DETAILED ACTION
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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/24/2026 has been entered.
Election/Restrictions
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.
Claims Status
Claims 1, 3-6, 14, and 35-48 are pending.
Claims 44-48 were added.
Claims 1, 3-6, 14, and 35-48 are currently under examination.
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 Objections
Claim 45 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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, 4-6, 14, 35-48 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards abstract ideas (mental process) of obtaining or having obtained an expression level of a plurality of genes, 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 analysis and administering, without significantly more. The claim(s) recite(s) abstract ideas and a natural phenomenon. 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 having 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 using a genomic subtyping classifier capable of discriminating between claudin-low, basal, luminal-infiltrated, and luminal non- infiltrated subtypes of bladder cancer based on the levels of expression of each of the plurality of genes, wherein the subtyping comprises assignment of claudin-low, basal, luminal-infiltrated, or 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.
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 using a genomic subtyping classifier” is an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and is considered to be active steps requiring the analysis of a sample. (See MPEP 2106.04(a)(2)).
Additionally, the subtyping the bladder cancer of the subject using a genomic subtyping classifier is an abstract idea related to a mathematical concept. (See MPEP 2106.04(a)(2)).
The correlation between levels of gene expression and bladder cancer subtypes (e.g., claudin-low, basal, luminal-infiltrated and luminal non-infiltrated) is based on a natural phenomenon.
Although the independent claim 1 step (c) recites administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype, which is of great generality being routine and conventional as demonstrated in the prior art rejections documented below and is not a particular treatment.
Dependent claims set forth further limitations about the subject, treatment step, expression detection type, sample type, 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 using a genomic subtyping classifier” is an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and is considered to be active steps requiring the analysis of a sample. Additionally, the subtyping the bladder cancer of the subject using a genomic subtyping classifier is an abstract idea related to a mathematical concept. 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.”
Although the independent claim 1 step (c) recites administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype, this administration step is not particular, as the treatment is the regarded as the standard class of treatment for muscle invasive bladder cancer. For the same reason, the limitation “wherein the anti-cancer treatment other than neoadjuvant chemotherapy is selected from group consisting of surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy” recited in newly added claim 44 filed on 08/24/2026 is not particular. Similarly, the limitations recited in newly added claims 45-48 are not particular (See 103 rejection below and Subject Matter Eligibility: Life science examples 43, 44, and 49), and 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 a treatment of great generality (the standard class of treatment for muscle invasive bladder cancer) based on subtyping results of a patient comprising basal subtype 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.) in view of Kardos et al. (“Kardos”; (2016). Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI insight, 1(3), e85902.) as discussed in the 103 rejection below.
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).
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…(Abstract). Thus, the claim does not provide additional steps which are significantly more.
Dependent claims set forth further limitations about the 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
Applicant's arguments filed 08/24/2026 (Pg. 6-9) have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 08/24/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Claim 1 of the present application does not make the appropriate treatment optional or simply express the result of a process step,-instead, it requires a specific class of therapy (neoadjuvant chemotherapy, that is not just any common treatment) that is particular to certain specific subject (the subject having the basal subtype)” (Pg. 7)
Response: Applicant’s arguments, with respect to claims 1, 4-6, 14, 35-43 and 45, have been fully considered and found unpersuasive because applicants amendments do not overcome the lack of patentably matter under U.S.C. 35 101. The previously presented and amended claims recite abstract ideas (mental process) of obtaining or having obtained an expression level of a plurality of genes, 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 analysis and administering. The judicial exceptions are not integrated into a practical application because the claim limitations do not appear to improve the current technology or technical field beyond well-understood, routine, conventional activity. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no specific limitations that provide significantly more. Although the independent claim 1 step (c) administering neoadjuvant chemotherapy to the subject when the subtyping of step b) indicates that the subject has the basal subtype is not a particular treatment, and which is of great generality (standard treatment for MIBC), as demonstrated in the prior art rejections documented below.
