CTNF 17/945,689 CTNF 100559 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Status of the Claims Claims 1-11 are pending and under consideration in this action. Priority This application is a CON of PCT/JP2020/041984, filed 11/10/2020, which claims foreign priority from Japanese Application 2020-055116, filed 03/25/2020, as reflected in the filing receipt mailed 11/01/2022. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The claims to the benefit of priority are acknowledged and the effective filing date of claims 1-11 is 3/25/2020. Information Disclosure Statement The information disclosure statements (IDS) submitted on 1/11/2023, 6/8/2023, 10/30/2023, and 7/14/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS’s have been considered by the examiner. Claim Objections 07-29-01 AIA Claim 1 is objected to because of the following informalities: Claim 1 recites the phrase “ the representative value and the base methylation degree at the target site are calculated to be uncalculable ”, which should be corrected to “ the representative value and the base methylation degree at the target site are calculated to be incalculable ” for clarity . Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. 07-34-01 Claims 1-11 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. Claim 1 recites the phrase “ wherein in a case where the sets of the methylation degrees in all the sequence analyses vary from each other or include a specifically large or small methylation degree, or in a case where the sets of the methylation degrees in all the sequence analyses vary from each other and include a specifically large or small methylation degree ”. The terms “specifically large” and “specifically small” in claim 1 are relative terms which renders the claim indefinite. The terms “specifically large” and “specifically small” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification (Para. [0072]) reiterates the claim language, but does not provide, for example, any parameters for what defines a “specifically large” or “specifically small” methylation degree. Claims 2-11 are also rejected due to their dependency from claim 1. Applicant is kindly reminded that any amendment must find adequate support in the Specification as originally filed. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 1-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims recite both (1) mathematical concepts (mathematical relationships, formulas or equations, or mathematical calculations) and (2) mental processes, i.e., concepts performed in the human mind (including observations, evaluations, judgements or opinions) (see MPEP § 2106.04(a)). Step 1: In the instant application, claims 1-10 are directed towards a process, which falls into one of the categories of statutory subject matter ( Step 1: YES ). Claim 11 is directed towards a computer-readable storage medium, which does not fall within one of the categories of statutory subject matter ( Step 1: NO ). Regarding claim 11, the BRI of computer-readable storage medium encompasses non-statutory forms of signal transmission and therefore equates to “signals per se”. Claims that equate to “signals per se” are not a statutory category of invention (see MPEP § 2106.03). However, claim 11 could be amended to be statutory subject matter by replacing the phrase “computer-readable storage medium” with the phrase “non-transitory computer-readable storage medium”. Nonetheless, this amendment would still result in a rejection of the claim under 35 U.S.C 101 for recitation of a judicial exception without significantly more. In the interest of compact prosecution, claim 11 has been analyzed using the Alice/Mayo two-part test below. Step 2A, Prong One: In accordance with MPEP § 2106, claims found to recite statutory subject matter ( Step 1: YES ) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon ( Step 2A, Prong One ). The following instant claims recite limitations that equate to one or more categories of judicial exceptions: Claims 1-2, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads, or correcting individual bases; see Specification Para. [0019]) in “ correcting a base of the co-methylation site in a read based on quality information included in the sequence analysis data ”; and a mathematical concept in “ calculating a base methylation degree at the target site from corrected reads ”. Clams 1, 3, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads, or correcting individual bases; see Specification Para. [0019]) in “ correcting a read based on quality information included in the sequence analysis data and excluding a read in which a base does not coincide between the co-methylation sites ” and a mathematical concept in “ calculating a base methylation degree at the target site from remaining reads ”. Claims 1, 4, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads, or correcting individual bases; see Specification Para. [0019]) in “ correcting a paired-end read based on quality information included in the sequence analysis data ”; and a mathematical concept in “ calculating a base methylation degree