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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 03/18/2026 has been entered.
Claims Status
Claims 1-4 & 10-17 filed on 03/18/2026 are pending. Claims 5-9 are withdrawn from consideration as being drawn to a non-elected invention. Claims 1 & 10 are currently under examination directed to the elected species of position 111,813,690 on chromosome 1 claims 1 & 10 (see response dated 03/25/2025). The species of positions 91,182,528 and 91,182,534 on chromosome 1 is rejoined in claims 1 & 10. The addition of new claims 15-17 in the response filed on 03/18/2026 is acknowledged. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-4 & 15-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitations of “urothelial cancer” in lines 34, 35, 36, & 38 of the claim is unclear if it is meant to refer back to upper urinary tract urothelial carcinoma (UTUC) or not.
Regarding claim 15, the recitations of “urothelial cancer” in line 2 of the claim is unclear if it is meant to refer back to upper urinary tract urothelial carcinoma (UTUC) or not.
Regarding claim 16, the recitation of “urothelial cancer” in line 2 of the claim is unclear if it is meant to refer back to upper urinary tract urothelial carcinoma (UTUC) or not.
Regarding claim 17, the recitation of “urothelial cancer” in line 2 of the claim is unclear if it is meant to refer back to upper urinary tract urothelial carcinoma (UTUC) or not.
Claims 2-4 are rejected due to their dependence on claim 1.
Claim Rejections - 35 USC § 101
Claims 1-4 & 10-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for identifying upper urinary tract urothelial carcinoma in a cell/tissue or subject through detecting a DNA methylation level of at least one CpG site selected from a group and then determining whether the cell/tissue or subject has upper urinary tract urothelial carcinoma on when DNA methylation level is increased or decreased. This recitation is a natural correlation between DNA methylation level of at least on CpG site and that the cell/tissue or subject has upper urinary tract urothelial carcinoma. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites identifying upper urinary tract urothelial carcinoma in a cell/tissue or subject and determining that the subject has upper urinary urothelial carcinoma which are recitations of abstract ideas because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of detecting DNA methylation level of at least one CpG site selected from a group in genomic DNA and treating the genomic DNA with bisulfite, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
Although the claims recite “treating the cells or tissues in a patient having urothelial cancer for urothelial cancer by contacting them with an anti-cancer drug or radiation and/or … surgically”, this step is conditional as it is based on a patient having urothelial cancer. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting methylation level. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
The steps of detecting a DNA methylation level of at least one CpG site in genomic DNA are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Response to Arguments
The response traverses the rejection. The response asserts that claim 1 as amended now requires one or more concrete treatment steps that administer a therapy or an additional diagnostic procedure to a patient having cells or tissues with urothelial cancer and to see Examples 9 and 43 of the Guidelines. Further, the response asserts that the claims go on to administering a specific treatment, such as those described at the end of claim 1, to a diagnosed patient and add meaningful limits and integrate the exception into a diagnostic and treatment process. Further, the response asserts that treating a patient diagnosed with UTUC identified by the diagnostic steps simply reflects the inherent, conventional use of the diagnostic result and therefore does not introduced new matter. This argument has been thoroughly reviewed but was not found persuasive. First, as discussed further above, although the claims recite “treating the cells or tissues in a patient having urothelial cancer for urothelial cancer by contacting them with an anti-cancer drug or radiation and/or … surgically”, this step is conditional as it is based on a patient having urothelial cancer. Accordingly, these generally recited elements are considered nothing more than instructions to apply the law of nature because no particular conditions are required by the step of detecting methylation level. As such, the “administering” step is merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294. Further, the treatment with an anti-cancer drug or radiation or surgically is very broad and encompasses a wide range of possible treatments and therefore are not meaningful constraints on the treatment such that a particular treatment consideration would apply because it is not limited to any particular cancer treatment (see example 49 of 2024 Guidance Update on Patent Subject Matter Eligibility). Second, not introduced new matter is not a standard for subject matter eligibility under 35 USC 101.
