DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments and Arguments
2. Claims 1-5, 8, 9, 14, 19-21, 24, 25, 30 and 38-42 are pending.
Claims 1, 2, 19 and 40-42 have been amended.
Claims 1-5, 8, 9, 14, 19-21, 24, 25, 30 and 38-42 are examined on the merits.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 103
3. The rejection of claim(s) 1, 4, 5, 8, 9, 38 and 40 under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016) is withdrawn in light of Applicant’s amendment to independent claim 1, see In the Claims (page 1) and Remarks, both filed December 19, 2025.
4. The rejection of claim(s) 2, 3, 14 and 41 under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016), Radvanyi, Francois, US 2013/0059303 A1 (published March 7, 2013/ IDS reference 1 submitted January 29, 2021) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016) is withdrawn in light of Applicant’s amendments to independent claim 2, see In the Claims (page 1) and Remarks, both filed December 19, 2025. Claim 44 has been cancelled.
5. The rejection of claim(s) 19-21, 24, 25, 30, 39, 42 and 45 under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016), Radvanyi, Francois, US 2013/0059303 A1 (published March 7, 2013/ IDS reference 1 submitted January 29, 2021) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016) is withdrawn in light of Applicant’s amendment to independent claim 19, see In the Claims (page 4) and Remarks, both filed December 19, 2025. Claim 45 has been cancelled.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
6. Claim(s) 1, 4, 5, 8, 9, 38 and 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of The Cancer Genome Atlas Research Network with Supplemental Information (SI) (Nature 507: 314-322, 20 March 2014 with SI pages 1-122), Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016).
Scott teaches the use of next-generation sequencing (NGS) analysis of urine [cytology materials] from 41 patients [high-risk] HR [non-muscle-invasive urothelial carcinoma] NMIUC, see page 416, Background section; page 417, 2nd column, 2nd full paragraph and Specimens section; and page 419, last paragraph in 2nd column. “The extracted tumor samples…were…prepared with the Memorial Sloan Kettering Integrated Molecular of Actionable Cancer Targets (MSK-IMPACT) assay.”, see sentence bridging pages 418 and 419. “[S]amples included ThinPreps or cytospins from urine cytology slides.”, as well as “[t]umor DNA from cytology slides…”, see page 417, 2nd column including Specimens section; and Sample…and Targeted…sections on pages 418 and 419. “The genomic data obtained from the MSK-IMPACT assay [included] somatic mutations”, such as KDM6A, see Background on page 416; page 419, 1st column, 3rd sentence; Figure 3 on page 420; and supplemental Table. The alterations detected in urine were representative of high-grade urothelial carcinoma of the bladder, flat urothelial carcinoma in situ and high-risk (HR) non-muscle-invasive urothelial carcinoma (NMIUC), see Background on page 416; page 417, 2nd column, 1st paragraph; and Figure 4 on page 421.
Scott does not teach one or more urothelial cancer-associated genes comprising KMT2B, BRCA1, BRCA2, FANCD2, KRAS, RAD51, nor ELF3, FOXA1, FOXQ1, RHOB, RXRA, TXNIP, ZFP36L1, PAIP1, KLF5, EP300, NRAS or KDM6A, nor EP300, STAG2. Scott does not teach the assessment of such urothelial cancer-associated genes allows one to distinguish between cancer types, as well as treatments, wherein surgery is performed.
However, the Network teaches mutational signatures, molecular alterations, as well as molecular characterization of urothelial bladder carcinoma, see entire document. Figure 1b teaches many of the genes are statistically significantly mutated in bladder cancer including KDM6A, EP300, STAG2, RXRA, ELF3, TXNIP, FOXQ1, RHOB, FOXA1, PAIP1, ZFP36L1, in addition to NRAS, see page 315, column 1, 1st paragraph; page 316, Figure 1b and its caption; page 316, paragraph bridging both columns; and page 319, Figure 4a., Figure4b., Figure 5b and their corresponding captions.
Ali teaches methods of determining the presence of a mutated nucleic acid molecule from a biological sample and therapeutic methods, see page 4, sections 0041 and 0044-0050. Several genomic alterations including BRCA1, KRAS and MLL2 are identified in urothelial and/or a micropapillary carcinoma, see page 6, sections 0074, 0075, 0078, 0080; page 8, section 0095; and Figures 1, 2C, 4A, 4H-4K, 4M, 4O, 4S, 4U, 4W, 4Y, 6. MLL2 is also art known as KMT2B.
