DETAILED ACTION
Applicant’s response filed 06/23/2026 has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied.
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 .
Status of the Claims
Claims 1-12 are pending and under consideration in this action. Claim 12 is newly added in the amendment filed 06/23/2026.
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 1-12 is 3/25/2020.
Claim Objections
Withdrawn Objections
The objection to claim 1 is withdrawn in view of Applicant’s amendments to the claims filed 06/23/2026 (Applicant’s Remarks, Pg. 6).
Newly Recited Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites the phrase “correcting the read reads by replacing a base of the co-methylation site having lower sequence reliability with a base having higher sequence reliability…” in method (1) of the claim, which should be corrected to “correcting the ” for clarity.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
Maintained Rejections
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.
Claims 1-12 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.
This rejection is maintained from the previous Office Action.
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 2-12 are also rejected due to their dependency from claim 1.
Response to Arguments under 35 U.S.C. 112(b)
Applicant’s arguments filed 06/23/2026 have been fully considered but they are not persuasive.
1. Applicant argues that the technical concept of method (8) is to determine a criterion for calculating the methylation degree (i.e., a cutoff value for considering the degree incalculable) based on data variation and the methylation degree itself It is commonly understood by one of ordinary skill in the art that a specific cutoff value should be adjusted and set according to the conditions of each case because the true methylation degree of a sample varies from case to case, the degree of measurement errors in reads (e.g., base conversion errors during bisulfite treatment, PCR amplification errors, sequencer reading errors, etc.) varies from case to case, and the required accuracy of the calculated methylation degree also varies. Therefore, even if the claim does not strictly specify "to what specific extent a large or small methylation degree is included," the scope of the claimed invention is not indefinite to one of ordinary skill in the art (Applicant’s Remarks, Pg. 7).
It is respectfully submitted that this is not persuasive for the following reasons:
MPEP § 2173.05(b)(I) recites:
"Claim language employing terms of degree has long been found definite where it provided enough certainty to one of skill in the art when read in the context of the invention." Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1370, 112 USPQ2d 1188, 1192-93 (Fed. Cir. 2014) (citing Eibel Process Co. v. Minnesota & Ontario Paper Co., 261 U.S. 45, 65-66 (1923) (finding ‘substantial pitch’ sufficiently definite because one skilled in the art ‘had no difficulty … in determining what was the substantial pitch needed’ to practice the invention)). Thus, when a term of degree is used in the claim, the examiner should determine whether the specification provides some standard for measuring that degree. Hearing Components, Inc. v. Shure Inc., 600 F.3d 1357, 1367, 94 USPQ2d 1385, 1391 (Fed. Cir. 2010); Enzo Biochem, Inc., v. Applera Corp., 599 F.3d 1325, 1332, 94 USPQ2d 1321, 1326 (Fed. Cir. 2010); Seattle Box Co., Inc. v. Indus. Crating & Packing, Inc., 731 F.2d 818, 826, 221 USPQ 568, 574 (Fed. Cir. 1984). If the specification does not provide some standard for measuring that degree, a determination must be made as to whether one of ordinary skill in the art could nevertheless ascertain the scope of the claim (e.g., a standard that is recognized in the art for measuring the meaning of the term of degree). For example, in Ex parte Oetiker, 23 USPQ2d 1641 (Bd. Pat. App. & Inter. 1992), the phrases "relatively shallow," "of the order of," "the order of about 5mm," and "substantial portion" were held to be indefinite because the specification lacked some standard for measuring the degrees intended.
As described in MPEP § 2173.05(b)(I) and in the rejection above, the Specification does not provide, for example, any definition or parameters of “specifically large” or “specifically small”. While the Specification does indicate that there are errors in the accuracy of the quantification of the methylation degree, due to base conversion errors during bisulfite treatment, PCR amplification errors, and sequencer reading error (see at least Para. [0005] and [0067]), it does not provide an example indicating how these errors correlate to the specifically large or specifically small methylation degrees. Analogous to Ex parte Oetiker, 23 USPQ2d 1641 (Bd. Pat. App. & Inter. 1992), where the phrases "relatively shallow," "of the order of," "the order of about 5mm," and "substantial portion" were held to be indefinite because the specification lacked some standard for measuring the degrees intended, the instant Specification does not provide any standard for “specifically large” or “specifically small”. Accordingly, these phrases are indefinite and this argument is not persuasive.