The response also asserts that claims 1, 4, & 10 do not simply recite the discovery of a correlation between methylation at a specific CpG site and UTUC and instead, they require specific, concrete, laboratory steps performed with a limited number of biological methylation markers and thus the claimed methods provide a practical application of the alleged judicial exception by specifically targeting defined genomic regions for diagnostic purposes. Further, the response asserts that the claims are not an abstract observation or mental process because they require the physical act of detecting methylation at specific positions which involves technical steps and laboratory manipulation. Further, the response asserts that the argument that the claim language does not integrate the method into a practical application because it represent mere data gathering cannot be sustained in light of the amendment to claim 1 to require a concrete, practical treatment step. This argument has been thoroughly reviewed but was not found persuasive. First, as discussed further above and previously, while the claims recite steps of detecting DNA methylation level of at least one CpG site selected from a group in genomic DNA and treating the genomic DNA with bisulfite, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method. Second, metal processes, concepts performed in the human mind, such as observation, evaluation, judgment, and opinion are directed towards abstract ideas (see MPEP 2106.04(a)(3)). Further, as discussed further above the treatment with an anti-cancer drug or radiation or surgically is very broad and encompasses a wide range of possible treatments and therefore are not meaningful constraints on the treatment such that a particular treatment consideration would apply because it is not limited to any particular cancer treatment (see example 49 of 2024 Guidance Update on Patent Subject Matter Eligibility).
The response also asserts that new claim 14 requires the use of primers or probes further distinguishing it from a method recited no more than a natural correlation and has been amended to highlight the active step. This argument has been thoroughly reviewed but was not found persuasive as the use of a primer or a probe is generally recited (i.e., use of general and not specific probes) and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited.
The response also asserts that dependent claim 2 recites chemical modification of the DNA prior to detection of methylation, claim 3 is directed to specific modes of detecting methylation, and claim 4 is directed to DNA collected from UTUC in urine which further distinguish the method and materials from those found in nature. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above and because the steps of detecting a DNA methylation level of at least one CpG site in genomic DNA are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)).
The response also asserts that there is no preemption, as others could use different markers or measuring, comparing, determining, and selecting parameters and criteria, etc. for detecting UTUC. This argument has been thoroughly reviewed but was not found persuasive as preemption is not a standard for subject matter eligibility under 35 USC 101.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 1-4 & 14-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fujimoto (Fujimoto et al.; Vol. 108, page 1, April 15th, 2019), as cited in the IDS dated 06/27/2022, in view of Yoon (Yoon et al.; Oncology Reports, Vol. 35, pages 1195-1203, October 2015), Guo (Guo et al.; Urologic Oncology, Vol. 36, pages e15-e23, April 2018), as cited on the IDS dated 07/22/2024, and Cai (Cai, Liu, & Wu; Surgical Oncology, Vol. 20, pages 43-55, October 2009).
Regarding amended claim 1, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Fujimoto teaches the genome-wide DNA methylation analysis of upper urinary tract urothelial carcinoma tissue (cell or tissue containing upper urinary urothelial cell) and bladder urothelial carcinoma tissue using the 450K Infinium array (pg. 1 only paragraph lines 1-18), in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1, and then diagnosing upper urinary tract urothelial carcinoma between control and upper urinary tract urothelial carcinoma with the DNA methylation level (determining whether the cell or tissue has upper urinary tract carcinoma on the basis of the detected DNA methylation level).
Fujimoto does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7 or treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Cai teaches various treatment methods for patients with UTUC comprising treatment with adjuvant therapy, immunotherapy, chemotherapy, and radiotherapy (treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation) (abstract lines 1-12; pg. 50 column 1 2nd full paragraph lines 1-13). Cai also teaches that various treatments have different safety and effectiveness comprising treatment with immunotherapy (an anti-cancer drug) providing an effective treatment in patients with UTUC and treatment with chemotherapy and radiotherapy (an anti-cancer drug and radiation) providing improvement in UTUC reoccurrence rates (abstract lines 9-12).