Fabrizio teaches somatic mutations within genes from a patient obtained biological sample including urine, see page 30, lines 16-21; and Table 1 on page 47. The genes include BRCA1, BRCA2, FANCD2, KRAS, RAD51, as well as EP300, STAG2, NRAS, and KDM6A, see Table 1 on page 47. Fabrizio also teaches cancers expressing these somatic mutations are “… bladder cancer (e.g., urothelial bladder cancer (e.g., transitional cell or urothelial carcinoma, non-muscle invasive bladder cancer, muscle-invasive bladder cancer, and metastatic bladder cancer) and non-urothelial bladder cancer) and sampled from urine, page 26, lines 5-20; page 30, lines 16-21; and page 35, lines 14-17.
Additionally, Murakami teaches urine samples comprising urothelial cancer-associated genes and DNA within urine are used to detect and distinguish several types of cancers including bladder cancer, renal pelvis cancer, mild and advanced urothelial cancer, non-muscle invasive early stage urothelial cancer, adenocarcinoma and ureter cancer, see abstract; caption underneath Table 3 spanning columns 9 and 10; and claims 1 and 8-14.
Murakami also teaches treatment can be administered once the expression level of markers is determined, see claim 1 in column 69. Treatment consists of tumor resection, surgery, chemotherapy and cystectomy, see claim 1 in column 69. It is art known cystectomy is surgical removal of all or part of the bladder.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of Scott with secondary references, Ali, Fabrizio and Murakami to assay a urine sample for candidate tumor suppressor genes and identify mutations involved in bladder carcinoma that initiate and/or impact tumor behavior, see all documents in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that its routine in the art to obtain a urine sample and analyze expression patterns to diagnose various urothelial cancers in order to tailor the treatment for each type of urothelial cancer, see all references in their entireties; and in particular, Scott’s Discussion beginning on page 422; Fabrizio, A. Diagnostic…segment spanning pages 43-49; and Murakami’s abstract.
One of ordinary skill in the art would have also been motivated to do so with a reasonable expectation of success by all the references and in particular, Scott, wherein “[u]rine specimens can provide a genomic signature of [high-risk non-muscle-invasive urothelial carcinoma] HR NMIUC that can help with the molecular classification of [urothelial carcinoma of the bladder] UCB and can tailor the treatment of patients with HR NMIUC”, see page 425, 1st column; Fabrizio, page 66, line 24-page 68, line 9; and Murakami, column 17, line 59-column 18, line 20; and all references in their entirety.
7. Claim(s) 2, 3, 14 and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of The Cancer Genome Atlas Research Network with Supplemental Information (SI) (Nature 507: 314-322, 20 March 2014 with SI pages 1-122), Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016), Radvanyi, Francois, US 2013/0059303 A1 (published March 7, 2013/ IDS reference 1 submitted January 29, 2021) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016).
Scott teaches the use of next-generation sequencing (NGS) analysis of urine [cytology materials] from 41 patients [high-risk] HR [non-muscle-invasive urothelial carcinoma] NMIUC, see page 416, Background section; page 417, 2nd column, 2nd full paragraph and Specimens section; and page 419, last paragraph in 2nd column. “The extracted tumor samples…were…prepared with the Memorial Sloan Kettering Integrated Molecular of Actionable Cancer Targets (MSK-IMPACT) assay.”, see sentence bridging pages 418 and 419. “[S]amples included ThinPreps or cytospins from urine cytology slides.”, as well as “[t]umor DNA from cytology slides…”, see page 417, 2nd column including Specimens section; and Sample…and Targeted…sections on pages 418 and 419. “The genomic data obtained from the MSK-IMPACT assay [included] somatic mutations”, such as KDM6A, see Background on page 416; page 419, 1st column, 3rd sentence; Figure 3 on page 420; and supplemental Table.
The alterations detected in urine were representative of high-grade urothelial carcinoma of the bladder, flat urothelial carcinoma in situ and high-risk (HR) non-muscle-invasive urothelial carcinoma (NMIUC), see Background on page 416; page 417, 2nd column, 1st paragraph; and Figure 4 on page 421.
