canceled.
Claims 1, 3-6, 14, and 35-43 are pending and currently under examination.
Response to the Arguments
Objections to the claims in the previously mailed non-final have been withdrawn in light of applicants claim amendments.
Applicant’s arguments (Pg. 7) regarding previous rejections of claims 4-5 under 35 U.S.C. 112 have been fully considered and are persuasive. The 35 U.S.C. 112 rejections documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments on Pg. 7.
Applicant’s arguments (Pg. 5-6) regarding previous rejections of claims 1, 3-6, 14, 16, 35-43 under 35 U.S.C. 101 have been fully considered but are not persuasive. The 35 U.S.C. 101 rejections documented in the previously mailed non-final have been maintained and revised, as necessitated by amendment, and document below.
Applicant’s arguments (Pg.8) regarding previous rejections of claims 1, 3-6, 14, 16, 35-43 under 35 U.S.C. 103 have been fully considered but are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final have been maintained and revised, as necessitated by amendment, and document below.
Applicant’s arguments regarding previous rejections of claims 1, 3-6, 14, and 35-43 under Nonstatutory Double Patenting have been fully considered and are not persuasive. The Nonstatutory Double Patenting rejection documented in the previously mailed non-final have been maintained and revised as necessitated by amendment, and document below.
The revised rejections for claims 1, 3-6, 14, and 35-43 are documented below in this Final Office Action are necessitated by claim amendments filed on 11/13/2025.
Priority
This application is a CON of 15/875,871 filed on 01/19/2018, now Patent No. 11208697 which claims benefit of 62/448,921 filed on 01/20/2017. Accordingly, the priority date of instant claims is determined to be 01/20/2017, the filing date of 62/448,921.
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 1, 3-6, 14, and 35-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards mental/abstract ideas of obtaining/have obtained, comparing, and subtyping according to a genomic subtyping classifier, a natural correlation of gene expression in bladder cancer to subtypes of blood cancer and routine and conventional method of administering, without significantly more. The claim(s) recite(s) abstract ideas, a natural phenomenon and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more.
Claim analysis
The instant claim 1 is directed towards: A method for determining a treatment for a subject with bladder cancer, the method comprising: a) obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer, wherein the plurality of genes comprise BAMBI, TMEM45B, MYL9 and GRHL3; b) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes, wherein said genomic subtyping classifier comprises assignment of the bladder cancer to a subtype selected from claudin-low, basal, luminal-infiltrated, and luminal non-infiltrate; and c) administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, the luminal non- infiltrated subtype, or the claudin-low subtype, wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy.
The obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes is an abstract idea. (See MPEP 2106.04(a)(2)).
Additionally, the subtyping the bladder cancer of the subject according to a genomic subtyping classifier is an abstract idea related to a mathematical concept. (See MPEP 2106.04(a)(2)).
The correlation between a levels of gene expression and bladder cancer subtypes (e.g., claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated) is based on a natural phenomenon.
The administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, the luminal non- infiltrated subtype, or the claudin-low subtype, wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy is considered to be an active step requiring the analysis of a sample and general treatment based results. The active step is not only conditional, but also routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the neoadjuvant chemotherapy type, subject, expression detection and level, sample and cancer treatment types, and additional treatment step.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract ideas and natural phenomena.
With regard to claim 1, the claims recite “A method for determining a treatment for a subject with bladder cancer, the method comprising: a) obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer, wherein the plurality of genes comprise BAMBI, TMEM45B, MYL9 and GRHL3; b) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes, wherein said genomic subtyping classifier comprises assignment of the bladder cancer to a subtype selected from claudin-low, basal, luminal-infiltrated, and luminal non-infiltrate...” The obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes is an abstract idea. The genomic subtyping classifier is an abstract idea related to mathematical concepts.
The correlation between a levels of gene expression and bladder cancer subtypes (e.g., claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated) is based on natural phenomena, thus is considered a natural correlation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Regarding claim 1, the claim recites “c) administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, the luminal non- infiltrated subtype, or the claudin-low subtype, wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy.”