Fujimoto, Yoon, Guo, and Cai are considered to be analogous to the claimed invention because they are all in the same field of detection of detection and analysis methods in urothelial and bladder carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC) and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the treatment of patients having UTUC with an anti-cancer drug or radiation as taught in Cai because Cai teaches that this method would provide treatments comprising treatment with immunotherapy (an anti-cancer drug) providing an effective treatment in patients with UTUC and treatment with chemotherapy and radiotherapy (an anti-cancer drug and radiation) providing improvement in UTUC reoccurrence rates.
Regarding claims 2 & 3, Yoon teaches the genomic DNA was bisulfite converted (genomic DNA treated with bisulfite) to quantify the DNA methylation at approximately 27,578 CpG sites across the genome (detecting the methylation level of at least one CpG site) using the Infinium-based Human Methylation27 BeadChip array (pg. 1196 paragraph bridging column 1 & 2 lines 1-10) (see claim 2). Yoon also teaches the DNA methylation level was quantified through the Infinium-based HumanMethylation27 BeadChip Arrays (performed using a bead array method) (pg. 1196 paragraph bridging column 1 & 2 lines 1-10) and further validated with pyrosequencing (pg. 1199 column 1 1st full paragraph lines 1-4) (see claim 3).
Regarding claim 4, Fujimoto teaches that the DNA methylation quantification in a urine specimen is expected to enable diagnosis of upper urinary tract urothelial carcinoma (DNA is isolated from an upper urinary tract urothelial cell contained in urine).
Regarding amended claim 14, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Fujimoto teaches the genome-wide DNA methylation analysis of upper urinary tract urothelial carcinoma tissue (cell or tissue containing upper urinary urothelial cell) and bladder urothelial carcinoma tissue using the 450K Infinium array (pg. 1 only paragraph lines 1-18), in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1 and the Infinium probe IDs including cg07197785 (forward primer is 24 bases and reverse primer is 22 bases) that is specific to position 111,813,690 on chromosome 1 (use of a probe which has a chain length of at least 12 bases and hybridizes to at least one CpG site selected from the group including position 111,813,690 on chromosome 1), and then diagnosing upper urinary tract urothelial carcinoma between control and upper urinary tract urothelial carcinoma with the DNA methylation level (determining whether the subject has upper urinary tract carcinoma on the basis of the detected DNA methylation level).
Fujimoto does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, in which the genomic DNA was bisulfite converted, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Fujimoto, Yoon, Guo, and Cai are considered to be analogous to the claimed invention because they are all in the same field of detection of detection and analysis methods in urothelial and bladder carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the detection of increased DNA methylation levels in BARHL2 on bisulfite treated genomic DNA (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC).
Regarding new claims 15-17, Cai teaches various treatment methods for patients with UTUC comprising treatment with adjuvant therapy, immunotherapy, chemotherapy, and radiotherapy (treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation) (abstract lines 1-12; pg. 50 column 1 2nd full paragraph lines 1-13).
Claim(s) 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fujimoto (Fujimoto et al.; Vol. 108, page 1, April 15th, 2019), as cited in the IDS dated 06/27/2022, in view of Yoon (Yoon et al.; Oncology Reports, Vol. 35, pages 1195-1203, October 2015) and Guo (Guo et al.; Urologic Oncology, Vol. 36, pages e15-e23, April 2018), as cited on the IDS dated 07/22/2024.
Regarding claim 10, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Fujimoto teaches the genome-wide DNA methylation analysis of upper urinary tract urothelial carcinoma tissue (cell or tissue containing upper urinary urothelial cell) and bladder urothelial carcinoma tissue using the 450K Infinium array (pg. 1 only paragraph lines 1-18), in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1, and then diagnosing upper urinary tract urothelial carcinoma between control and upper urinary tract urothelial carcinoma with the DNA methylation level (determining whether the subject has upper urinary tract carcinoma on the basis of the detected DNA methylation level).
Fujimoto does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Fujimoto, Yoon, and Guo are considered to be analogous to the claimed invention because they are all in the same field of detection of DNA methylation levels in carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC).
