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 .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Claims 1, 10, and 12-24 are pending.
Claims 2-9 and 11 are cancelled.
Applicant’s election of Group I, SEQ ID NOs: 1-6 in the reply filed on 6/6/2023 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 12-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/6/2023.
Claims 1, 10, and 23-24 are being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (see pages 42-43). No new IDS was filed in the response of 10/8/2025 and the amended specification still contains a listing of references not present in the IDS. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
Applicant’s amendment to the specification to remove the browser-executable code on page 28, paragraph 4 is acknowledged. The objection to the specification is withdrawn.
Claim Objections
Necessitated by Amendments
Claim 1 is objected to because of the following informalities: “to aid risk stratification for selection treatments/active surveillance” should read “to aid risk stratification for selection of treatments/active surveillance”. Appropriate correction is required.
Claim Rejections - 35 USC § 112a – Written Description
The rejection of claims 1 and 10 under 35 U.S.C. 112(a) is withdrawn in light of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 101
Maintained in Part
Claim 23 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (e.g., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims are directed to a judicial exception encompassing a law of nature and an abstract idea (mental process). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception as set forth below. The judicial exception is not integrated into a practical application of the judicial exception.
The following inquiries are used to determine whether a claim is drawn to patent-eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes – the claim is directed to a process.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes – Where the claim is directed to “calculating a normalized index of methylation (NIM) score” the claim is directed to a mathematical calculation (abstract idea).
Step 2A, prong 2. Does the claim recite additional elements that integrate the judicial exception into a practical application? No – The claim provides no further limitations which integrate the judicial exceptions into any form of practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No – The claim merely recites performing a methylation assay on a urine or urine sediment sample, which is insignificant extra-solution activity as well as well-known, routine, and conventional (MPEP 2106.05(g); Rigau et al., 2013).
For these reasons the claim is rejected under 35 USC 101 as directed to subject matter that is not significantly more than a judicial exception.
Response to Remarks
Upon further consideration, the rejection of claim 24 under 35 USC 101 is withdrawn. The examiner has determined that claim 24 does not satisfy the condition of Step 2A, prong 1 (Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)?). Claim 24 does not recite a judicial exception.
Applicant has traversed the rejection of claims 23 and 24 under 35 USC 101 (pg 8-9 of Remarks). Applicant’s arguments in regards to claim 24 are moot given the withdrawal of the rejection of claim 24 under 35 USC 101 for the reason stated above.
Applicant argues that “where a claim sets forth a particular solution to reach a goal, as opposed to merely describing a desired outcome, the claim is not ‘directed to’ an abstract idea” (pg 8 of Remarks). However, the “goals” that are being achieved in claim 23 are assaying of a sample for methylation and calculation of a normalized index of methylation (an abstract idea/mathematical formula). There is no practical integration of this judicial exception, merely recitation as to steps of measuring methylation levels of a subset of genes in a patient and calculating a NIM score. Applicant goes on to argue that the benefits of the specific subset of genes in relation to categorizing the aggressiveness of the prostate cancer, however this is inconsequential as this independent claim recites no association of the methylation status with high-risk prostate cancer, merely a detection of methylation and calculation of a value. Furthermore, the claim recites determination of methylation of genes (a data collection step) with a high level of generality, indicating that the element of the claim pertaining to data gathering is a mere instruction (MPEP 2106.06(d)). Additionally, there is no incorporation of this determination in the calculation of the NIM score (i.e., no direction to incorporate the methylation information gathered from SEQ ID NOs: 1-6 into calculation of the NIM score).
For these reasons, the rejection of claim 23 under 35 USC 101 is maintained.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Amendments
Claims 1, 10, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Yegnasubramanian et al. (Cancer Research, 2004) in view of Perry et al. (British Journal of Cancer, 2007; cited on IDS submitted 6/22/2021) and Wang et al. (US 20100003670 A1, published Jan. 7, 2010).