Although the independent claim 1 step (c) recites administering neoadjuvant chemotherapy to the subject, this administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. See MPEP 2106.04(d)(2).
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claim 1, the claim requires the routine and conventional active steps of analysis of a sample and general treatment based on subtyping results similar to that of Choi et al. (“Choi”; (2014). Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer cell, 25(2), 152–165.)
Choi discloses Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy (Pg.152 Summary). Thus, the claim does not provide additional steps which are significantly more.
Dependent claims set forth further limitations about the neoadjuvant chemotherapy type, subject, expression detection and level, sample and cancer treatment types, and additional treatment step, which are all routine and conventional based on Choi et al. (“Choi”; (2014). Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer cell, 25(2), 152–165.) in view of Kardos et al. (“Kardos”; (2016). Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI insight, 1(3), e85902.).
Response to Arguments
Applicants’ argument: “Here, like the claim in Vanda, pending claim 1 is not directed to a judicial exception because it is directed to a method for treating a subject having prostate cancer that "practically appl[ies] natural relationships" and/or abstract ideas. Applicant also notes that the claim at issue in Vanda was also conditional, and therefore that is also not a basis to reject the claims”
Response: Applicants’ arguments filed 11/13/2025 have been fully considered but they are not persuasive. Claim 1 recites a similar abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application. See MPEP 2106.04(d)(2). Furthermore, rejection includes the judicial exception based on the genetic subtype classifier, which is drawn to an abstract idea of mathematical concepts.
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.
Claim(s) 1, 3-6, 14 and 35-43 are rejected under 35 U.S.C. 103 as being unpatentable over Choi et al. (“Choi”; (2014). Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer cell, 25(2), 152–165.) in view of Kardos et al. (“Kardos”; (2016). Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI insight, 1(3), e85902.).
Interpretation: “genomic subtyping classifier” reads on any genomic subtyping classifier that can classify a claudin-low subtype, a basal subtype, a luminal infiltrated subtype, and/or a luminal non-infiltrated subtype.
Choi discloses Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy (Pg.152 Summary).
Regarding claim 1, Choi teaches a method wherein “We performed whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 primary fresh-frozen MIBCs obtained by transurethral resection at our institution. We identified three distinct molecular subtypes (Figure 1A; Table 1)” (Pg. 156, Muscle-Invasive Bladder Cancers Can Be Grouped into Basal and Luminal Subtypes (Para. 1). “Luminal Subtypes” reads on luminal infiltrated and/or luminal non-infiltrated.
Regarding claim 1, Choi teaches a method wherein “We applied our subtype classifier to the other group’s data set (‘‘Lund cohort’’; Sjodahl et al., 2012) and confirmed that the Lund squamous cell carcinoma subtype corresponded to the basal subtype … the MD Anderson p53-like subtype and the Lund ‘‘infiltrated’’ (MS2b.1) tumors were enriched with extracellular matrix biomarkers…” (Pg. 158, col.1 Para. 1). Choi teaches a method comprising Neoadjuvant Chemotherapy (NAC) as a primary treatment for a subject with basal subtype and other anticancer treatment(s) to a subject with luminal or TP53-like subtype (Table 1- Primary treatment).
Thus, Choi teaches a method comprising a) obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer, b) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes, wherein said genomic subtyping classifier comprises assignment of the bladder cancer to a subtype selected from claudin-low, basal, luminal-infiltrated, and luminal non-infiltrate; and c) administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, the luminal non- infiltrated subtype, or the claudin-low subtype.
However, Choi does not explicitly teach a method “wherein the plurality of genes comprise at least four genes comprising BAMBI, TMEM45B, MYL9 and GRHL3” (elected species).