Scott does not teach one or more urothelial cancer-associated genes comprising KMT2B, BRCA1, BRCA2, FANCD2, KRAS, RAD51, ELF3, FOXA1, FOXQ1, RHOB, RXRA, TXNIP, ZFP36L1, PAIP1, KLF5 nor EP300, STAG2 and NRAS. Scott does not teach the assessment of such urothelial cancer-associated genes allows one to distinguish between cancer types, as well as treatments, wherein surgery is performed.
Scott does not teach comparing a subject’s urine mutation profile obtained prior to and after administration of neoadjuvant therapy, nor subsequent surgery. Scott does not teach neoadjuvant therapy that is cystectomy, chemotherapy or immunotherapy.
Scott also does not teach the taught method is able to be implemented in individuals with renal pelvis cancer and ureter cancer.
However, the Network teaches mutational signatures, molecular alterations, as well as molecular characterization of urothelial bladder carcinoma, see entire document. Figure 1b teaches many of the genes are statistically significantly mutated in bladder cancer including KDM6A, EP300, STAG2, RXRA, ELF3, TXNIP, FOXQ1, RHOB, FOXA1, PAIP1, ZFP36L1, in addition to NRAS, see page 315, column 1, 1st paragraph; page 316, Figure 1b and its caption; page 316, paragraph bridging both columns; and page 319, Figure 4a., Figure4b., Figure 5b and their corresponding captions.
Ali teaches methods of determining the presence of a mutated nucleic acid molecule from a biological sample and therapeutic methods, see page 4, sections 0041 and 0044-0050. Several genomic alterations including BRCA1, KRAS and MLL2 are identified in urothelial and/or a micropapillary carcinoma, see page 6, sections 0074, 0075, 0078, 0080; page 8, section 0095; and Figures 1, 2C, 4A, 4H-4K, 4M, 4O, 4S, 4U, 4W, 4Y, 6. MLL2 is also art known as KMT2B.
Fabrizio teaches somatic mutations within genes from a patient obtained biological sample including urine, see page 30, lines 16-21; and Table 1 on page 47. The genes include BRCA1, BRCA2, FANCD2, KRAS, RAD51, as well as EP300, STAG2, NRAS, and KDM6A, Table 1. Fabrizio also teaches cancers expressing these somatic mutations are “… bladder cancer (e.g., urothelial bladder cancer (e.g., transitional cell or urothelial carcinoma, non-muscle invasive bladder cancer, muscle-invasive bladder cancer, and metastatic bladder cancer) and non-urothelial bladder cancer) and sampled from urine, page 26, lines 5-20; page 30, lines 16-21; and page 35, lines 14-17.
Radvanyi teaches administering an adjuvant or neoadjuvant anti-tumoral therapy to a subject based on detecting a mutation in a urine sample, see section 0010, page 1; section 0046, page 3; claims 3-6 on page 16. Radvanyi teaches a method for providing information to a subject known to affected with bladder cancer having a mutation and relaying information regarding a follow-up strategy, page 5, sections 0072-0075; and page 6, sections 0078-0082 and 0085. The adjuvant and neoadjuvant treatments taught by Radvanyi include partial or radical cystectomy, chemotherapy (i.e. cisplatin, gemcitabine, docetaxel, doxorubicin, methotrexate, vincristine), BCG or immunotherapy, see last sentence in section 0010 on page 1; sections 0066-0068, 0073, 0074, page 5; and claims 4-6 on page 16. “Surgery for bladder cancer may include transurethral resection of the bladder, i.e. cancerous bladder tissue is removed through the urethra, and partial or complete removal of the bladder (radical cystectomy)., page 5, section 0066.
Additionally, Murakami teaches urine samples comprising urothelial cancer-associated genes and DNA within urine are used to detect, monitor and distinguish several types of cancers including bladder cancer, renal pelvis cancer, mild and advanced urothelial cancer, non-muscle invasive early stage urothelial cancer, adenocarcinoma and ureter cancer, see columns 7 and 8; caption underneath Table 3 spanning columns 9 and 10; paragraph bridging columns 15 and 16; last paragraph in column 16; column 17, last full paragraph; line 30 in column 20-line 35 in column 21; and claims 1 and 8-14.
Murakami also teaches treatment can be administered once the expression level of markers is determined, see claim 1 in column 69. Treatment consists of tumor resection, surgery, chemotherapy and cystectomy, see claim 1 in column 69. It is art known cystectomy is surgical removal of all or part of the bladder.