Yegnasubramanian et al. teach assaying biological samples from human subjects to determine the presence and methylation status of specific genes including GSTP1, APC, and PTGS2 (Abstract). The instant specification teaches that SEQ ID NO: 1 is GSTP1, SEQ ID NO: 5 is APC, and SEQ ID NO: 6 is PTGS2 (page 8). Yegnasubramanian et al. teach calculating a normalized methylation index (NIM) score for each gene which normalizes each gene against a fully-methylated control and calculates a ratio of this normalized index to the normalized index of a control/reference gene (Materials and methods - Bisulfite Modification of DNA Samples and Real-Time Methylation-Specific PCR (RT-MSP)). Additionally, Yegnasubramanian et al. teach adding together NIM scores for multiple genes to determine an NIM mean/average. They demonstrate that higher NIM averages are associated with metastatic prostate cancer (reads on high-risk prostate cancer according to specification page 7; averages were calculated using 16 different genes; Fig. 6B and Methylation of CpG Islands in Metastatic Prostate Cancers, paragraph 1).
Yegnasubramanian et al. does not explicitly teach assaying for methylation of IGFBP3. However, the connection of IGFBP3 methylation to prostate cancer diagnosis and prognosis was known in the art, as taught by Perry et al. 2007.
Perry et al. teach assessing methylation of IGFBP3 (reads on SEQ ID NO: 3) and GSTP1 as biomarkers of both disease occurrence and progression (Abstract). Specifically, Perry et al. teach that IGFBP3 hypermethylation was only detected in samples in which GSTP1 was also hypermethylated (relevant to claim 10) and in which the Gleason score was greater than or equal to 7 (indicating aggressive/high-risk prostate cancer; Abstract).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to have modified the method of Yegnasubramanian et al. (which teaches calculation of NIM scores for multiple genes involved in prostate cancer and determining averages) to also assess the methylation status of IGFBP3 as taught by Perry et al. One would have been motivated to include IGFBP3 in addition to the other genes included in Yegnasubramanian et al.’s study given the connection between hypermethylation of GSTP1 (already included) and IGFBP3, as taught by Perry et al. The correlation between IGFBP3 hypermethylation and a Gleason score greater than or equal to 7 (associated with high-risk prostate cancer) would be a beneficial locus to include in analyses aimed at assessing the difference between low- and high-risk prostate cancers.
Yegnasubramanian et al. in view of Perry et al., 2007 does not explicitly teach using urine or urine cell-sediment as the biological sample, using ACTB as the control/reference gene in calculating NIM, a NIM cut off of at least 1.25, or subsequent biopsy to aid in risk stratification for selection of treatments/active surveillance. However, use of ACTB to calculate NIM values of genes associated with prostate cancer from urine samples, followed by biopsy, was known in the art, as taught by Wang et al.
Wang et al. teaches a method of characterizing a prostate cancer according to the degree/amount of epigenetic change (methylation score) and whether this exceeds a pre-determined value (paragraph [0009]). If the cancer exceeds the threshold value it is considered to be “aggressive” (reads on high-risk) and “patients showing a methylation level beyond a predetermined level are biopsied” (reads on performing a trans-rectal prostate biopsy; paragraph [0013]). Wang et al. teaches that more aggressive cancers, with a Gleason score >7 determined by biopsy, would then be selected for more aggressive treatments (reads on aid risk stratification for selection treatments; paragraph [0056]). Wang et al. teaches determining the methylation status of one or more genes from a group including GSTP1 and APC in a urine sample (paragraph [0009], paragraph [0076]). Further, Wang et al. teach calculating a methylation ratio in which the amount of methylated biomarker is relative to the amount of methylated control/reference biomarker, which is preferably a gene such as beta actin (reads on ACTB, paragraph [0041 and 0054]). Establishment of a predetermined value or threshold is something that is well known in the art and can be based off calculated methylation ratios depending on the cancer assayed and the genes used in the assay (paragraph [0042]).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to have modified the method of Yegnasubramanian et al. in view of Perry et al. (which teaches calculation of NIM scores for multiple genes involved in prostate cancer and determining averages) to perform this assay on urine samples, establish a threshold to characterize the prostate cancer for future treatment, and use ACTB as a control gene, as taught by Wang et al. One would be motivated to use urine samples as urine samples are less invasive than tissue samples. Using ACTB as a reference or control gene would be desirable, as Wang et al. teaches that this gene is constitutively expressed in the cells of samples (paragraph [0041]). Establishing a threshold is an effective way of characterizing the type of prostate cancer one is working with (aggressive vs indolent/benign) and methods for establishing cut offs could be achieved through routine experimentation. Additionally, characterizing the prostate cancer as aggressive and subsequently treating this cancer with a prostate cancer treatment would be desirable for patient health. One would have a reasonable expectation of success given that known methods of assaying methylation status at loci known to be associated with prostate cancer are being performed followed by treatment or biopsy of those samples deemed to be high-risk.