at the target site from corrected reads ”. Claims 1, 5, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads, or correcting individual bases; see Specification Para. [0019]) in “ correcting a read based on quality information included in the sequence analysis data and excluding a paired-end read in which a base at the target site does not coincide between the paired-end reads ”; and a mathematical concept in “ calculating a base methylation degree at the target site from remaining reads ”. Claims 1, 6, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads or correcting individual bases; see Specification Para. [0019]) in “ correcting a read based on quality information included in the sequence analysis data ”; a mental process (i.e., evaluating reads for the same molecular barcode) in “ classifying corrected reads into a group of reads having the same molecular barcode ”; a mental process (i.e., an evaluation of frequently appearing bases) in “ determining a base that most frequently appears at the target site on each of the read groups ”; and a mathematical concept in “ calculating a base methylation degree at the target site from a set of the bases that most frequently appear ”. Claims 1, 7, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads or correcting individual bases; see Specification Para. [0019]) in “ correcting a read based on quality information included in the sequence analysis data ”; a mental process (i.e., an evaluation of reads for the same molecular barcode) in “ classifying corrected reads into a group of reads having the same molecular barcode, excluding a read having no identity in a sequence of a region including the target site in each of the read groups, and obtaining a read group having the same molecular barcode and the same sequence of the region including the target site ”; a mental process (i.e., an evaluation of the molecular barcode and sequence) in “ determining a base at the target site in each of the read groups having the same molecular barcode and the same sequence of the region including the target site ”; and a mathematical concept in “ calculating a base methylation degree at the target site from a set of the determined bases ”. Claims 1, 8, and 10-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads or correcting individual bases; see Specification Para. [0019]) and a mathematical concept in “ correcting a read based on quality information included in the sequence analysis data, for each of the sequence analysis data from an individual sequence analysis, and calculating a base methylation degree at the target site from corrected reads ”; and a mathematical concept in “ calculating a representative value from sets of the methylation degrees in all the sequence analyses and adopting the representative value as a base methylation degree at the target site ”. Claims 1, and 9-11 recite a mental process (i.e., evaluating the reads for correction by excluding reads, selecting reads or correcting individual bases; see Specification Para. [0019]) and a mathematical concept in “ correcting a read based on quality information included in the sequence analysis data, for each of the sequence analysis data from an individual sequence analysis, and calculating a base methylation degree at the target site from corrected reads ”; a mathematical concept in “ calculating a representative value from sets of the methylation degrees in all the sequence analyses and adopting the representative value as a base methylation degree at the target site, wherein in a case where the sets of the methylation degrees in all the sequence analyses vary from each other or include a specifically large or small methylation degree, or in a case where the sets of the methylation degrees in all the sequence analyses vary from each other and include a specifically large or small methylation degree, the representative value and the base methylation degree at the target site are calculated to be uncalculable ”. These recitations are similar to the concepts of collecting information, and displaying certain results of the collection and analysis is Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)), and organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships. The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification, and are determined to be directed to mental processes that in the simplest embodiments are not too complex to practically perform in the human mind. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. Specifically, claim 1 involves nothing more than correcting reads based on quality information and subsequently using the corrected reads for classification and/or calculation of a base methylation degree. Since there are no specifics in the methodology, the step reciting correcting a read based on quality information is, under the BRI, something that can be performed mentally. Additionally, the step reciting classifying the corrected reads based on matching molecular barcodes is something that, under the BRI, can be performed mentally. The step reciting calculating a base methylation degree is, under the BRI, performed using mathematical operations. For example, the instant Specification (see, for example, Para. [0083]) discloses that the methylation degree of site A was calculated as the sum of reads for two groups divided by the total. Therefore, the claimed steps are not further defined beyond something that reads on evaluating the data, making a determination, and performing a calculation. As such, said steps are directed to judicial exceptions. The instant claims must therefore be examined further to determine whether they integrate the abstract idea into a practical application ( Step 2A, Prong One: YES ). Step 2A, Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP § 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP § 2106.04(d)(I)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP § 2106.04(d)(III)). The following independent claims recite limitations that equate to additional elements: Claim 1 recites “ acquiring sequence analysis data obtained by subjecting DNA having at least one co-methylation site to a sequence analysis using a sequencer ”; “ acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis according to a paired-end method using a next generation sequencer ”; and “ acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer ”. Regarding the above cited limitations in claim 1 of (i) acquiring sequence analysis data obtained by subjecting DNA having at least one co-methylation site to a sequence analysis using a sequencer ; (ii) acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis according to a paired-end method using a next generation sequencer ; and (iii) acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer . These limitations equate to insignificant, extra-solution activity of mere data gathering because these limitations gather data before or after the recited judicial exceptions of calculating a base methylation degree (see MPEP § 2106.04(d)). Additionally, none of the recited dependent claims recite additional elements which would integrate the judicial exception into a practical application. Specifically, claim 11 recites generic computer components that equate to mere instructions to implement an abstract idea on a generic computer. As such, claims 1-11 are directed to an abstract idea ( Step 2A, Prong Two: NO ). Step 2B : Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself ( Step 2B ). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The instant independent claims recite the same additional elements described in Step 2A, Prong Two above. Regarding the above cited limitations in claim 1 of (i) acquiring sequence analysis data obtained by subjecting DNA having at least one co-methylation site to a sequence analysis using a sequencer ; (ii) acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis according to a paired-end method using a next generation sequencer ; and (iii) acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer . The courts have recognized that these limitations equate to laboratory techniques that are well-understood, routine, and conventional (WURC) activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) (see MPEP 2106.05(d)). Detecting DNA or enzymes in a sample is a WURC limitation in Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157, and Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017). Analyzing DNA to provide sequence information or detect allelic variants is a WURC limitation in Genetic Techs. Ltd. , 818 F.3d at 1377; 118 USPQ2d at 1546. Amplifying and sequencing nucleic acid sequences is a WURC limitation in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014). These additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the instant claims do not amount to significantly more than the judicial exception itself ( Step 2B: NO ). As such, claims 1-11 are not patent eligible . Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-15 AIA Claim s 1-5, 8, and 10 are rejected under 35 U.S.C. 102( a)(1 ) as being anticipated by Affinito et al. (Nucleotide distance influences co-methylation between near by CpG sites. Genomics . 112(1): 144-150 (2020); published 1/10/2020) . Regarding claim 1, Affinito et al. teaches a method of evaluating the degree of co-methylation between nearby methylated CpGs (i.e., a calculation method for a base methylation degree ) (Abstract). Regarding method (1) , Affinito et al. teaches that they investigated the structural and spatial factors influencing CpGs methylation by performing an ultra-deep targeted methylation analysis on human, mouse and zebrafish genes. Methylation is not a random process and that closer neighboring CpG sites are more likely to share the same methylation status. Moreover, if the distance between CpGs increases, the degree of co-methylation decreases (i.e., a method of calculating a base methylation degree at a target site on DNA having a co-methylation site ) (Abstract). Affinito et al. further teaches that three samples for each human, mouse and zebrafish tissue were analyzed. Genomic DNA was extracted from each tissue and subsequently converted by sodium