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 35-48 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. When both luminal and luminal infiltrated are discussed in the same context then luminal is interpreted as non-infiltrated luminal subtype. When luminal is discussed without further indication of infiltrated luminal then luminal is interpreted as both non-infiltrated and infiltrated luminal 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 claims 1 and 45, 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)” and We therefore propose the names ‘‘basal’’ and ‘‘luminal’’ for two of the MIBC subtypes. Although the tumors in the third subtype also expressed luminal biomarkers, we have termed this MIBC subtype ‘‘p53-like’’ because its distinguishing feature was an activated wild-type p53 gene expression signature (Pg. 156, Muscle-Invasive Bladder Cancers Can Be Grouped into Basal and Luminal Subtypes (Para. 1). “Luminal” and “p53-like” subtypes read on luminal infiltrated and luminal non-infiltrated.
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Regarding claims 1 and 45, 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; Figure 3). Furthermore, Choi depicts Figure 3B which illustrates LUND infiltrated feature is also comprised in Luminal subtypes in addition to other subtypes. (Figure 3, see below)
Choi teaches a method wherein “basal MIBCs responded to NAC” also suggests “aggressive early management of basal MIBCs with NAC offers the best chance for improved survival for patients with this potentially deadly form of this disease” (Pg. 161 col. 2, Para. 1). “NAC” reads on neoadjuvant chemotherapy. Thus, Choi suggests 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 using a genomic subtyping classifier capable of discriminating between basal and luminal subtypes with infiltrated and non-infiltrated features of bladder cancer based on the levels of expression of each of the plurality of genes, wherein the subtyping comprises assignment of basal, luminal- infiltrated, or 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.
In addition, Choi teaches ” cisplatin-based chemotherapy is only effective in
30%–40% of cases” (Pg. 152 col. 2, para. 1) and suggests “It will be important to determine the molecular basis of these p53-like signatures in future studies so that therapeutic approaches can be developed to overcome de novo and/or prevent acquired chemoresistance” (Pg. 163, col. 1, Tumor Cohorts, para. 1). Thus, the 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 p53-like subtype as well as the number of non-responders classified as Basal and luminal; and highlighted variability of features in the illustrative comparison of MDA subtypes and LUND features as mentioned above. (Pg. 163. Discussion, last para.; Figure 7A; Figure 3B).
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); and discriminating between claudin-low, basal, luminal-infiltrated, or luminal non-infiltrated subtype.
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 claims 1 and 45, 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 suggest 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 claims 1 and 45, 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). Furthermore, Kardos teaches Figure 1d which highlights two clusters (cluster I and II) which comprise the luminal subtype. Kardos also teaches “Though our study was not designed to formally test this, we report here a high degree of variability, in which adaptive immune gene segments were prognostic among the bladder cancer subtypes” (Pg. 12-13) and “gene classifiers, which can accurately subtype high-grade bladder tumors, may serve to identify useful predictive biomarkers of response (i.e., claudin-low) or lack of response (i.e., luminal) to PD1 axis inhibition” (Pg. 13). Hence, one of ordinary skill in the art would be motivated to combine the teachings of Kardos with those of Choi to further distinguish subtyping of MIBC and improve the prediction of those cancers that will respond to PD1 axis inhibition. Thus, Choi and Kardos suggest a method comprising: b) subtyping the bladder cancer of the subject using a genomic subtyping classifier capable of discriminating between claudin-low, basal, luminal-infiltrated, and luminal non-infiltrated subtypes of bladder cancer based on the levels of expression of each of the plurality of genes, wherein the subtyping comprises assignment of claudin-low, basal, luminal-infiltrated, or luminal non-infiltrated subtype.
Thus, Choi and Kardos suggest the limitations according to claims 1 and 45.
