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 .
Claims Status
Claims 112-114 & 116-125 filed on 01/13/2026 are pending. Claims 127-130 are withdrawn from consideration as being drawn to a non-elected invention. Claims 112-114 & 116-125 are currently under examination directed to the elected species of TMC6 in claims 112-114 & 116-125, of plasma sample in claim 120, of TMC6 primer sequences (SEQ ID NOs: 43 & 44) in claim 121, and of B3GALT6 in claim 122 (see response dated 08/08/2025). The species of tissue sample is rejoined with plasma sample in claim 120. The cancellation of claims 115, 126, & 131 in the reply filed on 01/13/2026 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 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Information Disclosure Statement
Only the abstracts of the references in the IDS submitted on 01/13/2026 that are lined through, under the foreign patent documents section, were considered because an English copy of the full documents were not provided.
Claim Rejections - 35 USC § 102
Claim(s) 112-114, 116, 117, 119, 120, & 123-125 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Manoochehri (Manoochehri et al.; Molecular Oncology, Vol. 14, pages 1252-1267, April 14th 2020).
Regarding amended claim 112, Manoochehri teaches a method for detecting genome wide methylation in pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET) samples through analyzing genome wide methylation using the Illumina Infinium 450K DNA methylation platform, in which the Illumina Infinium 450k array contains the cg007704579 probe detecting a CpG site on chr17:76,124,173-76,124,173, which is consistent with the teachings of the instant specification that teaches TMC6_B on chr17:76,124,136-76,124,298 (one or more genes is selected from TMC6), and further validating the differently methylated regions (DMRs), including the DMR in TMC6 (determining methylation level of one or more genes selected from TMC6) (Table S2), through bisulfite restriction analysis (treating sample with a reagent that modifies DNA in a methylation specific manner), amplifying with specific primer pairs (amplifying treated genomic DNA using a set of primers) (determining a methylation level of one or more genes by polymerase chain reaction wherein the one or more genes is selected from TMC6) (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13). Manoochehri also teaches human pancreatic tissue samples were collected PDAC and PNET tissue samples during surgery (sample is obtained from a human subject wherein methylation indicates human subject has or is suspected of having PNET (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 1st full paragraph lines 1-2; pg. 1254 column 1 1st full paragraph lines 1-15).
Regarding amended claim 113, Manoochehri teaches detection of differently methylated regions (DMRs), including the DMR in TMC6 (one or more genes selected from TMC6) (Table S2), through bisulfite restriction analysis (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13).
Regarding amended claim 114, Manoochehri teaches detection of differently methylated regions (DMRs), including the DMR in TMC6 (one or more genes selected from TMC6) (Table S2), through bisulfite restriction analysis (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13).
Regarding claim 116, Manoochehri teaches the reagent that modifies DNA in a methylation specific manner is bisulfite (pg. 1254 column 1 3rd full paragraph lines 1-13).
Regarding claim 117, Manoochehri teaches the DNA is treated with a bisulfite reagent to produce bisulfite-treated DNA (pg. 1254 column 1 3rd full paragraph lines 1-13).
Regarding claim 119, Manoochehri teaches determining a methylation level through methylation-specific PCR (pg. 1254 column 1 3rd full paragraph lines 1-13).
Regarding claim 120, Manoochehri teaches the genomic DNA is isolated from tissue samples (pg. 1253 column 2 2nd full paragraph lines 1-4).
Regarding claim 123, Manoochehri teaches determining the methylation level of at least on CpG site in a differently methylated region (DMR), including the DMR in TMC6 (methylation level of at least one CpG site in a DMR from the one or more genes) (pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13; Table S2).
Regarding claim 124, Manoochehri teaches that protein encoding genes were elected for further analysis in the DMR (wherein the at least one CpG site is present in a coding region) (pg. 1254 column 1 2nd full paragraph lines 9-10).
Regarding claim 125, Manoochehri teaches analyzing genes that are significantly hypermethylated in differently methylated regions (determining a methylation score or methylation frequency) (pg. 1254 column 1 2nd full paragraph lines 1-3).
Response to Arguments
The response traverses the rejection. The response asserts that Manoochehri discloses the use of Illumina’s Infinium humanMethylation450 Beadchip array and that one of ordinary skill in the art would recognize that the use of these arrays does not include nucleic acid amplification and that Manoochehri only discloses nucleic acid amplification generally. Further, the response asserts that Manoochehri fails to disclose amplifying the treated DNA using a set of primers for one or more genes. This argument has been thoroughly reviewed but was not found persuasive as the standard laboratory protocol for use of the Illumina Infinium HumanMethylation 450 Beadchip array requires anamplification step as part of the protocol comprising amplification after bisulfite conversion. Therefore, Manoochehri does teach amplifying the treated DNA using a set of primers for one or more genes comprising TMC6. Further, Manoochehri teaches further validating the differently methylated regions (DMRs), including the DMR in TMC6 (Table S2), through bisulfite restriction analysis (treating sample with a reagent that modifies DNA in a methylation specific manner) and amplifying with specific primer pairs (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13).