bisulfite by EZ DNA Methylation Kit. Paired-end sequencing was performed in 281 cycles per read (281×2) using Illumina MiSeq (i.e., acquiring sequence analysis data obtained by subjecting DNA having at least one co-methylation site to a sequence analysis using a sequencer ) (Pg. 145, Col. 1, Para. 4). Affinito et al. further teaches that the pair-end reads were merged together using the PEAR tool with a minimum of 40 overlapping residues and then were converted to FASTA format using PRINSEQ. An average of about 56,000 reads/sample were obtained. FASTA converted reads where analyzed using the AmpliMethProfiler pipeline in order to obtain 1 or 0 values for each methylated or unmethylated CpG for each sample. They retained only those reads which satisfied the following parameters: i) length ± 50% compared with the reference length; ii) at least 80% sequence similarity of the primer with the corresponding gene; iii) at least 98% bisulfite efficiency; iv) alignment for at least 60% of their bases with the reference sequence; and v) maximum percentage of ambiguously aligned CpG sites equal to 0 (i.e., correcting a base of the co-methylation site in a read based on quality information included in the sequence analysis data ) (Pg. 145, Col. 1, Para. 5 – Col. 2, Para. 1). Affinito et al. further teaches that they analyzed 12 datasets from 4 genes. Each dataset was organized in an incidence matrix in which each row represents a CpG site and each column represents a read. The presence of a methylation at a specific CpG site was denoted by a 1, and its absence was denoted by a 0 (i.e., calculating a base methylation degree at the target site from corrected reads ) (Pg. 145, Col. 2, Para. 2). Regarding method (2) , Affinito et al. teaches the limitations of acquiring sequence analysis data obtained by subjecting DNA having at least one co-methylation site to a sequence analysis using a sequencer , correcting a read based on quality information included in the sequence analysis data, and calculating a base methylation degree at the target site from the remaining reads as described for method (1) above. Affinito et al. further teaches that they retained only those reads which had a maximum percentage of ambiguously aligned CpG sites equal to 0 (i.e., excluding a read in which a base does not coincide between the co-methylation sites ) (Pg. 145, Col. 1, Para. 5 – Col. 2, Para. 1). Regarding method (3) , Affinito et al. teaches the limitation of acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis as described for method (1) above. Affinito et al. further teaches that paired-end sequencing was performed in 281 cycles per read (281×2) using Illumina MiSeq (i.e., according to a pair-end method using a next generation sequencer ) (Pg. 145, Col. 1, Para. 4). Affinito et al. further teaches the limitations of correcting a paired-end read based on quality information included in the sequence analysis data and calculating a base methylation degree at the target site from corrected reads as described for method (1) above. Regarding method (4) , Affinito et al. teaches the limitations of acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis according to a paired-end method using a next generation sequencer and correcting a read based on quality information included in the sequence analysis data as described for method (3) above. Affinito et al. further teaches that FASTA converted reads were analyzed using the AmpliMethProfiler pipeline in order to obtain 1 or 0 values for each methylated or unmethylated CpG for each sample. Reads were excluded that had maximum percentage of ambiguously aligned CpG sites equal to 0 (i.e., excluding a paired-end read in which a base at the target site does not coincide between the paired-end reads ) (Pg. 145, Col. 1, Para. 5 – Col. 2, Para. 1). Affinito et al. further teaches the limitation of calculating a base methylation degree at the target site from the remaining reads as described for method (2) above. Regarding method (7) , Affinito et al. teaches that paired-end sequencing was performed in 281 cycles per read (281×2) using Illumina MiSeq. The pair-end reads were merged together using the PEAR tool with a minimum of 40 overlapping residues and finally they were converted to FASTA format using PRINSEQ. An average of about 56,000 reads/sample were obtained (i.e., acquiring a plurality of sequence analysis data obtained by subjecting DNA to a plurality of sequence analyses using a sequencer ) (Pg. 145, Col. 1, Para. 4-5). Affinito et al. further teaches that FASTA converted reads where analyzed using the AmpliMethProfiler pipeline in order to obtain 1 or 0 values for each methylated or unmethylated CpG for each sample. They retained only those reads which satisfied the following parameters: i) length ± 50% compared with the reference length; ii) at least 80% sequence similarity of the primer with the corresponding gene; iii) at least 98% bisulfite efficiency; iv) alignment for at least 60% of their bases with the reference sequence; and v) maximum percentage of ambiguously aligned CpG sites equal to 0 (i.e., correcting