Kardos discloses the discovery of a claudin-low subtype of high-grade, muscle-invasive UC defined by biologic characteristics of the claudin-low subtype of breast cancer. Claudin-low tumors were uniformly enriched for immune gene signatures but simultaneously expressed immune checkpoint molecules, demonstrating that, despite being immune infiltrated, claudin-low tumors are also actively immunosuppressed. Interestingly, the predicted neoantigen burden was not significantly increased in claudin-low tumors. Instead, they highly expressed cytokines and chemokines associated with leukocyte chemotaxis into the tumor immune microenvironment as a result of an imbalance between PPARγ and NF-κB signaling. These results highlight the association between molecular subtype and the degree of immune infiltration and immune suppression and suggest that mechanisms other than neoantigen burden can drive the development of immune infiltrated tumors and also that claudin-low tumors are poised to respond to immune checkpoint inhibition (Pg. 1-2. Introduction, last para.).
Regarding claim 1, Kardos teaches a method comprising “hierarchical clustering on 408 high-grade, muscle-invasive bladder tumors from The Cancer Genome Atlas (TCGA) urothelial bladder carcinoma (BLCA)“ (Pg. 2, Results Para.1; Figure 1). Kardos teaches a method of analysis of a plurality of genes comprising BAMBI, TMEM45B, MYL9 and GRHL3 (Supplemental Table 4- appended to end of NPL). Thus, Choi and Kardos teach a method wherein a) obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer, wherein the plurality of genes comprises at least four genes comprising BAMBI, TMEM45B, MYL9 and GRHL3.
Regarding claim 1, Kardos teaches a method wherein “Z scores were calculated for each claudin, basal, and luminal subtype and box plots made of the distributions” (Pg. 14, Para. 1). Kardos teaches a method “Bladder basal and luminal predictions and centroid distances were made using the BASE47 PAM Classifier derived by Damrauer et al.” and “Breast cancer claudin predictions were made using the Distance-Weighted Discrimination (DWD) Claudin Classifier provided by Prat et al.” (Pg. 14, Para.2). Kardos teaches a method wherein “A comparison of our claudin-low, basal, and luminal predictions on the 408 provisional TCGA BLCA tumors with the MD Anderson oneNN classification system (p53-like, basal, and luminal) (2) re-demonstrated the high concordance of luminal subtype designations (14) as well as the notion that claudin-low tumors arise primarily from basal tumors (Supplemental Figure 2, A and B). We further compared our claudin-low, basal, and luminal predictions on the 129 published TCGA BLCA tumors with TCGA 4-subtype classification (clusters I, II, III, and IV) (6). Our claudin-low tumors were primarily found in TCGA clusters III and IV” (Pg. 3, last para.; Pg. 5, Para.1). Kardos also teaches a method wherein “Luminal tumors were sparsely infiltrated and showed low expression levels of molecules associated with immunosuppression” (Pg. 12, Discussion, Para. 2). “Luminal tumors were sparsely infiltrated” reads on luminal non-infiltrated. “luminal subtype” reads on luminal infiltrated and/or luminal non-infiltrated. Thus, Choi and Kardos teach a method comprising: b) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of each of the plurality of genes, wherein said subtyping comprises assigning the bladder cancer to one of four subtypes selected from the group consisting of a claudin-low, a basal, a luminal-infiltrated, and a luminal non-infiltrated subtype.
Choi and Kardos are both considered to be analogous to the claimed invention because they are in the same field of bladder cancer subtyping. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer according to a genomic subtype classifier to a basal or luminal subtype as taught by Choi to incorporate the method comprising the plurality of genes comprising at least four genes comprising from BAMBI, TMEM45B, MYL9 and GRHL3 and subtyping the bladder cancer according to a genomic subtype classifier to a Claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated subtype as taught by Kardos because an ordinary artisan would be motivated to further optimize the method of Choi utilizing a genomic subtyping classifier due to the need to understand the molecular basis of the unclear p53-like subtype and the large proportion of non-responders associated with the subtype as well as the number of non-responders classified as Basal and luminal (Pg. 163. Discussion, last para.; Figure 7A). It would be obvious to the ordinary artisan to in include a plurality of genes comprising BAMBI, TMEM45B, MYL9 and GRHL3 and subtyping the bladder cancer according to a genomic subtype classifier to a Claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated subtype of Kardos to the obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer according to a genomic subtype classifier to a basal or luminal subtype of Choi to have yielded the predictable result of obtaining the expression levels of BAMBI, TMEM45B, MYL9 and GRHL3 to assess expression level changes of the genes in further characterization of subtyping bladder cancer. The broadest reasonable interpretation of the “genomic subtyping classifier” reads on any genomic subtyping classifier that can classify a claudin-low subtype, a basal subtype, a luminal infiltrated subtype, and/or a luminal non-infiltrated subtype based on the levels of expression of each of the plurality of genes. Therefore, the combination of the methods prior art teaches the claimed limitations according to claim 1 with a reasonable expectation of success. Thus, further characterizing the ability to determine treatment of bladder cancer patients based on optimized subtyping of the bladder cancer according to the levels of expression of each of the plurality of genes.