Regarding claims 11 & 12, Yoon teaches the genomic DNA was bisulfite converted (genomic DNA treated with bisulfite) to quantify the DNA methylation at approximately 27,578 CpG sites across the genome (detecting the methylation level of at least one CpG site) using the Infinium-based Human Methylation27 BeadChip array (pg. 1196 paragraph bridging column 1 & 2 lines 1-10) (see claim 11). Yoon also teaches the DNA methylation level was quantified through the Infinium-based HumanMethylation27 BeadChip Arrays (performed using a bead array method) (pg. 1196 paragraph bridging column 1 & 2 lines 1-10) and further validated with pyrosequencing (pg. 1199 column 1 1st full paragraph lines 1-4) (see claim 12).
Regarding claim 13, Fujimoto teaches that the DNA methylation quantification in a urine specimen is expected to enable diagnosis of upper urinary tract urothelial carcinoma (DNA is isolated from an upper urinary tract urothelial cell contained in urine).
Claim(s) 1-4 & 14-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kitchen (Kitchen et al.; Epigenetics, Vol. 11, pages 237-246, April 2016), in view of Yoon (Yoon et al.; Oncology Reports, Vol. 35, pages 1195-1203, October 2015), Guo (Guo et al.; Urologic Oncology, Vol. 36, pages e15-e23, April 2018), as cited on the IDS dated 07/22/2024, and Cai (Cai, Liu, & Wu; Surgical Oncology, Vol. 20, pages 43-55, October 2009).
Regarding amended claim 1, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Kitchen teaches a genome-wide methylation analysis of genomic DNA in high-grade non-muscle invasive bladder cancer using the HumanMethylation450 (450k) BeadChip array, in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1, in bladder cancer tumors (tissue or cell containing carcinoma) compared to normal bladder controls (abstract lines 1-19; pg. 243 column 1 2nd full paragraph lines 1-10; pg. 243 paragraph bridging column 1 & 2 lines 1-6) for determining DNA methylation level in the development and progression of tumor types in bladder cancer (determining whether the cell or tissue has carcinoma on the basis of the detected DNA methylation level) (pg. 242-243 paragraph bridging pg. 242 & pg. 243 lines 1-10).
Kitchen does not teach the detection of genome-wide methylation analysis using the HumanMethylation450 BeadChip in upper urinary tract urothelial carcinoma and does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7 or treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV). Yoon also teaches that increased levels of methylation of BARHL2 is significantly associated with tumor size, grade, and stage (pg. 1199 column 1 2nd full paragraph lines 2-11).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Cai teaches various treatment methods for patients with UTUC comprising treatment with adjuvant therapy, immunotherapy, chemotherapy, and radiotherapy (treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation) (abstract lines 1-12; pg. 50 column 1 2nd full paragraph lines 1-13). Cai also teaches that various treatments have different safety and effectiveness comprising treatment with immunotherapy (an anti-cancer drug) providing an effective treatment in patients with UTUC and treatment with chemotherapy and radiotherapy (an anti-cancer drug and radiation) providing improvement in UTUC reoccurrence rates (abstract lines 9-12).
Kitchen, Yoon, Guo, and Cai are considered to be analogous to the claimed invention because they are all in the same field of detection of detection and analysis methods in urothelial and bladder carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in bladder cancer samples using the 450K array in Kitchen to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Yoon teaches that doing so would provide a method to assess tumor size, grade, and stage and to incorporate the detection of DNA methylation levels with this method in upper tract urothelial carcinoma (UTUC) as taught in Guo because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC) and it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the treatment of patients having UTUC with an anti-cancer drug or radiation as taught in Cai because Cai teaches that this method would provide treatments comprising treatment with immunotherapy (an anti-cancer drug) providing an effective treatment in patients with UTUC and treatment with chemotherapy and radiotherapy (an anti-cancer drug and radiation) providing improvement in UTUC reoccurrence rates.
Regarding claim 2, Kitchen teaches the genomic DNA was extracted and then bisulfite converted (genomic DNA treated with bisulfite) to quantify the DNA methylation at approximately 480,000 CpG sites across the genome (detecting the methylation level of at least one CpG site) (pg. 243 column 1 2nd full paragraph lines 1-10; pg. 243 paragraph bridging column 1 & 2 lines 1-6).