a read based on quality information included in the sequence analysis data, for each of the sequence analysis data from an individual sequence analysis ) (Pg. 145, Col. 1, Para. 5 – Col. 2, Para. 1). Affinito et al. further teaches the limitation of calculating a base methylation degree at the target site from corrected reads as described for method (1) above. Affinito et al. further teaches that they estimated, for each gene analyzed, the mean methylation values of each CpG. As expected, the different CpGs showed different methylation values. These differences were well conserved among different samples of the same gene (i.e., calculating a representative value from sets of the methylation degrees in all the sequence analyses and adopting the representative value as a base methylation degree at the target site ) (Pg. 146, Col. 1, Para. 4). Regarding claim 2, Affinito et al. teaches all the limitations in method (1), as described for claim 1 above. Regarding claim 3, Affinito et al. teaches all the limitations in method (2), as described for claim 1 above. Regarding claim 4, Affinito et al. teaches all the limitations in method (3), as described for claim 1 above. Regarding claim 5, Affinito et al. teaches all the limitations in method (4), as described for claim 1 above. Regarding claim 8, Affinito et al. teaches all the limitations in method (7), as described for claim 1 above. Regarding claim 10, Affinito et al. teaches all the limitations in methods (1)-(4) and (7), as described for claim 1 above (i.e., wherein the calculation method is carried out by combining two or more selected from the group consisting of the methods (1) to (8) ). Therefore, Affinito et al. teaches all the limitations in claims 1-5, 8, and 10 . Claim Rejections - 35 USC § 103 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-22-aia AIA 1. Claim s 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Affinito et al . as applied to claim s 1-5, 8, and 10 above, and further in view of Corioni et al. (U.S. Patent Application Publication US 2019/0017113 A1; published 1/17/2019) . Regarding claim 6, Affinito et al. teaches the limitation of correcting a read based on quality information included in the sequence analysis data as described for method (2) in claim 1 above. Affinito et al. further teaches that they analyzed 12 datasets from 4 genes. Each dataset was organized in an incidence matrix in which each row represents a CpG site and each column represents a read. The presence of a methylation at a specific CpG site (i.e., cytosine is the most frequently appearing base) was denoted by a 1, and its absence was denoted by a 0 (i.e., calculating a base methylation degree at the target site from a set of the bases that most frequently appear ) (Pg. 145, Col. 2, Para. 2). Regarding claim 7, Affinito et al. teaches the limitation of correcting a read based on quality information included in the sequence analysis data as described for method (2) in claim 1 above. Affinito et al. further teaches that they analyzed 12 datasets from 4 genes. Each dataset was organized in an incidence matrix in which each row represents a CpG site and each column represents a read. The presence of a methylation at a specific CpG site (i.e., the determined base is cytosine) was denoted by a 1, and its absence was denoted by a 0 (i.e., calculating a base methylation degree at the target site from a set of the determined bases ) (Pg. 145, Col. 2, Para. 2). Affinito et al. , as applied to claims 1-5, 8, and 10 above, does not teach acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer (claims 6 and 7); classifying corrected reads into a group of reads having the same molecular barcode (claims 6 and 7); determining a base that most frequently appears at the target site on each of the read groups (claim 6); obtaining a read group having the same molecular barcode and the same sequence of the region including the target site (claim 7); and determining a base at the target site in each of the read groups having the same molecular barcode and the same sequence of the region including the target site (claim 7). Regarding claim 6, Corioni et al. teaches a method of preparing DNA for sequencing using next generation sequencing by attaching a molecular barcode (i.e., acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer ) (Para. [0035]-[0036], [0046] and [0049]). Corioni et al. further teaches that a barcode is used for grouping the polynucleotides. For example, a computer processor can identify the barcodes and assemble the reads by organizing the barcodes together (i.e., classifying corrected reads into a group of reads having the same molecular barcode ) (Para. [0053]). Corioni et al. further teaches that a genomic rearrangement may be identified based on data generated from sequencing of the first primer extension and the second primer extension. Sequencing data from the first primer extension provides the sequence of base pairs of the target sequence. Sequencing data from the second primer extension provides the sequence of base pairs for the adapter, which can be used to