Claim Rejections - 35 USC § 101
Withdrawn Rejections
The rejection of claim 11 under 35 U.S.C. 101 for being directed to non-statutory subject matter is withdrawn in view of Applicant’s amendments to the claims filed 06/23/2026 (Applicant’s Remarks, Pg. 7).
Maintained Rejections
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 1-12 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)).
Any newly recited portion is necessitated by claim amendment.
Framework with which to evaluate Subject Matter Eligibility as outlined in MPEP § 2106:
Step 1: Are the claims directed to a process, machine, manufacture or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework as it pertains to the instant claims:
Step 1:
In the instant application, claims 1-10 and 12 are directed towards a process, and claim 11 is directed towards a manufacture, which falls into one of the categories of statutory subject matter (Step 1: YES).
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., an evaluation of sequence reliability for base exchange) in “correcting the read reads by replacing a base of the co-methylation site having lower sequence reliability with a base having higher sequence reliability 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., an evaluation of reads with higher sequence reliability as representative) in “correcting a paired-end read based on quality information included in the sequence analysis data by selecting a read having a higher sequence reliability as a representative of the paired-end read in a case where 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 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., an evaluation of reads to exclude based on base reliability) “correcting a read based on quality information included in the sequence analysis data by excluding a read in which base reliability at the target site is lower than a reference value, for each of the sequence analysis data from an individual sequence analysis”; a mathematical concept in “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., an evaluation of reads to exclude based on base reliability) “correcting a read based on quality information included in the sequence analysis data by excluding a read in which base reliability at the target site is lower than a reference value, for each of the sequence analysis data from an individual sequence analysis”; a mathematical concept in “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, 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 incalculable”.
Claim 12 recites a mental process (i.e., an evaluation of the deviation in the methylation degree) in “wherein in the method (8), the representative value and the base methylation degree at the target site are calculated to be incalculable in a case where there is a deviation of 3% or more in the methylation degree in the plurality of sequence analyses”.
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 of reads 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 of reads 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 1-12 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 of reads 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 1-12 are not patent eligible.
Response to Arguments under 35 U.S.C. 101
Applicant’s arguments filed 06/23/2026 have been fully considered but they are not persuasive.
1. Applicant argues that as amended, claim 1 recites methods (1) through (8), including (1) read correction by base replacement, (2) removal of reads with mismatched bases, (3) selection of a representative read, (4) removal of paired-end reads with mismatched bases, (5) division into read groups and determination of the most frequently appearing base at the target site, (6) division into read groups, removal of reads lacking sequence identity within each group, and determination of the base at the target site, (7) removal of reads with low base reliability and calculation of a representative value from sets of methylation degrees, and (8) removal of reads with low base reliability, calculation of a representative value from sets of methylation degrees, and determination of whether calculation is possible. These processes are not merely mental processes or mathematical calculations, but technical improvements in bioinformatics that manipulate data by actively utilizing structures inherent in DNA sequence analysis data (e.g., co-methylation sites and molecular barcodes) and quality indicators derived from a sequencer (e.g., reliability scores) (Applicant’s Remarks, Pg. 7-8).
It is respectfully submitted that this is not persuasive for the following reasons:
As described in the rejection above, each of methods (1) through (8) recites either mental processes and/or mathematical calculations. For example, as amended, method (1) recites both a mental and a mathematical concept. Under the broadest reasonable interpretation (BRI), the limitation of correcting the reads by replacing a base of the co-methylation site having lower sequence reliability with a base having higher sequence reliability based on quality information included in the sequence analysis data is an evaluation of the sequence reliability for a base of the co-methylation site, with the base being replaced if the sequence reliability is higher than the original. The evaluation of the sequence reliabilities for a base at a co-methylation site is a process capable of being performed in the human mind. Additionally, under the BRI, the limitation of calculating a base methylation degree at the target site from corrected reads recites a mathematical concept. 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, method (1) recites abstract ideas.