The teachings of Choi and Kardos are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 3-6, 14, 35-40 and 43 depend on claim 1. Claim 42, depends on claim 41, which depends on claim 40, which depends on claim 1.
Regarding claim 3, Choi teaches a method wherein “cisplatin-based chemotherapy (NAC) is the current standard-of-care for high-risk MIBC” (Pg. 159, p53-like MIBCs Are Resistant to Neoadjuvant Chemotherapy Para. 1). Thus, Choi and Kardos teach a method wherein the neoadjuvant chemotherapy comprises administering cisplatin.
Regarding claim 4, Choi teaches a method wherein “We performed whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 primary fresh-frozen MIBCs obtained by transurethral resection at our institution” (Pg. 156, Muscle-Invasive Bladder Cancers Can Be Grouped into Basal and Luminal Subtypes (Para. 1). Choi teaches a method wherein “available FFPE pretreatment tumors” (Pg. 163, last para., last line). Thus, Choi and Kardos teach a method wherein the subject is not treated with neoadjuvant chemotherapy prior to performing the method.
Regarding claim 5, Choi teaches a method wherein matched pre- and post-treatment MIBCs collected within the context of a prospective Phase II clinical trial of neoadjuvant dose-dense MVAC (DDMVAC) (Pg. 161, Para.1). Thus, Choi and Kardos teach a method wherein the subject is treated with the neoadjuvant chemotherapy prior to performing the method.
Regarding claim 6, Choi teaches a method wherein “we identified three molecular subtypes of muscle-invasive bladder cancer (MIBC)” (Pg. 152, Significance, Para. 1) and “Muscle-invasive bladder cancers can be grouped into basal and luminal subtypes” (Pg. 156, Results, Para.1). Thus, Choi and Kardos teach a method wherein the subject has muscle-invasive bladder cancer.
Regarding claim 14, Choi teaches a method wherein “We performed whole genome mRNA expression profiling” (Pg. 156, Muscle-Invasive Bladder Cancers Can Be Grouped into Basal and Luminal Subtypes (Para. 1). Thus, Choi and Kardos teach a method wherein said level of expression is obtained by measuring the level of an RNA transcript.
Regarding claim 35, Choi teaches a method wherein “tissues were collected and analyzed” (Pg. 163, Human Specimens Para. 1). Thus, Choi and Kardos teach a method wherein he biological sample is a biopsy.
Regarding claim 36-37, Choi teaches a method comprising transurethral resections (TURs) (Pg. 163, Tumor Cohorts Para. 1). Thus, Choi and Kardos teach a method wherein the biological sample is a urine sample or a bladder tumor sample and wherein the biological sample is a transurethral resection (TUR) specimen.
Regarding claim 38, Choi teaches a method comprising “Human Specimens” (Pg. 163, Human Specimens Para. 1). Thus, Choi and Kardos teach a method wherein the subject is a human being.
Regarding claim 39, Choi teaches a method wherein miRNA U6 expression was used as an internal standard and the 2−ΔΔCt method was used to generate relative expression values. (Supplemental Information Pg. 25, Real-time Quantitative Reverse Transcriptase PCR analyses, para. 1). Thus, Choi and Kardos teach a method wherein the level of expression is increased or reduced compared to a control.
