CTNF 17/924,641 CTNF 97539 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 1-8 are pending and examined herein. Claims 9-12 are canceled. Priority As detailed on the 14 March 2023 filing receipt, the application claims priority as early as 14 May 2021, and draws priority to JP 2020/085433 and PCT JP2021/018512. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date. Information Disclosure Statement Information disclosure statements (IDS) were filed on 10 November 2022, 16 June 2024, and 31 December 2025. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner. Drawings 06-22 AIA The drawings are objected to because the figure is illegible . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Claim Objections 07-29-01 AIA Claim 1 is objected to because of the following informalities: the abbreviations “TD” and “SD” are not explained. The specification discloses the abbreviation “TD” refers to “Targets Detected” (pg. 10, third paragraph). The specification discloses the abbreviation “SD” refers to “Samples Detected.” Appropriate correction is required. 07-30-03-h AIA Claim Interpretation Claim 1 recites “analysis of RNA expression information obtained from secretion collected from a plurality of subjects as biological specimens.” The past tense of “obtained” is interpreted as the secretion samples from multiple subjects was collected outside the metes and bounds of the required claims. 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 1-8 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of RNA expression data processing. MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below. Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)? 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 (MPEP 2106.04(a-c))? Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))? Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)? Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)? The claims are directed to a method (claims 1-8), which falls within one of the categories of statutory subject matter. [Step 1: Yes] 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 (MPEP 2106.04(a-c))? With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as: • mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations) (MPEP 2106.04(a)(2)(I)); • certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or • mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)). Claim 1 recites counting detectable RNAs and determining a proportion of those in a bin, where counting is interpreted a mental or mathematical step, and binning is a mental step. Claim 1 recites excluding specimens outside a threshold, where excluding data is a binning step and thus a mental process of data selection. Exclusion can also be interpreted as a mathematical comparison of numbers to threshold values and thus also a mathematical concept. Claim 1 recites determining a proportion of specimens above a given expression threshold, where determining is interpreted a mental evaluation step and binning a proportion is a mental step. Claim 1 recites excluding specimens outside a threshold, where excluding data is a binning step and thus a mental process of data selection. Exclusion can also be interpreted as a mathematical. The claim element also recites extracting expression information as an analysis target, where, under a broadest reasonable interpretation in light of the specification, is interpreted as further abstract data analysis based on information or data per se and thus is also abstract (MPEP 2106.03(I)). Claim 2 recites additional information about the secretion, which is interpreted as directed to information further limiting the data being analyzed since collecting the sample is not required, and thus is interpreted as data per se (MPEP 2106.03(I)). Claim 3 recites additional information about the read counts being derived from RNA-Seq, but this is interpreted as further directed to limiting the data type as RNA-Seq itself is not required and thus is interpreted as data per se (MPEP 2106.03(I)). Claims 4-6 recite a threshold for interpreting whether RNA expression is negligible for the purposes of binning as zero and excluding specimens, and thus directed to the abstract steps discussed in claim 1. Claim 7 recites a threshold for interpreting whether an RNA should be included in a final analysis and thus directed to the abstract steps discussed in claim 1. Claim 8 recites correction by normalization and thus is a mathematical concept. A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation (MPEP 2106.04(a)(2)). Hence, the claims explicitly recite numerous elements that, individually and in combination, constitute abstract ideas. The claims must therefore be examined further to determine whether they integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A Prong One: Yes] Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))? The independent claims are not considered to recite any elements in addition to the abstract ideas. The claims are all method steps for analyzing data which are either mental or mathematical. None of the dependent claims recite any additional non-abstract elements; they are all directed to further aspects of the information being analyzed, the manner in which that analysis is performed, or the mathematical operations performed on the information. Because elements in addition to the abstract ideas are absent, the abstract ideas are not integrated into a practical application. [Step 2A Prong Two: No] Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)? 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 of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05). As discussed in the previous step, no elements in addition to the abstract idea are present in the claims. Therefore, no such elements are unconventional in their arrangement or no such elements can provide significantly more than the judicial exceptions. [Step 2B: No] Conclusion: Claims are Directed to Non-statutory Subject Matter For these reasons, the claims, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as being directed to non-statutory subject matter. Claim Rejections - 35 USC § 103 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. 