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) 118 & 122 is/are rejected under 35 U.S.C. 103 as being unpatentable over Manoochehri (Manoochehri et al.; Molecular Oncology, Vol. 14, pages 1252-1267, April 14th 2020), in view of Allawi (U.S. Patent Application Publication US 2019/0177769 A1), as cited in the IDS dated 04/03/2025.
The teachings of Manoochehri with respect to claim 112 is discussed above and incorporated herein.
Regarding claims 118 & 122, Manoochehri does not teach determining a methylation level comprising multiplex amplification (see claim 118) or comprising measuring at least one methylation reference marker selected from B3GALT6 DNA (see claim 122).
Allawi teaches a method for analyzing samples containing bisulfite-treated DNA with a plurality of different target through multiplexed amplification (paragraph [0009] lines 1-16; paragraph [0010] lines 1-7; paragraph [0011] lines 1-7; paragraph [0016] lines 1-7). Allawi also teaches that the plurality of different target regions in the bisulfite-treated DNA can comprise a reference target region in which the reference target region comprises B3GALT6, ZDHHC1, and/or β-actin (paragraph [0044] lines 1-4). Finally, Allawi teaches that this method can analyze a plurality of different targets with reduced risk of false negative results (paragraph [0010] lines 1-5).
Manoochehri and Allawi are considered to be analogous to the claimed invention because they are all in the same field of methods for analyzing samples containing bisulfite-treated DNA. 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 analyzing methylation levels in Manoochehri to incorporate the use of multiplex amplification and measuring the methylation level of the B3GALT6 reference marker in analyzing bisulfite-treated DNA as taught in Allawi because Allawi teaches that doing so would provide a method to analyze a plurality of different bisulfite-treated targets with the reduced risk of false negative results.
Claim(s) 121 is/are rejected under 35 U.S.C. 103 as being unpatentable over Manoochehri (Manoochehri et al.; Molecular Oncology, Vol. 14, pages 1252-1267, April 14th 2020), in view of GenBank Accession Number AY099356.
The teachings of Manoochehri with respect to claim 112 is discussed above and incorporated herein.
Regarding amended claim 121, Manoochehri does not teach the primers specific for TMC6 are capable of binding to an amplicon bound by SEQ ID NO: 43 and 44.
However, regarding amended claim 121, Manoochehri teaches a method for detecting genome wide methylation in pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET) samples through analyzing genome wide methylation using the Illumina Infinium 450K DNA methylation platform and further validating the differently methylated regions (DMRs), including the DMR in TMC6 (determining methylation level of one or more genes selected from TMC6) (Table S2), through bisulfite restriction analysis, amplifying with specific primer pairs to the genes analyzed (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13). Further, Manoochehri teaches determining the bisulfite converted sequence of a known target nucleic acid for the genes analyzed as well as constructing primer pairs to detect it (pg. 1254 column 1 3rd full paragraph lines 1-13). Further, Manoochehri teaches that this method enables sensitive and promising detection of cancer biomarkers in tumors (abstract lines 21-23).
Furthermore, the sequence of TMC6 (EVER1) is taught by GenBank Accession Number AY099356 (pg. 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 constructed methylation specific primers, including primers specific for TMC6 capable of binding an amplicon bound by SEQ ID NOs: 43 and 44, for the analysis of methylation levels in at least one gene including TMC6 taught by Manoochehri because Manoochehri teaches constructing primers that specifically hybridize to a target nucleic acid for quantifying differentially methylated regions in PDAC and PNET samples to enable sensitive and promising detection of cancer biomarkers in tumors. Absent secondary considerations, these primers are considered obvious in view of the teachings of the prior art.
Response to Arguments
The response traverses the rejection. The response asserts that Allawi fails to disclose treating DNA in a sample from a subject having or suspected of having PNET with a reagent that modifies DNA in a methylation-specific manner or amplifying the treated DNA using a set of primers for one or more genes and thus Allawi fails to remedy the deficiencies of Manoochehri. This argument has been thoroughly reviewed but was 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, the standard laboratory protocol for use of the Illumina Infinium HumanMethylation 450 Beadchip array requires an amplification step as part of the protocol comprising amplification after bisulfite conversion. Therefore, Manoochehri does teach amplifying the treated DNA using a set of primers for one or more genes comprising TMC6. Further, Manoochehri teaches further validating the differently methylated regions (DMRs), including the DMR in TMC6 (Table S2), through bisulfite restriction analysis (treating sample with a reagent that modifies DNA in a methylation specific manner) and amplifying with specific primer pairs (pg. 1253 column 1 1st full paragraph lines 1-8; pg. 1253 column 2 2nd full paragraph lines 1-4; pg. 1254 column 1 1st full paragraph lines 1-15; pg. 1254 column 1 3rd full paragraph lines 1-13).
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 112-114 & 116-125 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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