Murakami teaches “a medical professional may order a test and use the results in making a diagnosis or treatment plan for a patient. For example, in some embodiments a medical professional may collect a sample from a patient or have the patient otherwise provide a sample (or samples) for testing. The medical professional may then send the sample to a laboratory or other third party capable of processing and testing the sample... Testing may provide quantitative and/or qualitative information about the sample, including data related to the presence of a urothelial disease. Once this information is collected, in some embodiments the information may be compared to control information (e.g., to a baseline or normal population) to determine whether the test results demonstrate a difference between the patient's sample and the control. After the information is compared and analyzed, it is returned to the medical professional for additional analysis. Alternatively, the raw data collected from the tests may be returned to the medical professional so that the medical professional or other hospital staff can perform any applicable comparisons and analyses. Based on the results of the tests and the medical professional’s analysis, the medical professional may decide how to treat or diagnose the patient (or optionally refrain from treating).”, see column 22, lines 12-39.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of the Scott with the Network, Ali, Fabrizio, Radvanyi and Murakami to assess a multiplicity of urothelial bladder carcinoma genes within a urine sample for mutations and genomic alterations, see all documents in their entireties.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of the Network with all references to assess known urothelial bladder carcinoma genes, “including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways”, see abstract on page 315; and entire document. These genes are known to have recurrent somatic mutations, see paragraph bridging pages 315 and 316.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references and in particular, the Network given prior to 2018, “[t]his study identifies a number of mutations and regions of copy number variation that involve genes not previously reported as altered in a significant fraction of bladder cancers. It also identifies potential therapeutic targets in most of the samples analysed.”, see the Network, page
315, column 1, 2nd paragraph; and all references in their entirety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of the Network with all references to assess known urothelial bladder carcinoma genes, “including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways”, see abstract on page 315; and entire document. These genes are known to have recurrent somatic mutations, see paragraph bridging pages 315 and 316.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references and in particular, the Network given prior to 2018, “[t]his study identifies a number of mutations and regions of copy number variation that involve genes not previously reported as altered in a significant fraction of bladder cancers. It also identifies potential therapeutic targets in most of the samples analysed.”, see the Network, page
315, column 1, 2nd paragraph; and all references in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that its routine in the art to analyze expression patterns to diagnose various urothelial cancers in order to tailor the treatment for each type of urothelial cancer, see all references in their entireties; and in particular, Scott’s Discussion beginning on page 422; Fabrizio abstract; Radvanyi, section 0044-0063, spanning pages 3-5; and Murakami’s abstract.
One of ordinary skill in the art would have also been motivated to do so with a reasonable expectation of success by all the references, see all references in their entireties.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of all references to assess and compare a subject’s urine mutation profile collected before and after anti-bladder cancer treatment. As the information yielded from this assessment allows one to determine the best treatment plan, determine if treatment is required or not, determine if additional treatment is necessary, as well as knowing if no mutations are detected as proposed in Muramaki, a clinician should refrain from treatment, see column 22, lines 33-39; and all documents in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that particular mutations are indicative of particular types and status of bladder cancer, prognosis and survival, as well as no indication of mutations means no unnecessary treatment is performed, see all references in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that particular mutations are indicative of particular types and status of bladder cancer, prognosis and survival, see all references in their entirety.
8. Claim(s) 19-21, 24, 25, 30, 39 and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Scott, S.N. et al., (Cancer Cytopathology, 125(6): 416-426, published online March 24, 2017/ IDS reference 9 submitted January 29, 2021), and further in view of The Cancer Genome Atlas Research Network with Supplemental Information (SI) (Nature 507: 314-322, 20 March 2014 with SI pages 1-122), Ali et al., US 2015/0023965 A1 (published January 22, 2015), Fabrizio et al., WO 2018/068028 A1 (effectively filed 06 October 2016), Radvanyi, Francois, US 2013/0059303 A1 (published March 7, 2013/ IDS reference 1 submitted January 29, 2021) and Murakami et al., US 11,028,443 B2 (effective filing date, August 30, 2016).
