DETAILED ACTION
Applicant’s response, filed 22 January 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 22 January 2026 has been entered.
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, 69-71, 113, and 114 are rejected.
Claim 46 is objected to.
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 drawings received 14 October 2020 is objected to for the reasons stated below.
The drawings are objected to because they fail to comply with 37 CFR 1.84(u)(1) which states view numbers must be preceded by the abbreviation “FIG.” (see MPEP 608.02(V) section 37 CFR 1.84(u)(1)). Therefore, “Figure 1, Figure 2, …” should read “FIG. 1, FIG 2, …”. 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.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “266” (in figure 2E). Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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
Claim 46 is objected to because of the following informalities: claim 46 appears to read “IIk = d2i” but should read “Nk = d2i” to match the variable “nk” in the cumulative distribution function provided in the claim. Appropriate correction is required.
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, 69-72, 113, and 114 in Office action mailed 22 August 2025 is withdrawn in view of the amendment of “at a high-throughput sequencing system: (A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x, wherein the liquid biological sample comprises cell-free nucleic acid molecules including cell-free DNA (cfDNA), and the first plurality of sequence reads being electronic form” received 22 January 2026. This amendment provides that a high-throughput sequencer is performing the sequencing step and removes the language of a computer processor/computer environment is performing the sequencing.
112/a New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection below is newly recited.
Claims 1 and 72 recite “up to 3mL of plasma”. The instant disclosure provides “plasma is then stored in 1 ml aliquots… In this way, a suitable amount of plasma (e.g. 1-5 ml) is prepared from the biological sample for the purposes of cell-free nucleic acid extraction” (instant disclosure [0112]) which provides support for plasma samples in the range of 1-3mL. However, the disclosure does not provide an adequate written description for a range with no lower limit (i.e. 0-3mL which is the range encompassed in the recited limitation of “up to 3mL of plasma”) (see MPEP 2163.05(III)). Therefore, the limitation of “up to 3mL of plasma” constitutes as new matter. This rejection may be overcome by amending the limitation from “up to 3mL of plasma” to “1-3mL of plasma”. Dependent claims 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69, 70, 113, and 114 are rejected by virtue of their dependency on a rejected claim without alleviating the rejection.
112/b
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.
The rejection below is newly recited.
Claims 45, 46, and 71 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The rejections below are newly recited.
Claim 45 recites “The method of claim 1, wherein a cumulative distribution function is used and wherein the cumulative distribution function has the form…” and claim 46 recites “The method of claim 1, wherein a cumulative distribution function is used and wherein the cumulative distribution function has the form…” which renders the claims indefinite. The MPEP states at 2111.04(I) that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”. The indefiniteness arises because it is unclear if this limitation is an intended use of the method or if this limitation is meant to further limit a manipulative step of the independent claim (it is further unclear what manipulative step in the independent claim this limitation is meant to limit). For the sake of furthering examination, these claims will be interpreted as further limiting the manipulative step of evaluating the observed frequency of each respective variant in the first variant set to a corresponding reference frequency for the respective variant in the first reference set.
Claim 71 recites “the system comprising: a high-throughput sequencing system: (A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x, wherein the liquid biological sample comprises cell-free nucleic acid molecules including cell-free DNA (cfDNA), and the and the first plurality of sequence reads are being in electronic form” which renders the metes and bounds of the claim indefinite. The MPEP 2173.05(p)(II) states a single claim which claims both an apparatus and the method steps of using the apparatus is indefinite. The indefiniteness arises because claim 71 recites an apparatus “a high-throughput sequencing system” and the method steps of using the apparatus “(A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x…”. This rejection may be overcome by amendment “a high-throughput sequencing system configured to: (A) 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…”. For the sake of furthering examination, this limitation will be interpreted as the “the system comprising: a high-throughput sequencing system configured to: (A) 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…” and a high-throughput sequencing system configured to perform sequencing in this manner is interpreted as any high-throughput sequencer that performs deep sequencing on a liquid sample. 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.