indicate or substantiate the presence of the target sequence. The combined data provided by the two primer extensions provides positional information for determining any genomic rearrangement in the polynucleotide. The sequences generated from the first primer extension and second primer extension relative to the reference sample can be used to identify the type and location of any genomic rearrangement (i.e. determining a base that most frequently appears at the target site on each of the read groups ) (Para. [0074]-[0075]). Regarding claim 7, Corioni et al. teaches the limitations of acquiring sequence analysis data obtained by subjecting DNA to which a molecular barcode is attached to a sequence analysis using a sequencer and classifying corrected reads into a group of reads having the same molecular barcode as described in method (5) in claim 6 above. Corioni et al. further teaches that barcodes can be included to identify individual reads or groups of reads and that detecting the sequence of the gene-specific barcode reliably indicates that the associated sequence is present (i.e., obtaining a read group having the same molecular barcode and the same sequence of the region including the target site ) (Para. [0053] and [0079]). Corioni et al. further teaches that a genomic rearrangement may be identified based on data generated from sequencing of the first primer extension and the second primer extension. Sequencing data from the first primer extension provides the sequence of base pairs of the target sequence. Sequencing data from the second primer extension provides the sequence of base pairs for the adapter, which can be used to indicate or substantiate the presence of the target sequence. The combined data provided by the two primer extensions provides positional information for determining any genomic rearrangement in the polynucleotide. The sequences generated from the first primer extension and second primer extension relative to the reference sample can be used to identify the type and location of any genomic rearrangement. The barcode is specifically associated with the gene, so that detecting the sequence of the gene-specific barcode reliably indicates that the associated sequence is present (i.e. determining a base at the target site in each of the read groups having the same molecular barcode and the same sequence of the region including the target site ) (Para. [0074]-[0075]). Therefore, regarding claims 6-7, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of evaluating the degree of co-methylation between nearby methylated CpGs of Affinito et al. with the method of using molecular barcodes in sequencing of Corioni et al. because incorporating molecular barcodes during sequencing allows one to distinguish PCR errors from mutations or other variants present in the data, thereby improving the quality of the reads (Corioni et al., Para. [0050]). One of ordinary skill in the art would be able to combine the teachings of Affinito et al. with Corioni et al. with reasonable expectation of success due to the same nature of the problem to be solved, since both are drawn towards a method for analyzing DNA sequencing data. Therefore, regarding claims 6-7, the instant invention is prima facie obvious (MPEP § 2142) . 07-21-aia AIA 2. Claim s 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Affinito et al. as applied to claims 1-5, 8, and 10 above . Regarding claim 9, Affinito et al. teaches the limitations of acquiring a plurality of sequence analysis data obtained by subjecting DNA to a plurality of sequence analyses using a sequence ; correcting a read based on quality information included in the sequence analysis data, for each of the sequence analysis data from an individual sequence analysis , and calculating a base methylation degree at the target site from corrected reads ; and calculating a representative value from sets of the methylation degrees in all the sequence analyses and adopting the representative value as a base methylation degree at the target site as described for method (7) in claim 1 above. Affinito et al. , as applied to claims 1-5, 8, and 10 above, does not teach wherein in a case where the sets of the methylation degrees in all the sequence analyses vary from each other or include a specifically large or small methylation degree, or in a case where the sets of the methylation degrees in all the sequence analyses vary from each other and include a specifically large or small methylation degree, the representative value and the base methylation degree at the target site are calculated to be uncalculable ; and a computer-readable storage medium storing a program for causing a computer to execute the calculation method for a base methylation degree according to claim 1 . Regarding claim 9, Affinito et al. does not explicitly disclose the limitation of wherein in a case where the sets of the methylation degrees in all the sequence analyses vary from each other or include a specifically large or small methylation degree, or in a case where the sets of the methylation degrees in all the sequence