Scott teaches the use of next-generation sequencing (NGS) analysis of urine [cytology materials] from 41 patients [high-risk] HR [non-muscle-invasive urothelial carcinoma] NMIUC, see page 416, Background section; page 417, 2nd column, 2nd full paragraph and Specimens section; and page 419, last paragraph in 2nd column. “The extracted tumor samples…were…prepared with the Memorial Sloan Kettering Integrated Molecular of Actionable Cancer Targets (MSK-IMPACT) assay.”, see sentence bridging pages 418 and 419. “[S]amples included ThinPreps or cytospins from urine cytology slides.”, as well as “[t]umor DNA from cytology slides…”, see page 417, 2nd column including Specimens section; and Sample…and Targeted…sections on pages 418 and 419. “The genomic data obtained from the MSK-IMPACT assay [included] somatic mutations”, such as KDM6A, see Background on page 416; page 419, 1st column, 3rd sentence; Figure 3 on page 420; and supplemental Table. The alterations detected in urine were representative of high-grade urothelial carcinoma of the bladder, flat urothelial carcinoma in situ and high-risk (HR) non-muscle-invasive urothelial carcinoma (NMIUC), see Background on page 416; page 417, 2nd column, 1st paragraph; and Figure 4 on page 421.
Scott does not teach one or more urothelial cancer-associated genes comprising KMT2B, BRCA1, BRCA2, FANCD2, KRAS, RAD51, ELF3, FOXA1, FOXQ1, RHOB, RXRA, TXNIP, ZFP36L1, PAIP1, KLF5 nor EP300, STAG2 and NRAS. Scott does not teach the assessment of such urothelial cancer-associated genes allows one to distinguish between cancer types, as well as treatments, wherein surgery is performed.
Scott does not teach administering neoadjuvant therapy, which is cystectomy, chemotherapy or immunotherapy. Scott does not teach monitoring the efficacy of neoadjuvant therapy comprising comparing a subject’s urine mutation profile before and after administration of neoadjuvant therapy, comparing the presence of one or more mutations in one or more urothelial cancer-associated genes between the two assessments and proceeding with surgery once it is evaluated both assessments have the presence of the same one or more mutations in the one or more urothelial cancer-associated genes.
Scott also does not teach the taught method is able to be implemented in individuals with renal pelvis cancer and ureter cancer.
However, the Network teaches mutational signatures, molecular alterations, as well as molecular characterization of urothelial bladder carcinoma, see entire document. Figure 1b teaches many of the genes are statistically significantly mutated in bladder cancer including KDM6A, EP300, STAG2, RXRA, ELF3, TXNIP, FOXQ1, RHOB, FOXA1, PAIP1, ZFP36L1, in addition to NRAS, see page 315, column 1, 1st paragraph; page 316, Figure 1b and its caption; page 316, paragraph bridging both columns; and page 319, Figure 4a., Figure4b., Figure 5b and their corresponding captions.
Ali teaches methods of determining the presence of a mutated nucleic acid molecule from a biological sample and therapeutic methods, see page 4, sections 0041 and 0044-0050. Several genomic alterations including BRCA1, KRAS and MLL2 are identified in urothelial and/or a micropapillary carcinoma, see page 6, sections 0074, 0075, 0078, 0080; page 8, section 0095; and Figures 1, 2C, 4A, 4H-4K, 4M, 4O, 4S, 4U, 4W, 4Y, 6. MLL2 is also art known as KMT2B.
Fabrizio teaches somatic mutations within genes from a patient obtained biological sample including urine, see page 30, lines 16-21; and Table 1 on page 47. The genes include BRCA1, BRCA2, FANCD2, KRAS, RAD51, as well as EP300, STAG2, NRAS, and KDM6A, Table 1. Fabrizio also teaches cancers expressing these somatic mutations are “… bladder cancer (e.g., urothelial bladder cancer (e.g., transitional cell or urothelial carcinoma, non-muscle invasive bladder cancer, muscle-invasive bladder cancer, and metastatic bladder cancer) and non-urothelial bladder cancer) and sampled from urine, page 26, lines 5-20; page 30, lines 16-21; and page 35, lines 14-17.
Radvanyi teaches administering an adjuvant or neoadjuvant anti-tumoral therapy to a subject based on detecting a mutation in a urine sample, see section 0010, page 1; section 0046, page 3; claims 3-6 on page 16. Radvanyi teaches a method for providing information to a subject known to affected with bladder cancer having a mutation and relaying information regarding a follow-up strategy, page 5, sections 0072-0075; and page 6, sections 0078-0082 and 0085. The adjuvant and neoadjuvant treatments taught by Radvanyi include partial or radical cystectomy, chemotherapy (i.e. cisplatin, gemcitabine, docetaxel, doxorubicin, methotrexate, vincristine), BCG or immunotherapy, see last sentence in section 0010 on page 1; sections 0066-0068, 0073, 0074, page 5; and claims 4-6 on page 16. “Surgery for bladder cancer may include transurethral resection of the bladder, i.e. cancerous bladder tissue is removed through the urethra, and partial or complete removal of the bladder (radical cystectomy).”, page 5, section 0066. The ability to assess the mutations at different times points permits monitoring of the levels, thereby informing one of the efficacy of the treatments.