Regarding claim 3, Kitchen teaches the DNA methylation level was quantified through the Infinium-based HumanMethylation450 (450K) BeadChip Arrays (performed using a bead array method) (pg. 243 paragraph bridging column 1 & 2 lines 1-6) and further validated with pyrosequencing (pg. 243-244 paragraph bridging pg. 243 & pg. 244 lines 1-6).
Regarding claim 4, Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8).
Regarding amended claim 14, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Kitchen teaches a genome-wide methylation analysis of genomic DNA in high-grade non-muscle invasive bladder cancer using the HumanMethylation450 (450k) BeadChip array, in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1 and the Infinium probe IDs including cg07197785 (forward primer is 24 bases and reverse primer is 22 bases) that is specific to position 111,813,690 on chromosome 1 (use of a probe which has a chain length of at least 12 bases and hybridizes to at least one CpG site selected from the group including position 111,813,690 on chromosome 1), in bladder cancer tumors (tissue or cell containing carcinoma) compared to normal bladder controls and in which the genomic DNA was extracted and then bisulfite converted (abstract lines 1-19; pg. 243 column 1 2nd full paragraph lines 1-10; pg. 243 paragraph bridging column 1 & 2 lines 1-6) for determining DNA methylation level in the development and progression of tumor types in bladder cancer (determining whether the subject has carcinoma on the basis of the detected DNA methylation level) (pg. 242-243 paragraph bridging pg. 242 & pg. 243 lines 1-10).
Kitchen does not teach the detection of genome-wide methylation analysis using the HumanMethylation450 BeadChip in upper urinary tract urothelial carcinoma and does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV). Yoon also teaches that increased levels of methylation of BARHL2 is significantly associated with tumor size, grade, and stage (pg. 1199 column 1 2nd full paragraph lines 2-11).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Kitchen, Yoon, Guo, and Cai are considered to be analogous to the claimed invention because they are all in the same field of detection of detection and analysis methods in urothelial and bladder carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in bladder cancer samples using the 450K array in bisulfite treated genomic DNA in Kitchen to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Yoon teaches that doing so would provide a method to assess tumor size, grade, and stage and to incorporate the detection of DNA methylation levels with this method in upper tract urothelial carcinoma (UTUC) as taught in Guo because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC).
Regarding new claims 15-17, Cai teaches various treatment methods for patients with UTUC comprising treatment with adjuvant therapy, immunotherapy, chemotherapy, and radiotherapy (treating the cells or tissues in a patient having urothelial cancer by contacting them with an anti-cancer drug or radiation) (abstract lines 1-12; pg. 50 column 1 2nd full paragraph lines 1-13).
Claim(s) 10-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kitchen (Kitchen et al.; Epigenetics, Vol. 11, pages 237-246, April 2016), in view of Yoon (Yoon et al.; Oncology Reports, Vol. 35, pages 1195-1203, October 2015) and Guo (Guo et al.; Urologic Oncology, Vol. 36, pages e15-e23, April 2018), as cited on the IDS dated 07/22/2024.
Regarding amended claim 10, the specification, on pg. 47, teaches that the DNA methylation status of the instant application was analyzed using the Infinium Human Methylation 450K BeadChip assay that covers 99% of RefSeq genes and 96% of CpG islands. Kitchen teaches a genome-wide methylation analysis of genomic DNA in high-grade non-muscle invasive bladder cancer using the HumanMethylation450 (450k) BeadChip array, in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1, in bladder cancer tumors (tissue or cell containing carcinoma) compared to normal bladder controls (abstract lines 1-19; pg. 243 column 1 2nd full paragraph lines 1-10; pg. 243 paragraph bridging column 1 & 2 lines 1-6) for determining DNA methylation level in the development and progression of tumor types in bladder cancer (determining whether the subject has carcinoma on the basis of the detected DNA methylation level) (pg. 242-243 paragraph bridging pg. 242 & pg. 243 lines 1-10).