07-20-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. Claims 1 and 3-8 07-21-aia AIA Claim s 1 and 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (The FASEB Journal 19(10): 25 pgs., 2005; newly cited) in view of Wang (2019 IEEE International Conference on Bioinformatics and Biomedicine: 1780-1786, 2019; newly cited), Blaimer (Plos One 11(8): 20 pgs., 2016; newly cited), and Brown (doctoral dissertation, Louisiana State University, 178 pgs., 2019; newly cited) . Claim 1 recites counting the number of detectable RNAs in detection target RNAs by judging RNAs of which an expression level is zero or can be regarded as zero to be undetectable, and determining proportion 1 (TD value) of the number of detectable RNAs with respect to the total number of the detection target RNAs for each specimen and excluding specimens for which proportion 1 is less than a threshold set within a range from 5% to 29% from the specimens to select analysis target specimens. Lee teaches sampling based on gene expression values, where expression values were scored. Lee teaches detecting transcripts as present or absent (pg. 3, third paragraph) and grading, to establish degradation, as samples without distinct 18S and 28S bands and/or a low molecular weight smear as degraded (pg. 3, first paragraph) and thus excluded from analysis. (pg. 7, third paragraph). Therefore, Lee teaches excluding subjects based on low expression but not a 5-29% threshold. Claim 1 recites determining, for each detection target RNA, proportion 2 (SD value) of the number of specimens for which the expression level thereof is higher than zero or higher than an expression level that can be regarded as zero with respect to the total number of the analysis target specimens based on the RNA expression information of the analysis target specimens selected above and excluding RNAs for which the proportion 2 is less than a threshold set within a range from 81% to 99% from the detection target RNAs and extracting expression information of RNAs other than the excluded RNAs as an analysis target. Wang teaches “genes with no expressions or very low expression levels are common in RNA-seq because of the tissue specificity of gene expression and need to be excluded” (pg. 1782, col.1, first paragraph), where genes are kept if they are about 0.1 transcripts per million in at least 20% of samples and at least six reads in at least 20% of samples. Therefore, Wang teaches excluding genes if they are not sufficiently found in enough samples but not at 81-99%. Blaimer teaches a comparative transcriptomic method in which specimens with low locus counts with respect to other specimens are excluded from a phylogeny, where about 5.1% of loci where shared and the specimen was excluded (pg. 16, first paragraph). Brown teaches a comparative transcriptomic pipeline in which loci had to present in 95% of subjects to be included (pg. 64, first paragraph). Claim 3 recites the information on the RNA expression level is a read count value by RNA-Seq. Wang teaches using RNA-seq for read counts (Fig. 1). Claim 4 recites the RNAs of which the expression level is zero or can be regarded as zero in the counting step are RNAs of which the read count value by RNA-seq is less than 10. Wang teaches keeping reads with at least 6 reads (pg. 1782, col. 1, first paragraph), thus also teaching less than 10. Claim 5 recites the threshold of the proportion 1 in the first excluding step is set to 20%. This claim is interpreted as further limiting the upper range being 20% rather than 29% such that the range is considered to be 5-20%. Blaimer teaches a comparative transcriptomic method in which specimens with low locus counts with respect to other specimens are excluded from a phylogeny, where about 5.1% of loci where shared and the specimen was excluded (pg. 16, first paragraph). Claim 6 recites the specimens for which the expression level is higher than zero or higher than an expression level that can be regarded as zero in the determining step are specimens for which the read count value in RNA-seq is higher than 0. Wang teaches specimens with expression levels that are detectable, and thus higher than zero, but are excluded due to low counts, meaning low quality (pg. 1782, col.1, first paragraph). Claim 7 recites the threshold of the proportion 2 in the second excluding step is set to 90%. This claim is interpreted as further limiting the lower bound of the range, now considered to recite 90-99%. Brown teaches a comparative transcriptomic pipeline in which loci had to present in 95% of subjects to be included (pg. 64, first paragraph). Claim 8 recites normalizing the total RNA expression information extracted by the method according to the first claim. Wang and Lee teach normalizing expression level (Wang: pg. 1782, col. 1, first paragraph; Lee: pg. 8, second paragraph). Combining Lee, Wang, Blaimer, and Brown An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the works of Lee and Wang because Lee teaches screening subjects based on low quality RNA samples and Wang teaches screening reads based on not being found in enough subjects. Therefore, both are directed to removing low quality reads. Furthermore, Wang teaches excluding subjects but on different grounds (pg. 1781, col. 2, last paragraph). Because both Wang and Lee are directed to the shared field of endeavor of RNA-based quality control for expression analyses, their combination would be expected to be successful by one having ordinary skill in the art at the time of filing. Combination with Brown and Blaimer are related to more specific ranges in the first and second filtering for quality control of the data set, wherein the first filter is for filtering specimens without sufficient loci and the second is filtering loci based on presence in subjects. Blaimer teaches omitting taxa in a phylogenetic dataset which recovered a low number of target loci, here ultraconserved elements, shared with the other taxa, which created erroneous or inconsistent phylogenetic results and thus required exclusion (pg. 16, first paragraph). Similarly, Brown teaches a minimum overlap of loci such that 95% of loci are required to be present to continue with the analysis, but an increased threshold was preferable to avoid inconsistent results from low quality samples (pg. 63, last paragraph to pg. 64, first paragraph). Therefore, both Brown and Blaimer are also directed to the field of nucleic acid analysis and quality control. Therefore, the invention is prima facie obvious. Claim 2 07-22-aia AIA Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Lee , Wang , Blaimer , and Brown as applied to claim s 1 and 3-8 above and further in view of Chen (doctoral dissertation, University of Liverpool, 281 pp., 2017; newly cited) . Claim 2 recites the secretion is skin surface lipids. Lee teaches samples from the skin (Fig. 7 caption) but not specifically surface lipids. Chen teaches differential expression of skin surface lipids (pg. 82, first paragraph). Combining Lee, Wang, Blaimer, Brown, and Chen The combination of the previously combined art teaches quality control in sequence analysis, where Lee at least teaches skin and subcutaneous tissue analysis among others (Table 1) while Wang teaches application across multiple tissues (pg. 1780, col. 1, only paragraph) and Brown teaches liver and brain tissues (pg. 109, Methods). The data analysis steps are agnostic to the type of tissue used, and so analysis of skin surface lipids, as taught in the differential expression analyses of Chen (pg. 82, first paragraph) would also be expected to succeed. Thus, the combination represents a simple substitution of one known element for another to obtain predictable results (MPEP 2143 B) and is prima facie obvious. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM 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, Olivia M. Wise can be reached at (571) 272-2249. 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. /Robert J. 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