Regarding claim 40, Choi teaches a method wherein “direct hybridization assays were performed” (Supplemental Information Pg. 20, Microarray Experiments and Data Processing, para. 1). Choi teaches a method wherein “ …analyzed by real-time PCR…used for expression analysis” (Supplemental Information Pg. 25, Real-time Quantitative Reverse Transcriptase PCR analyses, para. 1). Thus, Choi and Kardos teach a method wherein said level of expression is obtained by performing in situ hybridization, a PCR-based method, an array-based method, or an RNA sequencing method.
Regarding claim 41, Choi teaches a method wherein “analysis using the 6700 probes” (Supplemental Information Pg. 20, Microarray Experiments and Data Processing, para. 2). Thus, Choi and Kardos teach a method wherein said level of expression is obtained by using a reagent selected from the group consisting of a nucleic acid probe or one or more nucleic acid primers.
Regarding claim 42, Choi teaches a method wherein “total RNA along with miR-specific primers were used for expression analysis” (Supplemental Information Pg. 25, Real-time Quantitative Reverse Transcriptase PCR analyses, para. 1). Thus, Choi and Kardos teach a method wherein said level of expression is obtained by measuring the level of an RNA transcript.
Regarding claim 43, Choi teaches “Treatment selection depends heavily on clinico-pathologic features” (Pg. 152, Introduction, Para. 1). Choi also teaches “Presurgical (neoadjuvant) cisplatin-based chemotherapy (NAC) is the current standard-of-care for high-risk MIBC (Shah et al., 2011), and pathological response to NAC (downstaging to %pT1 at cystectomy) is a strong predictor of disease-specific survival (Pg. 159, p53-like MIBCs Are Resistant to Neoadjuvant Chemotherapy Para.1). In addition, Choi recognizes “Gene expression profiling has been used to identify molecular heterogeneity in other human cancers. For example, Perou and coworkers used gene expression profiling to identify molecular subtypes of breast cancer … luminal breast cancers respond to estrogen receptor (ER)-targeted therapy … and basal tumors to chemotherapy only (Rouzier et al., 2005). Previous studies in bladder cancer identified signatures associated with stage and outcomes and progression” (Pg. 154, Col.1-2, Para. 2). The upregulated genes that determined subtype assignments contained signature biomarkers for basal ... and luminal … breast cancers” (Pg. 156, Results, Para. 1). Thus, Choi suggests a method wherein after administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype, the method further comprises administering a cancer treatment selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy.
Response to Arguments
Applicant's arguments “the Examiner has failed to establish a prima facie case of obviousness for at least the reasons that the Examiner has not established a sufficient motivations to combine the references in view of a clear teaching away, that the proposed combination does not teach or suggest all of the recited claim limitations as required by MPEP
§ 2143.03, and because the Examiner has failed to establish that there is a reasonable expectation of success.” (Pg. 8) filed 11/13/2025 (Pg. 7-11) with respect to claims 1, 3-6, 14, and 35-43 have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 11/13/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “Kardos teaches away from the proposed combination… The claimed method would not be obvious in view of because Kardos chose to pursue a path that is divergent from the claimed method in spite of being aware of Choi' s classification system. If there were a motivation to combine Choi's classification system with Kardos' system as alleged by the Examiner to arrive at the claimed invention, why wouldn't Kardos have included Choi's classification in its own system?” (Pg. 8-9)
Response: Applicant’s arguments have been fully considered and found unpersuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Choi and Kardos are both considered to be analogous to the claimed invention because they are in the same field of bladder cancer subtyping. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer according to a genomic subtype classifier to a basal or luminal subtype as taught by Choi to incorporate the method comprising the plurality of genes comprising at least four genes comprising from BAMBI, TMEM45B, MYL9 and GRHL3 and subtyping the bladder cancer according to a genomic subtype classifier to a Claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated subtype as taught by Kardos because an ordinary artisan would be motivated to further optimize the method of Choi utilizing a genomic subtyping classifier due to the need to understand the molecular basis of the unclear p53-like subtype and the large proportion of non-responders associated with the subtype as well as the number of non-responders classified as Basal and luminal (Pg. 163. Discussion, last para.; Figure 7A). Furthermore, the MPEP states "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." (MPEP 2144.05).
