DETAILED ACTION
Applicant’s response, filed 09 July 2026, has been fully considered. 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
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 are pending and examined herein.
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69, 70, 113, and 114 are allowable.
Claim 71 is rejected.
Priority
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 are granted the claim to the benefit of priority to U.S. Provisional application 62/658479 filed 16 April 2018. Thus, the effective filling date of claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 is 16 April 2018.
Drawings
The objection to the drawings for failing to comply with 37 CFR 1.84(u)(1) and 37 CFR 1.84(p)(5) in Office action mailed 09 February 2026 is withdrawn in view of the replacement sheets received 09 July 2026.
The drawings received 09 July 2026 are objected to for the reason provided below.
The drawings are objected to because Fig. 2E contains a line through “The first condition is a predetermined stage of a breast cancer, a predetermined” in step 268 and Fig. 2F contains a line through “aberrant tissue sample consists of a second tumor fraction of a common tumor from the subject” in step 278. 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
The objection of claim 46 in Office action mailed 09 February 2026 is withdrawn in view of the amendment received 09 July 2026.
Claim Rejections - 35 USC § 112
The rejection on the ground of 112/a of claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 for claims 1 and 71 reciting “the liquid biological sample comprising up to 3 mL” in Office action mailed 09 February 2026 is withdrawn in view of the amendment of “the liquid biological sample comprising 1-5 mL of plasma” received 09 July 2026.
The rejection on the ground of 112/b of claims 45 and 46 in Office action mailed 09 February 2026 is withdrawn in view of the amendment which makes clear the steps of method claim 1 that claims 45 and 46 further limit received 09 July 2026.
The rejection on the ground of 112/b of claim 71 in Office action mailed 09 February 2026 is withdrawn in view of the amendment of “a high-throughput sequencing system configured to: (A) perform…” received 09 July 2026.
Claim Rejections - 35 USC § 101
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.
The rejection below has been modified necessitated by amendment.
Claim 71 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
(Step 1)
Claim 71 falls under the statutory category of a machine.
(Step 2A Prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. The instant claims further recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations.
Independent claims 71 recite mental processes of “using the first plurality of sequence reads derived from sequencing the liquid biological sample comprising 1-5 mL of plasma to identify a first variant set…”, “aligning each respective sequence read…”, “collapsing the first plurality of sequence reads…”, “stitching the multiple collapsed sequences…”, “constructing a directed graph data structure…”, “filtering the candidate variants using a machine learning model…”, “removing white blood cell (WBC) derived somatic variants…”, “determining the observed frequency…”, “obtaining a corresponding reference frequency…”, and “evaluating the observed frequency…”.
Independent claims 71 mathematical concepts of “filtering the candidate variants using a machine learning model…”, “determining the observed frequency…”, “obtaining a corresponding reference frequency…”, and “evaluating the observed frequency…”.
The claims recite analyzing/evaluating data, organizing data, and making observations and judgments as process of identify a first variant set, aligning sequence reads, collapsing sequence reads, stitching the multiple collapsed sequences, constructing a directed graph data structure, filtering the candidate variants using a machine learning model, removing white blood cell (WBC) derived somatic variants, determining the observed frequency, obtaining a corresponding reference frequency, and evaluating the observed frequency. The human mind is capable of analyzing/evaluating data, organizing data, and making observations/judgments.
The claims recite mathematical concepts of filtering the candidate variants using a machine learning model, determining the observed frequency, obtaining a corresponding reference frequency, evaluating the observed frequency, evaluating a cumulative density function or a cumulative distribution function for the respective variant, computing the first tumor fraction as a median value of a cumulative density function, and repeating calculations at time points. These steps are mathematical concepts because they encompass mathematical calculations of determining frequencies which is a ratio of numerical data representing an occurrence of a specific event over a total, evaluation frequencies using mathematical calculations, and using a machine learning model which may be a logistic regression, regression, or support vector machine (instant disclosure [00219]). Thus, claim 71 recites abstract ideas.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claims 71 of a high-throughput sequencer that is configured to perform deep sequencing on a liquid sample does not integrate the judicial exception into a practical application because this additional element only interacts with the judicial exceptions by providing data to be processed by the judicial exceptions. Thus, this additional element is adding insignificant extra solution activity of data gathering. It is noted that the volume of the liquid sample does not limit the structure of the high-throughput sequencer and is interpreted as an intended use of the system.