Choi and Kardos are considered to be analogous to the claimed invention because they are in the same field of bladder cancer subtyping and treatment. The teachings Choi and Kardos suggest a motivation to modify the teachings Choi as stated above. 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 of the subject using a genomic subtyping classifier capable of discriminating between basal and luminal subtype as suggested by Choi to incorporate the method wherein the plurality of genes comprise BAMBI, TMEM45B, MYL9 and GRHL3; and subtyping the bladder cancer of the subject using a genomic subtyping classifier capable of discriminating between claudin-low, basal, luminal-infiltrated and non-infiltrated subtypes as suggested by Kardos and provide a method for determining a treatment for a subject having bladder cancer. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 45. Doing so would allow for an improved classifier to help determine treatment options such a NAC, immunotherapy, resection and/or other therapies and prolong the overall survival of MIBC patients.
The teachings of Choi and Kardos are documented above in the rejection of claims 1 and 45 under 35 U.S.C. 103. Claims 3-6, 14, 35-40 and 43-45 depend on claim 1. Claim 42, depends on claim 41, which depends on claim 40, which depends on claim 1. Claims 46-48 depend on claim 44, 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 suggest a method wherein the neoadjuvant chemotherapy comprises administering cisplatin.
Regarding claim 4, Choi teaches Table 1 which indicates that primary treatment was optionally cystectomy. (Pg. 156, Table 1, Primary treatment). Choi also teaches a method wherein “available FFPE pretreatment tumors” (Pg. 163, last para., last line). Thus, Choi and Kardos suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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 suggest 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). “Pre-surgical” reads on surgery occurring after. 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) and “The upregulated genes that determined subtype assignments contained signature biomarkers for basal ... and luminal … breast cancers” (Pg. 156, Results, Para. 1). Furthermore, Kardos suggests that “a subset of basal tumors, are poised for response to immune checkpoint blockade. “poised for response to immune checkpoint blockade” reads on immunotherapies. Thus, Choi and Kardos suggest 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.
Regarding claims 44 and 46-47, Choi teaches a method wherein “Agents that target the ER and/or ErbB2 and -3 may therefore be clinically active in luminal MIBCs.” (Pg. 161, Col. 2, Para. 2) “Agents that target the ER and/or ErbB2” reads on hormonal therapy. Thus, Choi and Kardos suggest a method wherein the method comprises 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; and wherein the subtyping of step b) indicates that the subject has the luminal-infiltrated subtype, and the method comprises administering the anti- cancer treatment other than the neoadjuvant chemotherapy to the subject; wherein the subtyping of step b) indicates that the subject has the luminal non-infiltrated subtype, and the method comprises administering the anti- cancer treatment other than the neoadjuvant chemotherapy to the subject;
Regarding claims 44 and 48, Kardos teaches a method “Moreover, our studies further validate the notion of subtype-specific therapy in bladder cancer (i.e., … claudin-low = immune checkpoint blockade).” (Pg. 13). “immune checkpoint blockade” reads on immunotherapy. Thus, Choi and Kardos suggest a method wherein the subtyping of step b) indicates that the subject has the claudin-low subtype, and administering the anti-cancer treatment other than the neoadjuvant chemotherapy to the subject.
Response to Arguments
Applicant's arguments filed 08/24/2026 (Pg. 9-12) have been fully considered but they are not persuasive. To clarify some instances argued in the response filed 08/24/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “neither of the cited references teach or suggest a genomic subtyping classifier that can distinguish between subtypes comprising claudin-low, basal, luminal-infiltrated, and luminal non-infiltrated as recited in the presently pending claims… The Office Action does not cite any disclosure in Choi which addresses whether ''luminal'' subtypes identified by Choi are infiltrated or not” (Pg. 10)
Response: Applicant’s arguments have been fully considered and found unpersuasive. In response to applicant's arguments against the references individually, 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).