Claim Rejections - 35 USC § 101
The rejection on the ground of 101 of claims 1, 2, 5-8, 14, 21, 23, 28, 40-41, 43, 45-48, 55-56, 69, 70, 72, 113, and 114 in Office action mailed 22 August 2025 is withdrawn in view of the amendment of “the liquid biological sample comprising up to 3 mL of plasma extracted from a blood sample” and “at a high-throughput sequencing system: (A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x, wherein the liquid biological sample comprises cell-free nucleic acid molecules including cell-free DNA (cfDNA), and the first plurality of sequence reads being electronic form” received 22 January 2026. These claims are now patent eligible due to the claims now reciting an unconventional combination of additional elements of “the liquid biological sample comprising up to 3 mL of plasma extracted from a blood sample” and “at a high-throughput sequencing system: (A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x, wherein the liquid biological sample comprises cell-free nucleic acid molecules including cell-free DNA (cfDNA), and the first plurality of sequence reads being electronic form”. Therefore, the claims are now patent eligible for providing significantly more than the judicial exceptions under Step 2B of the 101 analysis. It is noted that the rejection of independent claim 72 has been withdrawn in view of the amendment which cancels claims 72.
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.
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 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/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 22 January 2026 have been fully considered but they are not persuasive.
Applicant argues the claimed invention sets forth a computational workflow for the estimation of tumor fraction from nucleic acid load in a liquid biological sample – solving the problem of inaccurate slide-based qualitative review (Reply p. 15). Applicant argues that claim 71 recites analogous limitations to claim 1 and accordingly the reasons with respect to claim 1 cross apply to claim 71 (Reply p. 18).
This argument has been fully considered but found to be not persuasive. It is noted that the method claims have been indicated at patent eligible for the recitation of these newly recited additional elements. 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”. The determination of an improvement to technology has two steps, the identification of additional elements (which define the technology) and the evaluation of the additional elements to determine if the improvement is realized in the additional elements either by the additional elements themselves or the additional element in combination with the judicial exception (i.e. the interaction between the judicial exceptions and the additional elements). It is noted that the computational workflow of estimating tumor fraction by analyzing data is a judicial exception which can not provide the improvement. Further, claim 71 (the system configured to perform the method steps) is not patent eligible due to the system only requiring that a high-throughput sequencer that is configured to perform high-depth sequencing on a liquid biological sample. The limitations of the liquid sample and the performance of sequencing at high-depths does not require additional structural limitations to sequencers that have been in use previously (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 limitations only provide additional process limitations of using a commercially available sequencer in a specific manner. Therefore, the reasons with respect to process claim 1 do not cross-apply to system claim 71 because the limitations of the liquid sample volume and the process of using a sequencer do not limit the structure of the system claim which is configured to perform the recited steps.
Applicant states that claim 1 recites limitations of “the liquid biological sample comprising up to 3mL of plasma extracted from a blood sample” and “(A) performing sequencing on the liquid biological sample of the subject to generate a first plurality of sequence reads at a sequencing depth of 60,000x, wherein the liquid biological sample comprises cell-free nucleic acid molecules including cell-free DNA (cfDNA), and the first plurality of sequence reads being electronic form” are additional elements (Reply p. 13). Applicant argues that combining a minimal input volume (up to 3mL of plasma) with high-depth sequencing at 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 (Reply p. 16-17). Applicant argues that claim 71 recites analogous limitations to claim 1 and accordingly the reasons with respect to claim 1 cross apply to claim 71 (Reply p. 18).
These arguments have been fully considered but found to be not persuasive. It is noted that the method claims have been indicated at patent eligible for the recitation of these newly recited additional elements. However, claim 71 (the system configured to perform the method steps) is not patent eligible due to the system only requiring that a high-throughput sequencer that is configured to perform high-depth sequencing on a liquid biological sample. The limitations of the liquid sample and the performance of sequencing at high-depths does not require additional structural limitations to sequencers that have been in use previously (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 limitations only provide additional process limitations of using a commercially available sequencer in a specific manner. Therefore, the reasons with respect to process claim 1 do not cross-apply to system claim 71 because the limitations of the liquid sample volume and the process of using a sequencer do not limit the structure of the system claim which is configured to perform the recited steps.
Conclusion
No claims are allowable.
Claims 1, 2, 5-8, 14, 21, 23, 28, 40, 41, 43, 45-48, 55, 56, 69-71, 113, and 114 are free of the prior art for the reasons discussed in the Office action mailed 22 August 2025.
This Office action is a Non-Final action. A shortened statutory period for reply to this action is set to expire THREE MONTHS from the mailing date of this action.
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/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685