Applicants’ argument: “The Examiner has failed to articulate any reason to modify the cited references to arrive at the claimed method of assigning the subject to one of at least the four listed subtypes... any proposed modification of Kardos' or Choi's method to include an additional bladder cancer subtype only meets the limitations of the currently claimed method if the additional subtype is the single subtype "luminal non-infiltrate" and not any of the other subtypes disclosed by Kardos or Choi. Office Action at p. 14 (emphasis added). The Examiner fails to articulate any reason one of skill in the art would have modified Kardos or Choi to include "luminal non-infiltrate" (assuming Kardos or Choi even disclosed such a "luminal non-infiltrate" subtype, which they do not) as the one and only additional subtype instead of one of the other subtypes disclosed by Kardos or Choi, for example the "laminal'' subtype of Kardos or the "p53-like" subtype of Choi. Therefore, even if there were a motivation to combine Kardos' three subtype classification (basal, laminal, claudin-low) with Choi's three subtype classification (basal, luminal, p53-like), one of skill in the art could have chosen any of Kardos' or Choi's subtypes…” (Pg. 9-10)
Response: Applicant’s arguments have been fully considered and found unpersuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, an ordinary artisan would be motivated to further optimize the method of Choi utilizing a genomic subtyping classifier due to the need to understand the molecular basis of the unclear p53-like subtype and the large proportion of non-responders associated with the subtype as well as the number of non-responders classified as Basal and luminal (Pg. 163. Discussion, last para.; Figure 7A). Choi and Kardos are both considered to be analogous to the claimed invention because they are in the same field of bladder cancer subtyping. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of obtaining or having obtained an expression level of a plurality of genes in a biological sample from a subject having bladder cancer and subtyping the bladder cancer according to a genomic subtype classifier to a basal or luminal subtype as taught by Choi to incorporate the method comprising the plurality of genes comprising at least four genes comprising from BAMBI, TMEM45B, MYL9 and GRHL3 and subtyping the bladder cancer according to a genomic subtype classifier to a Claudin-low, basal, luminal-infiltrated and/or luminal non-infiltrated subtype as taught by Kardos. Furthermore, the MPEP states "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." (MPEP 2144.05).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., any proposed modification of Kardos' or Choi's method to include an additional bladder cancer subtype only meets the limitations of the currently claimed method if the additional subtype is the single subtype "luminal non-infiltrate" and not any of the other subtypes disclosed by Kardos or Choi. Office Action at p. 14 (emphasis added) are not recited in the rejected claim(s). 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, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, Kardos does suggest a luminal non-infiltrated subtype ((Pg. 12, Discussion, Para. 2; (Pg. 14, Para. 1)) as “Luminal tumors were sparsely infiltrated” reads on luminal non-infiltrated and “luminal subtype” reads on luminal infiltrated and/or luminal non-infiltrated subtype.
Applicants’ argument: “In the instant case, the Examiner has not articulated any basis for there being a reasonable expectation of success - the Office Action does not even mention "reasonable expectation of success." Applicant respectfully submits that because neither Kardos nor Choi apparently discloses a "luminal non-infiltrate" subtype, there can be no reasonable expectation of success in performing a method of subtyping bladder cancer as being "luminal non-infiltrate” (Pg. 11).
Response: Applicant’s arguments have been fully considered and found unpersuasive as discussed above. Kardos does suggest a luminal non-infiltrated subtype ((Pg. 12, Discussion, Para. 2; (Pg. 14, Para. 1)) as “Luminal tumors were sparsely infiltrated” reads on luminal non-infiltrated and “luminal subtype” reads on luminal infiltrated and/or luminal non-infiltrated subtype. Furthermore, the broadest reasonable interpretation of the “genomic subtyping classifier” reads on any genomic subtyping classifier that can classify a claudin-low subtype, a basal subtype, a luminal infiltrated subtype, and/or a luminal non-infiltrated subtype based on the levels of expression of each of the plurality of genes. Therefore, the combination of the methods prior art teaches the claimed limitations according to claim 1 with a reasonable expectation of success.