For the sake of not reiterating the rejection above, methods (2) through (8) also recite mental processes and/or mathematical concepts. Additionally, evaluation of improvements to technology using the additional elements of the claim are evaluated under Step 2A, Prong Two and Step 2B (see MPEP § 2106.04(d)). Therefore, claim 1 recites abstract ideas and this argument is not persuasive.
2. Applicant also argues that with respect to Step 2A, Prong Two and Step 2B, amended claim 1 provides an "inventive concept" that transforms an abstract idea into a patent-eligible application and is not merely data gathering or well-understood, routine, and conventional activity. As described in the Background Art section of the present specification, the conventional calculation of the base methylation degree using the bisulfite sequencing method has a technical problem that the accuracy of quantification is limited due to base conversion errors during the bisulfite treatment, PCR amplification errors, sequencer reading errors, etc. In view of the above, the claimed invention solves the technical problem of reducing the influence of such errors and improving the accuracy of calculating the methylation degree by executing an ordered combination of steps: "data acquisition [Wingdings font/0xE0] cross-referencing specific structures (co-methylation sites or molecular barcodes) with quality information [Wingdings font/0xE0] base replacement/read exclusion based on the reliability of the target co-methylation site base [Wingdings font/0xE0] recalculation of the methylation degree". The configuration comprising such claimed base replacement/correction processes combined with other steps recited in the claims is not mere data gathering or a well-understood, routine, and conventional activity but provides an inventive concept that transforms the abstract idea into a patent-eligible application (Applicant’s Remarks Pg. 8).
It is respectfully submitted that this is not persuasive for the following reasons:
MPEP 2106.04(d)(II) recites:
The analysis under Step 2A Prong Two is the same for all claims reciting a judicial exception, whether the exception is an abstract idea, a law of nature, or a natural phenomenon (including products of nature). Examiners evaluate integration into a practical application by: (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception(s); and (2) evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application, using one or more of the considerations introduced in subsection I supra, and discussed in more detail in MPEP §§ 2106.04(d)(1), 2106.04(d)(2), 2106.05(a) through (c) and 2106.05(e) through (h).
Several of the limitations included in the ordered combination of steps, as indicated by Applicant, recite judicial exceptions, as described in Step 2A, Prong One and argument (1) above. These include cross-referencing specific structures (co-methylation sites or molecular barcodes) with quality information (e.g., classifying corrected reads into a group of reads having the same molecular barcode in method (5)), base replacement/read exclusion based on the reliability of the target co-methylation site base (e.g., correcting the reads by replacing a base of the co-methylation site having lower sequence reliability with a base having higher sequence reliability based on quality information included in the sequence analysis data in method (1)), and recalculation of the methylation degree (e.g., calculating a base methylation degree at the target site from corrected reads in method (1)). The integration of a judicial exception into a practical application can only be achieved by additional elements, not by a limitation that recites a judicial exception. Thus, the recited limitations are not considered as an improvement in the conventional calculation of the base methylation degree. This argument is thus not persuasive.
3. Applicant also argues that since this combination does not exist in the prior art, it has a meaningful additional element that goes beyond the judicial exception itself (Applicant’s Remarks, Pg. 9).
It is respectfully submitted that this is not persuasive for the following reasons:
MPEP § 2106.05(I) recites:
“Although the courts often evaluate considerations such as the conventionality of an additional element in the eligibility analysis, the search for an inventive concept should not be confused with a novelty or non-obviousness determination. See Mayo, 566 U.S. at 91, 101 USPQ2d at 1973 (rejecting "the Government’s invitation to substitute §§ 102, 103, and 112 inquiries for the better established inquiry under § 101 "). As made clear by the courts, the "‘novelty’ of any element or steps in a process, or even of the process itself, is of no relevance in determining whether the subject matter of a claim falls within the § 101 categories of possibly patentable subject matter." Intellectual Ventures I v. Symantec Corp., 838 F.3d 1307, 1315, 120 USPQ2d 1353, 1358 (Fed. Cir. 2016) (quoting Diamond v. Diehr, 450 U.S. at 188–89, 209 USPQ at 9). See also Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1151, 120 USPQ2d 1473, 1483 (Fed. Cir. 2016) ("a claim for a new abstract idea is still an abstract idea. The search for a § 101 inventive concept is thus distinct from demonstrating § 102 novelty."). In addition, the search for an inventive concept is different from an obviousness analysis under 35 U.S.C. 103. See, e.g., BASCOM Global Internet v. AT&T Mobility LLC, 827 F.3d 1341, 1350, 119 USPQ2d 1236, 1242 (Fed. Cir. 2016) ("The inventive concept inquiry requires more than recognizing that each claim element, by itself, was known in the art. . . . [A]n inventive concept can be found in the non-conventional and non-generic arrangement of known, conventional pieces."). Specifically, lack of novelty under 35 U.S.C. 102 or obviousness under 35 U.S.C. 103 of a claimed invention does not necessarily indicate that additional elements are well-understood, routine, conventional elements. Because they are separate and distinct requirements from eligibility, patentability of the claimed invention under 35 U.S.C. 102 and 103 with respect to the prior art is neither required for, nor a guarantee of, patent eligibility under 35 U.S.C. 101. The distinction between eligibility (under 35 U.S.C. 101) and patentability over the art (under 35 U.S.C. 102 and/or 103) is further discussed in MPEP § 2106.05(d).”