Kitchen does not teach the detection of genome-wide methylation analysis using the HumanMethylation450 BeadChip in upper urinary tract urothelial carcinoma and does not teach wherein the methylation is increased compared to control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or the methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7.
Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV). Yoon also teaches that increased levels of methylation of BARHL2 is significantly associated with tumor size, grade, and stage (pg. 1199 column 1 2nd full paragraph lines 2-11).
Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2).
Kitchen, Yoon, and Guo are considered to be analogous to the claimed invention because they are all in the same field of detection of DNA methylation levels in carcinoma. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in bladder cancer samples using the 450K array in Kitchen to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Yoon teaches that doing so would provide a method to assess tumor size, grade, and stage and to incorporate the detection of DNA methylation levels with this method in upper tract urothelial carcinoma (UTUC) as taught in Guo because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC).
Regarding claim 11, Kitchen teaches the genomic DNA was extracted and then bisulfite converted (genomic DNA treated with bisulfite) to quantify the DNA methylation at approximately 480,000 CpG sites across the genome (detecting the methylation level of at least one CpG site) (pg. 243 column 1 2nd full paragraph lines 1-10; pg. 243 paragraph bridging column 1 & 2 lines 1-6).
Regarding claim 12, Kitchen teaches the DNA methylation level was quantified through the Infinium-based HumanMethylation450 (450K) BeadChip Arrays (performed using a bead array method) (pg. 243 paragraph bridging column 1 & 2 lines 1-6) and further validated with pyrosequencing (pg. 243-244 paragraph bridging pg. 243 & pg. 244 lines 1-6).
Regarding claim 13, Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8).
Response to Arguments
The response traverses the rejection. The response asserts that Fujimoto does not disclose or suggest the direction in which the methylation level changes comparted to a control as disclosed at the bottom of page 7 of the specification and that Fujimoto does not teach wherein the methylation is increased compared to a control at one or more CpG sites included in the marker groups 1, 2, 4, 8, and 9 and/or methylation level is reduced compared to control at one or more CpG sites included in the marker gene groups 3, 5, 6, and 7. Further, the response asserts that Fujimoto does not teach the specific cancer biomarkers required by claim 1 and therefore the test detecting the DNA methylation level at a marker CpG site cannot be performed at all and thus the claimed method can provide superior effects as compared with the method of Fujimoto. These arguments have been thoroughly reviewed but were not found persuasive. First, 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). Further, Fujimoto does teach the genome-wide DNA methylation analysis of upper urinary tract urothelial carcinoma tissue and bladder urothelial carcinoma tissue using the 450K Infinium array, in which the 450K array encompasses all positions listed in claim 1 of the instant application including position 111,813,690 on chromosome 1, therefore teaching the detection of specific methylation sites. Second, Fujimoto is not relied upon to whether increased or decreased methylation of particular markers is indicative in UTUC and instead Yoon is relied upon to teach this limitation.
The response also asserts that Yoon does not suggest detection and treatment of UTUC but is directed to identification of prognostic markers for a different cancer, non-muscle invasive bladder cancer (NMIBC), i.e. urothelial bladder cancer, whereas the present claims are directed to a method for identifying a cell or tissue have UTUC and this Yoon and the present application are different in their objectives and Yoon cannot suggest or provide a reasonable expectation of success for the claimed method because it is directed to a different type of cancer that do not express the same sets of cancer markers and moreover, there is not showing in Yoon that UTUC can be detected and treated based on the specific markers described in claim 1. These arguments have been thoroughly reviewed but were not found persuasive. First, 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). Second, as discussed further above, Guo teaches a method for examining the methylation status in upper tract urothelial carcinoma (UTUC) in DNA samples extracted from cell fragments in urine sample obtained from patients with urothelial carcinoma (pg. e16 paragraph bridging column 1 & 2 lines 1-8; pg. e16 column 2 1st full paragraph lines 1-8). Guo also teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma (abstract methods paragraph lines 1-2; abstract results paragraph lines 1-6; pg. e16 column 1 1st full paragraph lines 1-20). Guo also teaches that urine DNA methylation markers (DNA methylation level) are a reliable, noninvasive, and cost-effective diagnostic tool for bladder carcinoma and UTUC (abstract conclusions paragraph lines 1-2). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting DNA methylation levels in upper urinary tract urothelial carcinoma tissue samples using the 450K array in Fujimoto to incorporate the detection of increased DNA methylation levels in BARHL2 (methylation is increased compared to a control at one or more CpG sites included in marker group 1) as taught in Yoon because Guo teaches that bladder and UTUC share clinical and genomic similarities and that the same panel of DNA methylation biomarkers in urine sediments can be useful for noninvasive and early detection in urothelial carcinoma (UTUC). Therefore, as Guo teaches that due to clinical and genomic similarities in bladder cancer and UTUC that the same panel of DNA methylation biomarkers in urine sediments could be useful for noninvasive and early detection in urothelial carcinoma, there is a reasonable expectation of success for the claimed method.
