DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
Receipt is acknowledged of a request for continued examination under 37 CFR 1.114,
including the fee set forth in 37 CFR 1.17(e) and a submission, filed on 10/03/2024.
Status of Claims
Claims 1, 5-6, and 9-12 submitted on 10/03/2024 are currently pending and under examination. Claims 2-4, 7-8, and 13-16 have been cancelled.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5-6, and 9-12 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chinnaiyan et al (WO 2012/174256 A2; Published Date: Dec 20, 2012), WU (WO 2011/127194 A1; Published Date: Oct 13, 2011), Kobayashi et al (DNA Methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer; Genome Research, 2011, 21:1017-1027) and Mahapatra et al (Global methylation profiling for risk prediction of prostate cancer; Clin Cancer Res, 2012, 18(10):2882-2895).
Regarding claim 1, Chinnaiyan teaches a method of detecting in a genomic DNA sample from an individual the methylation status of promoter region of genes or promoters including but not limited to those listed in Table 4 (pg. 11). Chinnaiyan further teaches the method comprises the following steps as matching to the instant claim (see pg. 23-24): (a) digesting a first genomic DNA sample with a cocktail of methylation-sensitive restriction enzymes (i.e., a first restriction enzyme); (b) ligating the digested fragments with adaptors containing universal primer sequences for polymerase chain reaction (PCR); (d and e) performing a second round of enzymatic treatment to deplete non-GC rich sequences (i.e., digesting a second genomic DNA sample with a second restriction enzyme and ligating the second genomic DNA sample with adaptors); (f) amplifying digested genomic DNA using PCR; (h) analyzing digested genomic DNA using next-generation sequencing and qPCR (pg. 16); wherein the genomic DNA samples are obtained from an individual having prostate cancer (pg. 15); wherein detecting methylation from a promoter region from each gene in a panel of genes consisting of EYA4, ESR1 and ESR2 (Table 4 on pages 79, 81, and 89), and determining that the promoter region of EYA4 is hypermethylated (pg. 79). Regarding total methylation (TM) and allele specific methylation (ASM), Chinnaiyan discloses a comparative analysis of genomic data was performed and mapping reads to all CpG islands (pg. 24, lines 8-20), as well as methylated promoter regions of specific genes (pg. 24, lines 21-33) and specifically in prostate cancer tissues (pg. 27-28, section “Characterization of DNA methylation in Prostate Cancer Tissues).
However, Chinnaiyan does not teach wherein the method comprises step c, enriching the adaptor-ligated genomic DNA fragments from step b for methylated DNA fragments with a methylation-binding domain (MBD) polypeptide.
Wu teaches a method of profiling methylation using CpG island microarrays ([0181]) also comprising the following steps of the instant claim: (a) digesting genomic DNA with MseI (i.e., a first restriction enzyme); (b) ligating oligo-MseI adaptors to digested genomic DNA; (c) incubating “digested and linker-ligated genomic DNA” with GDT-tagged MBD2b protein and His-tagged MBD3L1 protein (i.e., enriching the adaptor-ligated genomic DNA from step b with a MBD polypeptide); (e and g) “enriched and unenriched fractions derived from each individual were then indirectly labeled with aminoallyl-dUTP, conjugated with either Alexa 647 or Alexa 555”; (f) methylation-enriched fraction and unenriched fraction is PCR-amplified; and (h) analyzing fractions using microarray ([0182]).
Thus, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the method of Chinnaiyan to further comprise step c as taught by Wu because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results, and in combination each element merely performs the same function as it does separately. Both Chinnaiyan and Wu teach methods of analyzing methylation status of specific genes or promoters using steps that comprise of digesting, ligating, amplifying, and sequencing genomic DNA. The addition of step c to enrich methylated fractions as taught by Wu merely represents an addition of known prior art element to perform the same function in another method that is relatively similar. One would have been motivated to have done so for the advantage of enriching methylated genomic DNA to remove undesired sequences for analysis and compare methylation status to unenriched fractions. One ordinary skill in the art would have had a reasonable expectation of success in doing so because Chinnaiyan and Wu teach methods to detect and analyze methylation status from genomic DNA.
However, neither Chinnaiyan or Wu teach wherein the enriched methylated fraction comprises a promoter region from ADAMTS12 and TNFRSF10D, and that the promoter region of ADAMTS12 is hypermethylated.