Applicants’ argument: “the claimed method provides better results than prior classification systems, including those of Choi (MD Anderson) and Kardos (UNC): "Compared to previously published methods, the single sample GSC was more discriminate in assigning individual patients to a definitive subtype as seen by the number of patients that have a dominant subtype score (Figure 3B and Figure 10).” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., method provides better results than prior classification systems, including those of Choi (MD Anderson) and Kardos (UNC): "Compared to previously published methods, the single sample GSC was more discriminate in assigning individual patients to a definitive subtype as seen by the number of patients that have a dominant subtype score) are not recited in the rejected claim(s). 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, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, the broadest reasonable interpretation of the “genomic subtyping classifier” reads on any genomic subtyping classifier that can classify a claudin-low subtype, a basal subtype, a luminal infiltrated subtype, and/or a luminal non-infiltrated subtype based on the levels of expression of each of the plurality of genes.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 3-6, 14 and 35-43 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US 11,208,697 B2 (“U.S. Patent No. ‘697”, Application No .15/875,871, Davicioni et al.) in view of Kamat et al. (“Kamat” (2016). Bladder cancer. Lancet (London, England), 388(10061), 2796–2810.). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of U.S. Patent No. ‘697.
Claims 1-11 of U.S. Patent No. ‘697 are drawn to:
1. A method for treating a subject with muscle-invasive bladder cancer, the method comprising: a) obtaining or having obtained an expression level of a plurality of genes in a biological sample obtained from a subject with muscle-invasive bladder cancer, wherein the plurality of genes are selected from Intercept, TMEM45B, ERBB2, TNFRSF21, FLRT3, SPINK1, LRRC37A2, SCCPDH, UGT1A3, ZNF486, UGT1A8, PPARG, UGT1A1, AHR, EPCAM, PVRL4, UGT1A4, IGFBP3, S100P, PTPRM, NQO1, RNF138P1, CPSF6, GATA3, UGT1A5, UGT1A10, ELF3, AGR2, EHF, SLC14A1, CXCL17, TMSB10, CCL5, MMP12, SAT1, CD68, ANXA1, IFITM2, KRT5, GJB2, MT1L, NDRG1, ASPN, SULF1, EFEMP1, G0S2, TIMP3, MUC16, GBP1, CGB2, SNAI2, DDIT4, CTSK, GBP5, C3, VIM, BGN, TGFBI, TIMP2, SAA1, LAMC2, FBP1, BAMBI, PAQR7, IGFL1, TMPRSS2, PLXNB2, MAL, TBX3, CRISP3, SCNN1B, RNF128, KRT7, KRT8, ADAM10, SNX31, KRT18, UPK3A, PSCA, UPK2, AHNAK, SPP1, TWIST2, SPARCL1, CASP14, MMP1, LAPTM5, MMP13, DUSP1, HIST1H2BF, GABRP, CFH, SFRP2, SERPINB3, MGP, FGFBP1, SAMD9, ITGA6, MALL, MYL9, IER3, SPRR2F, MMP2, HLA-DRA, DCN, TPM2, HLA-A, LYZ, LUM, COL3A1, POSTN, IFI30, CD74, VCAN, CALD1, COL1A2, HLA-DRB5, OLFM4, THBS2, KRT23, MYH11, CLDN1, RARRES1, HPGD, ACER2, RALBP1, GSTM3, BTBD16, MACC1, SEMASA, ACOX1, GSTM2, CYP4Z2P, ZNF91, STS, TOX3, PLP2, TACSTD2, ATP8B1, GRHL3, TNC, TPX2, DSP, TIMP1, UPK1B, DHRS2, PTN, SNCG, ACTG2, and SYTL2; b) subtyping the muscle-invasive bladder cancer of the subject according to a genomic subtyping classifier based on the expression level of each of the plurality of genes, wherein said subtyping comprises assigning the muscle-invasive bladder cancer to one of four subtypes selected from the group consisting of a claudin-low subtype, a basal subtype, a luminal-infiltrated subtype, and a luminal non-infiltrated subtype; and c) administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype and administering an anti-cancer treatment other than the neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, the luminal non-infiltrated subtype, or the claudin-low subtype, wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy.