The response also asserts that Yoon suggests that the DNA methylation level of BARHL2 gene is increased in patients with NMIBC as compared to normal controls and increased in a reoccurrence group compared to a non-reoccurrence group, however, that Yoon ultimately concludes that the methylation status of BARHL2 is not an independent predictive marker of prognosis from NMIBC meaning that BARHL2 gene is not a marker. Further, the response asserts that the Yoon uses the Infinium Human Methylation 27 BeadChip array whereas the claimed method uses the Infinium Methylation 450K BeadChip and therefore the data for BARHL2 gene provided by Yoon is not obtained from cg01921432. Further, the response asserts that the inventors confirmed that the only probe for BARHL2 gene in the Human Methylation 27 BeadChip used by Yoon is cg1724310 and calculation based on the dataset results for the first six samples presumed to be normal controls is 0.12 and for the subsequent 18 samples presumed to be bladder cancer patients is 0.7 and therefore Yoon does not provide a reasonable expectation of success for the specific probes used in the invention. These arguments have been thoroughly reviewed but were not found persuasive. First, 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). Second, 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., use of specific cg probes and specific BeadChip arrays) 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). Further, Fujimoto teaches the genome-wide DNA methylation analysis of upper urinary tract urothelial carcinoma tissue and bladder urothelial carcinoma tissue using the 450K Infinium array (pg. 1 only paragraph lines 1-18), and then diagnosing upper urinary tract urothelial carcinoma between control and upper urinary tract urothelial carcinoma with the DNA methylation level. Further, the claims recite determining that the cell or tissue has UTUC when the methylation level is increased compared to one or more CpG sites included in specific marker groups in which Yoon teaches detection of DNA methylation in non-muscle invasive bladder cancer with a genome-wide Illumina Infinium assay in which increased methylation in BARHL2 gene compared to control, which is consistent the instant specification at positions 91,182,528 and 91,182,534 on chromosome 1 corresponding to BARHL2 gene in marker group 1 according to the instant specification (Table 1 of the instant specification) (methylation is increased compared to a control at one or more CpG sites included in marker group 1) (abstract lines 1-13; pg. 1196 column 1 1st full paragraph lines 1-4; pg. 1199 column 1 2nd full paragraph lines 2-11; Table IV). Third, applicant’s arguments cannot take place of evidence in the record.
The response also asserts the Guo does not teach the specific markers required by claim 1 and that one would not have had a reasonable expectation of success for arriving at the invention of claimed 1 from the cited prior art because there was no suggestion to select specific markers required by claim 1, nor any suggestion of the direction in which these markers would correlate with UTUC. These arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth above and, 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).
The response also asserts that Kitchen and Guo in combination do not disclose, suggest, or teach the present invention and while Guo describes promoter methylation status of 10 genes voided in urine samples it does not teach methylation levels of CpG sites located at specific loci described by claim 1 or whether UTUC is associated with increased or decreased methylation of these sites. Further, the response asserts that one of ordinary skill in the art would not have been guided to or have had a reasonable expectation of successfully making and using the invention based on the combination of Kitchen and Guo. These arguments have been thoroughly reviewed but were not found persuasive for the reasons set forth above and, 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).
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1-4 & 10-17 are rejected.
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.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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