Additionally, whether or not the claimed elements appear to be free of the prior art is distinct from subject matter eligibility under 35 U.S.C. 101. As described in the rejection, and arguments above, only the additional elements can provide the technical improvements and amount to significantly more than the recited judicial exceptions. The additional elements recite steps for acquiring data and do not provide significantly more than the recited judicial exceptions. This argument is thus not persuasive and the rejection of claims 1-12 under 35 U.S.C. 101 is maintained.
Claim Rejections - 35 USC § 102
Withdrawn Rejections
The rejection of claims 2, 4, and 8 under 35 U.S.C. 102(a)(1) as being anticipated by Affinito et al. is withdrawn in view of Applicant’s amendments to the claims filed 06/23/2026, and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 10-12). Specifically, regarding method (1), Affinito et al. does not teach the replacement of a base of a co-methylation site having lower sequence reliability. Regarding method (3), Affinito et al. does not teach the correction of a paired-end read by selecting a read having higher sequence reliability as representative when the base at the target site does not coincide between the paired-end reads. Regarding methods (7) and (8), Affinito et al. does not teach the exclusion of a read where the base reliability at the target site is lower than a reference value.
Maintained Rejections
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 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 –
(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.
Claims 1, 3, 5, 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 nearby CpG sites. Genomics. 112(1): 144-150 (2020); published 1/10/2020; previously cited).
This rejection is maintained from the previous Office action. Any newly recited portion is necessitated by claim amendment.
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 (2), 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 read 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 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). 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 (4), Affinito teaches the limitation of acquiring sequence analysis data obtained by subjecting DNA to a sequence analysis as described for method (2) 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 limitation of correcting a read based on quality information included in the sequence analysis data as described for method (2) 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 claim 3, Affinito et al. teaches all the limitations in method (2), 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 10, Affinito et al. teaches all the limitations in methods (2) and (4), 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, 3, 5, and 10.
Response to Arguments under 35 U.S.C. 102
Applicant’s arguments filed 06/23/2026 have been fully considered but they are not persuasive.
1. Applicant argues that the Examiner rejects methods (1)-(4), (7), and (8) over Affinito et al. alone. However, Affinito et al. fail to disclose or suggest methods (2) and (4) as set forth above. Furthermore, in amended claim 1, methods (1), (3), (7), and (8) are further defined to recite aspects corresponding to Embodiments 1-1, 2-1, 4-1, and 4-2, respectively, which Affinito et al. fail to disclose or suggest as set forth above. For method (2), Affinito does not disclose excluding a read in which a base does not coincide between the co-methylation sites. For method (4), Affinito does not disclose excluding a paired-end read in which a base at the target site does not coincide between the paired-end reads (Applicant’s Remarks, Pg. 11-12).
It is respectfully submitted that this is not persuasive for the following reasons:
Examiner agrees that as amended, methods (1), (3), (7), and (8) are not disclosed by Affinito et al. Accordingly, the rejection of dependent claims 2, 4, and 8 (corresponding to methods (1), (3), and (7)) was withdrawn above. Method (8) is described in detail under the section for 35 U.S.C. 103 Rejections below.