The additional element in claims 71 of using a generic computer to perform judicial exception does not integrate the judicial exception into a practical application because this is simply applying the exception to a generic computer without an improvement to computer technology (see MPEP 2106.04(d)(1)).
Thus, the additional elements do not integrate the judicial exceptions into a practical application and claim 71 is directed to the abstract idea.
(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 because:
The additional element in claim 71 of using a generic computer to perform judicial exception is conventional see MPEP 2106.05(b) and 2106.05(d)(II).
The additional element in claims 71 a high-throughput sequencer that is configured to perform deep sequencing on a liquid sample is conventional as shown by the performance of ultra-deep targeted sequencing on cell-free DNA with a sequencer configured to perform the sequencing shown by Tian et al. (BioRxiv (2017): 189340; previously cited), Sung et al. (Oncotarget. 2017 Nov 15;8(63):106901-106912; previously cited) and Ojamies et al. (Leukemia 31, 1048–1058 (2017); previously cited). Further, the instant disclosure provides using a commercially available sequencer (Illumina HiSeqX) which is configured to perform deep sequencing on a liquid sample (instant disclosure [0134]).
Thus, the additional elements are not sufficient to amount to significantly more because they do not provide an inventive concept.
Response to Arguments
Applicant's arguments filed 09 July 2026 have been fully considered but they are not persuasive.
Applicant argues the combination of the abstract idea and the additional elements amount to a technical improvement to sequencing technology in the context of tumor fraction estimation (Reply p. 16). Applicant argues that the claimed invention incorporates a high-throughput sequencing system that is configured to perform next-generation sequencing on the liquid biological sample to extract sequencing data of the nucleic acid load and then the computational workflow is then applied to analyze the nucleic acid load and estimate the tumor fraction which avoids the aforementioned biases of manual, slide-based tumor fraction estimation by a human pathologist (Reply p. 18). Applicant further argues combining a minimal input volume (1-5ml of plasma) with high-depth sequencing at approximately 60,000x materially improves the functioning of sequencing technology for cfDNA tumor fraction estimation by overcoming the core technical constraint that ctDNA is present at very low levels relative to background cfDNA, particularly exemplified in early or intermediate stages of cancer progression (Reply p. 19).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. It is noted that the computational workflow of estimating tumor fraction by analyzing cfDNA data falls under the judicial exception, which alone cannot provide the improvement. The MPEP provides that apparatus claims cover what a device is, not what a device does (see MPEP 2114(II)). The limitations in system claim 71 of the liquid sample comprising 1-5 mL of plasma and that the high-throughput sequencing system is configured to: perform sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x do not require additional limits to the sequencer and the instant disclosure provides that commercially available sequencers are used (see instant disclosure [0134] which shows the use of a commercially available sequencer to perform this sequencing on the liquid sample at high-depth). These argued limitations further limit the content of the data itself, the first plurality of sequence reads which are derived from sequencing the liquid biological sample comprising 1-5 mL of plasma, which is being processed by the abstract analysis steps. Thus, the argued improvement is provided by the type of data being analyzed by the abstract data analysis which falls under the judicial exception itself which cannot provide the improvement.
Conclusion
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-70, 113, and 114 are allowable and claim 71 is not allowable.
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-70, 113, and 114 are patent eligible for similar reasons provided in the Office Action mailed 09 February 2026. Independent claim 1 provides an unconventional combination of additional elements of “the liquid biological sample comprising 1-5 mL of plasma extracted from a blood sample” and “at a high-throughput sequencing system: (A) performing sequencing of the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x” under step 2B of the analysis. The recited combination of the amount of plasma being sequenced at a sequencing depth of 60,000x is unconventional. Thus, the claims are patent eligible by reciting additional elements which amount to significantly more than the judicial exception itself.
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-70, 113, and 114 are free of the prior art for the reasons discussed in the Office action mailed 22 August 2025.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONATHAN EDWARD HAYES whose telephone number is (571)272-6165. The examiner can normally be reached M-F 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia 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.
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/J.E.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