Response to Remarks
Applicant's arguments filed 10/8/2025 have been fully considered but they are not persuasive for the following reasons.
Applicant has traversed the rejection of claims 1, 10, and 23-24 under 35 USC 103 over Yegnasubramanian in view of Perry and Wang (pages 9-11 of Remarks). Applicant has argued that Yegnasubramanian does not teach determining the methylation status of at least 4 genes selected from SEQ ID NO: 1-6 for determining the presence of high-risk prostate cancer and confirming said diagnosis via trans-rectal biopsy to aid risk stratification (pg 9 of Remarks). 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). Applicant has argued that Yegnasubramanian studies methylation of individual genes to calculate individual NIM scores and that there is “no description of how the individual biomarker NIMs are combined into a ‘score’” (pg 9 of Remarks). However, Yegnasubramanian describes determining an aggregate NIM score at the 16 methylation loci studied in which each NIM score for each gene is added together (“the sum of the NIM across all genes, excluding HIC1, called the aggregate-normalized index of methylation was greater in the metastases than in the primary prostate cancers (P < 0.0001; Fig. 7)”, Results - Methylation of CpG Islands in Metastatic Prostate Cancers).
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., “subject application precedes treatment” (pg 9 of Remarks)) 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).
Applicant has argued that Perry does not teach determining methylation status of at least 4 genes selected from SEQ ID NO: 1-6 for determining the presence of high-risk prostate cancer and confirming said diagnosis via trans-rectal biopsy to aid risk stratification (pg 10 of Remarks). 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).
Applicant has argued that Yegnasubramanian and Perry do not teach that determining methylation status of at least 4 genes from SEQ ID NO: 1-6 can point to the presence of high-risk prostate cancer and aid risk stratification for selection of treatment (pg 10 of Remarks). However, Wang teaches that determining methylation status at multiple genes and determining the degree of this methylation allows for classification of the aggressiveness of the cancer (see above). 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).
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., “combination of at least 4 genes selected from SEQ ID NO: 1-6 are combined with clinical variables such as PSA age, prior negative biopsy, family history…the performance of the combination of the claimed invention improves” (pg 10 of Remarks)) 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).
Applicant has asserted that “It is surprising and unexpected to find a combination of genes/sequences that when combined, accurately discriminate high-risk prostate cancer from other more latent forms of the disease” (pg 10 of Remarks). However, Yegnasubramanian and Wang demonstrate increased sensitivity and specificity when combining methylation information of multiple genes/sequences which allows for accurate discrimination of high-risk prostate cancer (Fig 7 and Table 3 of Yegnasubramanian; paragraphs [0059-0060, 0078] and Table 6 of Wang).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Yegnasubramanian, Perry, and Wang teach that combining methylation status (NIM values) of multiple genes in the determination of high-risk prostate cancer increases accuracy and specification of high-risk prostate cancer detection. In addition, these three references, together, teach detection of methylation of GSTP1 (SEQ ID NO: 1; Yegnasubramanian, Perry, and Wang), IGFBP3 (SEQ ID NO: 3; Perry), APC (SEQ ID NO: 5; Yegnasubramanian and Wang), and PTGS2 (SEQ ID NO: 6; Yegnasubramanian). Yegnasubramanian and Perry teach the association of genes GSTP1 and IGFBP3 with high-risk/aggressive prostate cancer, and Yegnasubramanian and Wang teach the association of GSTP1 and APC with high-risk prostate cancer (see above citations and rationales for combining). One would be motivated to 1) combine methylation values across multiple genes and 2) use genes known in the art to be associated with metastatic/aggressive prostate cancer.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683