Additionally, Murakami teaches urine samples comprising urothelial cancer-associated genes and DNA within urine are used to detect, monitor and distinguish several types of cancers including bladder cancer, renal pelvis cancer, mild and advanced urothelial cancer, non-muscle invasive early stage urothelial cancer, adenocarcinoma and ureter cancer, see columns 7 and 8; caption underneath Table 3 spanning columns 9 and 10; paragraph bridging columns 15 and 16; last paragraph in column 16; column 17, last full paragraph; line 30 in column 20-line 35 in column 21; and claims 1 and 8-14.
Murakami also teaches treatment can be administered once the expression level of markers is determined, see claim 1 in column 69. Treatment consists of tumor resection, surgery, chemotherapy and cystectomy, see claim 1 in column 69. It is art known cystectomy is surgical removal of all or part of the bladder. Assessment of the said levels at different increments of time allows the clinician to monitor the efficacy of neoadjuvant treatment.
Murakami teaches “a medical professional may order a test and use the results in making a diagnosis or treatment plan for a patient. For example, in some embodiments a medical professional may collect a sample from a patient or have the patient otherwise provide a sample (or samples) for testing. The medical professional may then send the sample to a laboratory or other third party capable of processing and testing the sample... Testing may provide quantitative and/or qualitative information about the sample, including data related to the presence of a urothelial disease.
Once this information is collected, in some embodiments the information may be compared to control information (e.g., to a baseline or normal population) to determine whether the test results demonstrate a difference between the patient's sample and the control. After the information is compared and analyzed, it is returned to the medical professional for additional analysis. Alternatively, the raw data collected from the tests may be returned to the medical professional so that the medical professional or other hospital staff can perform any applicable comparisons and analyses. Based on the results of the tests and the medical professional’s analysis, the medical professional may decide how to treat or diagnose the patient (or optionally refrain from treating).”, thereby monitoring the efficacy of the all treatments, see paragraph bridging columns 17 and 18; and column 22, lines 12-39.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of the Scott with Ali, Fabrizio, Radvanyi and Murakami to assess a multiplicity of urothelial bladder carcinoma genes within a urine sample for mutations and genomic alterations, see all documents in their entireties.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of the Network with all references to assess known urothelial bladder carcinoma genes, “including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways”, see abstract on page 315; and entire document. These genes are known to have recurrent somatic mutations, see paragraph bridging pages 315 and 316. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references and in particular, the Network given prior to 2018, “[t]his study identifies a number of mutations and regions of copy number variation that involve genes not previously reported as altered in a significant fraction of bladder cancers. It also identifies potential therapeutic targets in most of the samples analysed.”, see the Network, page 315, column 1, 2nd paragraph; and all references in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references and in particular, the Network given prior to 2018, “[t]his study identifies a number of mutations and regions of copy number variation that involve genes not previously reported as altered in a significant fraction of bladder cancers. It also identifies potential therapeutic targets in most of the samples analysed.”, see the Network, page 315, column 1, 2nd paragraph; and all references in their entirety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of all references to assess and compare a subject’s urine mutation profile collected before and after anti-bladder cancer treatment to determine if treatment was required or not, knowing if no mutations are detected it is proposed in Muramaki, a clinician will refrain from treatment, see column 22, lines 33-39; and all documents in their entirety.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that particular mutations are indicative of particular types and status of bladder cancer, prognosis and survival, as well as no indication of mutations means no unnecessary treatment performed, see all references in their entirety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to implement the teachings of all references to compare a subject’s urine mutation profile collected before and after anti-bladder cancer treatment to determine the efficacy of the neoadjuvant treatment to arrive at treatment decisions, such as the best treatment plan and determine if additional treatment is necessary. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by all the references that particular mutations are indicative of particular types and status of bladder cancer, prognosis and survival, see all references in their entirety.
Conclusion
9. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached on 8AM-8PM, Monday through Friday.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
29 January 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643