Kobayashi discloses profiling DNA methylation levels at 26,333 CpGs representing 14,104 gene promoters in primary prostate tumors and benign adjacent prostate tissues (abstract, and pg. 1018, right-column, second paragraph). Kobayashi further discloses that ADAMTS12 is one of the gene promoters identified to be hypermethylated (Supplemental Table 2), dataset provided below.
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In addition, Mahapatra discusses TNFRSF10D is one out of 25 genes known to have significant methylation in the promoter region in prostate cells and serves as a prognostic marker to predict the clinical recurrence of prostate cancer (abstract, Figure 1C, and Table 2).
Thus, it would have been obvious to one of ordinary skill in the art at the time the invention was made to have additionally analyzed the promoter methylation of ADAMTS12 and TNFRSF10D in combination with those disclosed by Chinnaiyan because it would have merely amounted to a simple combination of known genes whose hypermethylation is known to be associated with prostate cancer. One would have been motivated to have done so for the advantage of achieving a more comprehensive genome-scale analysis of those genes whose promoter methylation is implicated in prostate cancer.
In addition, Kobayashi and Mahapatra’s teachings would have given one of ordinary skill in the art a reasonable expectation of success to have detected hypermethylated ADAMTS12 and TNFRSF10D in prostate cancer. Given the important of DNA methylation to regulation of gene expression, the observation that hypermethylation of the promoter regions of genes are associated with cancer, and given the known important functions of each of EYA4, ADAMTS12, ESR1, ESR2, and TNFRSF10D, an genomic analysis of a sample of prostate cancer cells relative to normal prostate cells would have given one of ordinary skill in the art a reasonable expectation to have found wherein the enriched methylated fraction comprises promoter regions from each of these genes.
Given the teachings of the prior art and the level of ordinary skilled artisan at the time of the applicant’s invention, it must be considered, absent evidence to the contrary, that said skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Regarding claim 5, the obviousness to combine Chinnaiyan’s method with enrichment step c from Wu is discussed above as applied to claim 1. Wu teaches wherein the MBD polypeptide is from MBD2, specifically MBD2b ([0181]).
Regarding claim 6, Chinnaiyan further teaches identifying hypermethylation in Cp islands using “Takai Jones criteria”, which is measured with >2.5% CpG density (pg. 25, line 8). Further, results in Table 4 demonstrates hypermethylated promoters identifies using these criteria comprised of more than 2.5% CpG density.
Regarding claim 9, Chinnaiyan further teaches using the method to perform a genome-wide analysis of DNA methylation in prostate cancer with gene expression profiling data from prostate cancer cell line LNCaP and normal PrEC cells (pg. 23, lines 26-32, and pg. 24, lines 31-33) by comparing the extent of CpG island methylation between LNCaO and PrEC cells (pg. 25, line 7).
Regarding claims 10-12, Chinnaiyan further teaches wherein the genomic DNA sample is taken from “17 prostate tissues (6 benign adjacent, 2 normal, 5 localized prostate cancer and 4 metastatic prostate cancer specimens)” (pg. 27, lines 6-7).
Response to Arguments
Applicant’s remarks received on Feb 4, 2025, were primarily directed to Christensen et al (US 2011/0028333 A1) and have been fully considered and is found persuasive. Therefore, prior rejections on claims 1, 5-6, and 9-12 is withdrawn. However, claims 1, 5-6, and 9-12 remain unpatentable as set forth in the current Office Action (see discussions above regarding 35 U.S.C. 103 rejection).
In response to Applicant’s argument: “…identifying a molecular marker in one cancer type…is no guarantee that that same marker will be present in a different cancer type” (pg. 4 of Remarks) and “…identifying molecular markers in one cancer type (e.g., the methylation status of promoters of certain genes, as recited in the present claims) would not lead a person of ordinary skill in the art to have to a reasonable expectation of success that the same molecular markers would be indicative of a different cancer type.” (pg. 5 of Remarks), the current 35 U.S.C. 103 rejection explains Chinnaiyan, Kobayashi, and Mahapatra in combination teach promoters of EYA4, ADAMTS12, ESR1, ESR2, and TNFRSF10D genes are hypermethylated in prostate cancer; therefore, a persona of ordinary skill in the art would have had a reasonable expectation of success that methylation status of these promoters serve as indicative molecular markers of prostate cancer.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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