Applicants’ argument: “Applicant respectfully submits that neither reference provides any motivation to modify the disclosed classification systems to arrive at the claimed genomic subtyping classifier, as neither reference discloses a genomic classifier which distinguishes between at least luminal-infiltrated and luminal non-infiltrated subtypes” (Pg. 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, Choi and Kardos suggest the limitations according to claims 1 and 45. Choi and Kardos are considered to be analogous to the claimed invention because they are in the same field of bladder cancer subtyping and treatment. The teachings Choi and Kardos suggest a motivation to modify the teachings Choi, as stated in the non-final office action above, in the modified rejection of claims 1 and 45 under 35 U.S.C. 103 rejection. Furthermore, in brief, the teachings Choi suggest by way of the LUNDs features, luminal infiltrated features in the luminal subtype and p53-like subtype, which was noted as a luminal subtype with a p53 signature. Thus, Choi and Kardos suggest a capability to distinguishes between at least luminal-infiltrated and luminal non-infiltrated subtypes.
Applicants’ argument: “Applicant submits that the cited references do not teach or suggest the limitation of new dependent claim 44, ''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." Nor does it teach or suggest the limitations of at least new claims 46-47, which recite administering the 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 or the luminal non-infiltrated subtype.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated above in the non-final office action, Choi teaches a method wherein “Agents that target the ER and/or ErbB2 and -3 may therefore be clinically active in luminal MIBCs.” (Pg. 161, Col. 2, Para. 2) “Agents that target the ER and/or ErbB2” reads on hormonal therapy. Kardos teaches a method “Moreover, our studies further validate the notion of subtype-specific therapy in bladder cancer (i.e., … claudin-low = immune checkpoint blockade).” (Pg. 13). “immune checkpoint blockade” reads on immunotherapy. Thus, Choi and Kardos suggest the limitations of claims 44 and 46-47.
Applicants’ argument: “Choi teaches away from, or at a minimum does not teach or suggest, the present claims which recite administering an anti-cancer treatment other than neoadjuvant chemotherapy to subjects identified as luminal-infiltrated or luminal non-infiltrated subtype.” (Pg. 11)
Response: Applicant’s arguments have been fully considered and found unpersuasive because as stated above in the non-final office action, Choi teaches “cisplatin-based chemotherapy is only effective in 30%–40% of cases” (Pg. 152 col. 2, para. 1) and suggests “It will be important to determine the molecular basis of these p53-like signatures in future studies so that therapeutic approaches can be developed to overcome de novo and/or prevent acquired chemoresistance” (Pg. 163, col. 1, Tumor Cohorts, para. 1). Thus, Choi and Kardos suggest the present claims which recite administering an anti-cancer treatment other than neoadjuvant chemotherapy to subjects identified as luminal-infiltrated or luminal non-infiltrated subtype.
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).
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Claims 1, 3-6, 14 and 35-48 are 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.). 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.
Therefore, the invention as recited in claims 1, 3-6, 14 and 35-48 is prima facie obvious over U.S. Patent No. ‘697. One of ordinary skill in the art would have had a reasonable expectation of success given the given the obviousness of the claims 1, 3-6, 14 and 35-48 in view of claims 1-11 of U.S. Patent No. ‘697. It would have been obvious to provide a method for determining a treatment for a subject having bladder cancer according to the limitations recited in claim 1, 3-6, 14 and 35-48 of the instant application based on claims 1-11 of U.S. Patent No. ‘697.
Thus, the invention as a whole is rendered prima facie obvious over U.S. Patent No. ‘697.
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 08/24/2026 have been fully considered but they are not persuasive. Claims 1, 3-6, 14, 35-48 are 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).
Conclusion
No claims are in condition for allowance.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Rosenberg et al. (2016). Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet (London, England), 387(10031), 1909–1920. (Claim 1-Pg. 1918, Col. 2, Para. 2 clusters I and II).
Funt, S. A., & Rosenberg, J. E. (2017). Systemic, perioperative management of muscle-invasive bladder cancer and future horizons. Nature reviews Clinical oncology, 14(4), 221-234. (claims 44-48- (entire document) improving treatments of MIBC)
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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