2. The method of claim 1, wherein the neoadjuvant chemotherapy comprises administering cisplatin.
3. The method of claim 1, wherein the biological sample is a biopsy.
4. The method of claim 1, wherein the biological sample is a urine sample or a bladder tumor sample.
5. The method of claim 1, wherein the biological sample is a transurethral resection (TUR) specimen.
6. The method of claim 1, wherein the subject is a human being.
7. The method of claim 1, wherein the level of expression is increased or reduced compared to a control.
8. The method of claim 1, wherein said level of expression is obtained by performing in situ hybridization, a PCR-based method, an array-based method, an immunohistochemical method, an RNA assay method, or an immunoassay method.
9. The method of claim 8, wherein said level of expression is obtained by using a reagent selected from the group consisting of a nucleic acid probe, one or more nucleic acid primers, and an antibody.
10. The method of claim 9, wherein said level of expression is obtained by measuring the level of an RNA transcript.
11. The method of claim 9, wherein after administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype, the method further comprises administering one cancer treatment selected from the group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy.
Claims of U.S. Patent No. ‘697 are made obvious over the instantly claimed invention. Further, Kamat discloses bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualized treatment and follow-up is the key to a successful outcome… Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments (Abstract).
Kamat teaches “most patients with bladder cancer are diagnosed during diagnostic testing prompted by haematuria” (Pg. 2798, Clinical presentation, screening, and diagnostic assessment, Para. 1). Kamat teaches “most bladder cancers are urothelial carcinomas. At presentation, roughly 75% of patients have non-muscle invasive bladder cancer and 25% have muscle-invasive or metastatic disease. About 50% of non-muscle-invasive bladder cancers are low grade, whereas most muscle invasive or metastatic tumours are high grade” (Pg. 2796, Grade and stage of urothelial carcinoma, Para. 1). Kamat teaches bladder tumours can be grouped on the basis of gene expression patterns into basal and luminal subtypes, similar to the corresponding subtypes of breast cancer (figure 3) (Pg. 2797, Genetic characteristics of bladder cancer, Para. 2)
Therefore, it would have been obvious to one of ordinary skill in the art to include bladder cancer samples that would be further characterized by grade, type and subtype as suggested by Kamat to a method for treating a subject with muscle-invasive bladder cancer as recited in claims 1-11 of U.S. Patent No. ‘697 to have yielded the predictable result of a method for treating bladder cancers. One of ordinary skill in the art would have been motivated to do so in order to assess and optimally treat bladder cancers as taught by Kamat. One of ordinary skill in the art would have had a reasonable expectation of success given that previous studies have shown bladder cancer grading and gene expression profiling subtyping studies to identify signatures associated with stage can improve outcomes
Thus, the invention as a whole is rendered prima facie obvious over U.S. Patent No. ‘697 in view of Kamat.
Response to Arguments
Applicants’ argument: “As the pending claims have not yet been found in condition for allowance, Applicant requests that the rejection be held in abeyance. Applicant will consider the propriety of filing a terminal disclaimer when the claims are otherwise allowable.”
Response: Applicant's arguments filed 11/13/2025 have been fully considered but they are not persuasive. Claims 1, 3-6, 14, 35-43 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. US 11,208,697 B2 (Filed on Jan. 19, 2018, Pat. Pub. Dec. 28, 2021) in view of Kamat et al.
Conclusion of Response to Arguments
In view of the amendments, revised rejections and above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/KENDRA R VANN-OJUEKAIYE/
Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682