analyses vary from each other and include a specifically large or small methylation degree, the representative value and the base methylation degree at the target site are calculated to be uncalculable . However, Affinito et al. teaches that for each gene analyzed, the mean methylation values were estimated for each CpG. These differences were well conserved among different samples of the same gene (Pg. 146, Col. 1, Para. 4). It would be obvious to one of ordinary skill in the art to further analyze the sets of methylation degrees in all the sequences if the mean methylation values for different samples were not well conserved (e.g., there are outliers in the dataset). Numerous or significant outliers in the dataset could lead to the base methylation degree being incalculable (i.e., wherein in a case where the sets of the methylation degrees in all the sequence analyses vary from each other or include a specifically large or small methylation degree, or in a case where the sets of the methylation degrees in all the sequence analyses vary from each other and include a specifically large or small methylation degree, the representative value and the base methylation degree at the target site are calculated to be uncalculable ). Regarding claim 11 , in In re Venner , 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958), the court held that broadly providing an automatic or mechanical means to replace a manual activity which accomplish the same result is not sufficient to distinguish over the prior art (see also MPEP § 2144.04(III)). In the instant case, the claimed invention merely makes the process of Affinito et al. as computer-implemented or automatic and indeed accomplishes the same result. It is thus not sufficient to distinguish over Affinito et al. Therefore, the claimed invention, i.e. “ a computer-readable storage medium storing a program for causing a computer to execute the calculation method for a base methylation degree according to claim 1 ” would have been obvious to a person of ordinary skill in the art at the time the invention was made over the process disclosed by Affinito et al. There would have been a reasonable expectation of success because the court held regarding software that “writing code for such software is within the skill of the art, not requiring undue experimentation, once its functions have been disclosed.” Fonar Corp. , 107 F.3d at 1549, 41 USPQ2d at 1805. Therefore, regarding claims 9 and 11, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of evaluating the degree of co-methylation between nearby methylated CpGs of Affinito et al. to automate and augment the sequence read analysis to improve the quality of the analyzed reads (Affinito et al., Pg. 145, Col. 1, Para. 4 – Col. 2, Para. 1). One of ordinary skill in the art would be able to automate and augment the sequence read analysis with reasonable expectation of success since the method of Affinito et al. already includes several data processing steps. Therefore, regarding claims 9 and 11, the instant invention is prima facie obvious (MPEP § 2142). Conclusion No claims allowed. Inquiries Any inquiry concerning this communication or earlier communications from the examiner should be directed to DIANA P SANFORD whose telephone number is (571)272-6504. The examiner can normally be reached Mon-Fri 8am-5pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz Skowronek can be reached at (571)272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /D.P.S./Examiner, Art Unit 1687 /Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687 Application/Control Number: 17/945,689 Page 2 Art Unit: 1687 Application/Control Number: 17/945,689 Page 3 Art Unit: 1687 Application/Control Number: 17/945,689 Page 4 Art Unit: 1687 Application/Control Number: 17/945,689 Page 5 Art Unit: 1687 Application/Control Number: 17/945,689 Page 6 Art Unit: 1687 Application/Control Number: 17/945,689 Page 7 Art Unit: 1687 Application/Control Number: 17/945,689 Page 8 Art Unit: 1687 Application/Control Number: 17/945,689 Page 9 Art Unit: 1687 Application/Control Number: 17/945,689 Page 10 Art Unit: 1687 Application/Control Number: 17/945,689 Page 11 Art Unit: 1687 Application/Control Number: 17/945,689 Page 12 Art Unit: 1687 Application/Control Number: 17/945,689 Page 13 Art Unit: 1687 Application/Control Number: 17/945,689 Page 14 Art Unit: 1687 Application/Control Number: 17/945,689 Page 15 Art Unit: 1687 Application/Control Number: 17/945,689 Page 16 Art Unit: 1687 Application/Control Number: 17/945,689 Page 17 Art Unit: 1687 Application/Control Number: 17/945,689 Page 18 Art Unit: 1687 Application/Control Number: 17/945,689 Page 19 Art Unit: 1687 Application/Control Number: 17/945,689 Page 20 Art Unit: 1687 Application/Control Number: 17/945,689 Page 21 Art Unit: 1687 Application/Control Number: 17/945,689 Page 22 Art Unit: 1687 Application/Control Number: 17/945,689 Page 23 Art Unit: 1687 Application/Control Number: 17/945,689 Page 24 Art Unit: 1687 Application/Control Number: 17/945,689 Page 25 Art Unit: 1687 Application/Control Number: 17/945,689 Page 26 Art Unit: 1687