CTFR 18/089,565 CTFR 99265 DETAILED ACTION Applicant’s response, filed 04/29/2026, 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 Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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. They constitute the complete set presently being applied to the instant application. 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. 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 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. Claim Status Claims 1-4 and 7-19 are pending. Claims 8-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, as described above. Claims 5 and 6 are cancelled. Claims 1-4 and 7 are under examination. Claim 1 is objected to. Claims 1-4 and 7 are rejected. Priority The instant Application claims domestic benefit to US provisional application 63/294,359, filed 12/28/2021. Accordingly, each of claims 1-7 are afforded the effective filing date of the 12/28/2021. Information Disclosure Statement The information disclosure statements (IDS) filed on 03/01/2024, 06/06/2024, and 01/25/2024 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action. Drawings The Drawings submitted 03/31/2023 are accepted. Claim Objections The outstanding objections to the claims are withdrawn in view of the amendments submitted herein. The claims are objected to because of the following informalities. The instant objection is newly stated and is necessitated by claim amendment. Claim 1 recites, in the final limitation, a plurality of steps: “identifying… and selecting…”. As set forth in 37 CFR 1.75, where a claim sets forth a plurality of steps, each step of the claim should be separated by a line indentation (see MPEP 608.01(i)). Claim Rejections- 35 USC § 112 The outstanding rejections to the claims are withdrawn in view of the amendments submitted herein. 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. For the following rejections, underlined text indicates newly recited portions necessitated by claim amendment. Claims 1-4 and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. The previous 101 rejection is maintained. Any newly recited portions are necessitated by claim amendment. MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials. Framework with which to Evaluate Subject Matter Eligibility : 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 Analysis as Pertains to the Instant Claims: Step 1 With respect to Step 1 : yes, the claims are directed to method, i.e. , a process, machine, or manufacture within the above 101 categories [ Step 1: YES ; See MPEP § 2106.03]. Step 2A, Prong One With respect to Step 2A, Prong One , the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as: mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations); certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information). The claims also recite a law of nature or a natural phenomenon. The MPEP at 2106.04(b) further explains that laws of nature and natural phenomena include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. With respect to the instant claims , under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows: Independent claim 1 : identifying expression levels of multiple genes in normal tissue samples and tumor tissue samples, and selecting genes with higher expression levels in the tumor tissue samples than in the normal tissue samples; using tissue-specific genes or group-enriched genes with the higher expression levels in the tumor tissue samples than in the normal tissue samples to calculate a weight of each human tissue's contribution to plasma exosomes to obtain a calculated weight; using the calculated weight to simulate a plasma exosome expression level distribution of circulating biomarker in healthy people and cancer patients to obtain simulated plasma exosome expression level distributions, wherein an intersection area of probability density functions of plasma exosome expression levels of the healthy people and the cancer patients are calculated according to the simulated plasma exosome expression level distributions, and the intersection area is an overlapping index. comparing expression levels of plasma exosome genes of the healthy people and the cancer patients by the overlapping index selecting circulating biomarkers and combinations thereof suitable for detection and evaluation of the plasma exosomes Dependent claim 2: wherein a statistical analysis method is used to select the genes with the higher expression level in the tumor tissue samples than in the normal tissue samples , and the statistical analysis method includes a null hypothesis test and a fold change threshold. Dependent claim 3: using Welch's t-test to calculate a p value; adjusting the p value by using a permutation test to increase a test validity; and performing a screening by using a false discovery rate as a criterium to reduce a probability of selecting false high-expression genes. Dependent claim 4: comparing an exosome database and subcellular locations to see if the circulating biomarkers are expressed on the surface and/or inside exosome before calculating the weight of each human tissue's contribution to plasma exosomes. Dependent claim 7 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 7 further limits the overlapping index of claim 1. The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually identify, calculate, select, adjust, screen, compare and simulate. Without further detail as to the methodology involved in “identifying expression levels”, “calculate a weight of each human tissue's contribution “, “selecting circulating biomarkers “, under the BRI, one may simply, for example, use pen and paper to identify circulating biomarkers for cancer detection. For those mathematical steps involved in “ simulate a plasma exosome expression level distribution” and “calculate intersection area of probability density functions of plasma exosome expression levels” are considered mathematical concepts. Therefore, claim 1 and those claims dependent therefrom recite an abstract idea and a law of nature/natural phenomenon [ Step 2A, Prong 1: YES ; See MPEP § 2106.04]. Step 2A, Prong Two Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two , provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III). Additional elements, Step 2A, Prong Two With respect to the instant recitations, there are no additional elements Considerations under Step 2A, Prong Two Thus, none of the claims recite additional elements, therefore the judicial exceptions are not integrated into a practical application, and the claims are directed to one or more judicial exceptions [ Step 2A, Prong 2: NO ; See MPEP § 2106.04(d)]. Step 2B (MPEP 2106.05.A i-vi) According to analysis so far, there are no additional elements. Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106. Response to Applicant Arguments Applicant submits the Examiner's characterization of the claimed method as performable by pen and paper is therefore not technically accurate [p. 9, par. 1]. It is respectfully found not persuasive. The previous 101 rejection stated that the limitations are to each cover performance either in the mind and/or by mathematical operation. The above 101 rejection has further separated the mental concepts and mathematical concepts for better clarity. Applicant submits the claimed method integrates the mathematical concepts into a practical application in the field of cancer biomarker development, and is not directed to an abstract idea without significantly more [p. 9, par. 2]. It is respectfully found not persuasive. It is important to keep in mind that an improvement in the abstract idea itself ( e.g. a recited fundamental economic concept) is not an improvement in technology. Furthermore, it is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements or by the additional element(s) in combination with the recited judicial exception. See MPEP 2106.05(a). The claims have no additional elements recited therefore it can not integrate into a practical application. Applicant also states claim 1 is applies specific computational modeling to biological data, yet no computer is required or mentioned in the claims. The specification only states a computer for a identification system not the method of claim 1. Further, an overlapping index is just data and therefore not an additional element. Claim Rejections - 35 USC § 103 The outstanding 103 rejections to the claims are withdrawn in view of the amendments submitted herein. The prior art does not teach using the calculated weight to simulate a plasma exosome expression level distribution of circulating biomarker in healthy people and cancer patients to obtain simulated plasma exosome expression level distributions, wherein an intersection area of probability density functions of plasma exosome expression levels of the healthy people and the cancer patients are calculated according to the simulated plasma exosome expression level distributions, and the intersection area is an overlapping index. Conclusion No claims are allowed. 07-39 AIA 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. Inquiries Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dawn Bickham whose telephone number (703)756-1817. The examiner can normally be reached on Monday - Friday 8-4. 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 Wise can be reached on (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 an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /D.M.B./Examiner, Art Unit 1685 /Soren Harward/Primary Examiner, TC 1600 Application/Control Number: 18/089,565 Page 2 Art Unit: 1685 Application/Control Number: 18/089,565 Page 3 Art Unit: 1685 Application/Control Number: 18/089,565 Page 4 Art Unit: 1685 Application/Control Number: 18/089,565 Page 5 Art Unit: 1685 Application/Control Number: 18/089,565 Page 6 Art Unit: 1685 Application/Control Number: 18/089,565 Page 7 Art Unit: 1685 Application/Control Number: 18/089,565 Page 8 Art Unit: 1685 Application/Control Number: 18/089,565 Page 9 Art Unit: 1685 Application/Control Number: 18/089,565 Page 10 Art Unit: 1685 Application/Control Number: 18/089,565 Page 11 Art Unit: 1685
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