However, Affinito et al. discloses all the limitations recited in methods (2) and (4). With regards to method (2), the step of excluding a read in which a base does not coincide between the comethylation sites. Affinito et al. discloses that they retained only those reads which had a maximum percentage of ambiguously aligned CpG sites equal to 0 (Pg. 145, Col. 1, Para. 5 – Col. 2, Para. 1). Said differently, Affinito et al. teaches that reads were excluded because when compared to a reference the CpG site alignment is ambiguous. Since Affinito et al. also discloses the analysis of neighboring CpG sites (see at least Abstract), a misalignment (thereby leading to an exclusion of a read) due to base difference(s) in (any of the neighboring) CpG sites would therefore lead to the read being excluded. Since the base related to any of the neighboring CpG site is misaligned and excluded, this falls under the BRI of excluding a read in which a base does not coincide between the comethylation sites.
Analogously, with regards to method (4), the step of excluding a paired-end read in which a base at the target site does not coincide between the paired-end reads Affinito et al. teaches the analysis of paired-end reads (Pg. 145, Col. 1, Para. 4) and the same exclusion of reads with misaligned CpG sites as described in method (2) above. Therefore, Affinito appears to disclose all the limitations in methods (2) and (4), and this argument is not persuasive.
Claim Rejections - 35 USC § 103
Withdrawn Rejections
The rejection of claims 6-7 under 35 U.S.C. 103 as being unpatentable over Affinito et al in view of Corioni et al. is withdrawn in view of Applicant’s amendments to the claims filed 06/23/2026, and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 12-13). Specifically, for methods (5) and (6), while the method of Corioni et al. discloses the determination of a base that most frequently appears at the target site, neither Corioni et al. nor Affinito et al. discloses that this most frequently occurring base is used to correct the base methylation degree at the target site.
The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over Affinito et al. is withdrawn in view of Applicant’s amendments to the claims filed 06/23/2026, and Applicant’s Remarks were found persuasive (Applicant’s Remarks, Pg. 11-12). Regarding method (8), Affinito et al. does not teach the exclusion of a read where the base reliability at the target site is lower than a reference value.
Maintained Rejections
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.
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.
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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Affinito et al. as applied to claims 1, 3, 5, and 10 above.
This rejection is maintained from the previous Office action.
Affinito et al., as applied to claims 1, 3, 5, and 10 above, does not teach a non-transitory 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 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 non-transitory 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 claim 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 claim 11, the instant invention is prima facie obvious (MPEP § 2142).
Response to Arguments under 35 U.S.C. 103
Examiner notes that Applicant did not provide remarks regarding the automation of the claimed method as recited using the non-transitory computer-readable medium in claim 11. Accordingly, the rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over Affinito et al. is maintained.
Conclusion
No claims allowed.
Claims 2, 4, 6-9, and 12 appear to be free from the prior art because the prior art does not fairly suggest or teach the replacement of a base of a co-methylation site having lower sequence reliability, the correction of a paired-end read by selecting a read having higher sequence reliability as representative when the base at the target site does not coincide between the paired-end reads, the use of a most frequently occurring base to correct the base methylation degree at the target site, or the exclusion of a read where the base reliability at the target site is lower than a reference value. The closest prior art is Affinito et al. (Nucleotide distance influences co-methylation between nearby CpG sites. Genomics. 112(1): 144-150 (2020); previously cited). Affinito discloses method of evaluating the degree of co-methylation between nearby methylated CpGs, including the analysis of sequences having at least one co-methylation site, correction of reads based on quality information, and calculation of base methylation degree based on corrected reads. However, Affinito et al. does not teach the replacement of a base of a co-methylation having lower sequence reliability, the correction of a paired-end read by selecting a read having higher sequence reliability as representative when the base at the target site does not coincide between the paired-end reads, the use of a most frequently occurring base to correct the base methylation degree at the target site, or the exclusion of a read where the base reliability at the target site is lower than a reference value, as disclosed in instant claims 2, 4, and 6-9. Claim 12 appears to be free from the prior art due to its dependency on claim 9.
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.
Conclusion
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/D.P.S./Examiner, Art Unit 1687
/Lori A. Clow/Primary Examiner, Art Unit 1687
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