DETAILED ACTION
Applicant’s response, filed 25 March 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 .
Status of Claims
Claims 1, 3, 5-19, 21-23, 25-26, 35-36, 40, 44, and 52 are cancelled.
Claim 54 is newly added.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are pending.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are rejected.
Claims 2, 4, and 54 are objected to.
Claim Objections
Claims 2, 4, and 54 are objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claims 2 and 54 recite “(F)…the one or more models integrates …”, which is a grammatical error and should recite “the one or more models integrate …”.
Claim 4 recites “applying one or more models (i) integrating… to estimate a tumor fraction, (ii) inferring the tumor fraction”, which is a grammatical error and should recite “applying one or more models (i) integrating….fraction, and (ii) inferring…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendment.
Claims 2, 4, 37-38, and 54, and claims dependent therefrom recite “applying one or more models, wherein the one or more models (a) integrates genome coverage” (claims 2 and 54), “applying one or more models (i) integrating genome coverage” (claim 4), and “applying/apply one or more models integrating genome coverage” (claims 37-38). However, Applicant’s specification does not provide support for the one or more models used to estimate tumor fraction as integrating “genome coverage”, which understood by one of ordinary skill in the art to refer the average number of times each base across the genome is sequenced. It is further noted that Applicant’s remarks filed 25 March 2026 specifically state the amendment reciting “genome coverage” requires coverage measured across the whole genome or genome-wide regions (i.e. the whole genome), rather than local read depth, consistent with this interpretation.
Applicant’s specification in at least para. [0031], [0134], [0128], [0226], and [0339] discloses that a probabilistic model takes into account “genomic coverage and sequencing noise”, wherein the “genomic overage” is represented in the recited equation as a “cov” variable, defined as “the average number of unique reads per site in the ROI”, in addition to other variables in the claims (i.e. genomic coverage is an average coverage in a region of interest). Applicant’s specification at these paragraphs, discloses that in the equation “M is the number of tumor-specific compendium detections in the patient sample, σ is a measure of empirically-estimated noise, R is the total number of unique reads in a region of interest (ROI), N is tumor mutation load, and cov is the average number of unique reads per site in the ROI”, corresponding to the other variables integrated into the claimed model of “mutation load” and “detected mutations”. Applicant’s specification at para. [0155] defines a genomic “region of interest” stating a ROI can be any genomic region, including a region of a chromosome, a whole chromosome, etc., such that the region of interest cannot be a whole genome. Applicant’s specification at para. [0156] further states “cov denotes the local coverage in the patient mutation sites”. However, Applicant’s specification does not disclose any other models for predicting tumor fraction integrating genome coverage along with mutation load and detected mutations. Therefore, while Applicant’s specification does provide support for the model integrating “coverage”, as previously recited, this is not support for the integration of “genome coverage” as claimed.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitation above recited in claims 2, 4, 37-38, and 54, and claims dependent therefrom, to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. THIS IS A NEW MATTER REJECTION. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Claim Rejections - 35 USC § 112(b)
The rejection of claims 2, 4, 20, 24, 27-34, 37-43, 45-51, and 53 under 35 U.S.C. 112(b) in the Office action mailed 29 Dec. 2025 has been withdrawn in view of claim amendments and cancellations received 25 March 2026.
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.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claims 2 and 54, and claims dependent therefrom, are indefinite for recitation of “(D) detecting, within a third compendium of reads…reads corresponding to the filtered genetic markers to generate a tumor-associated genome-wide representation of the genetic markers in the third biological sample. It is unclear if the third compendium of reads is only required to correspond to the “filtered genetic markers”, or if the third compendium of reads is required to be associated with “the genetic markers” (i.e. all genetic markers including the filtered recurring sites and germline mutations). Clarification is requested. For purpose of examination, the limitation will be interpreted to mean “representation of the filtered genetic markers in the third biological sample”.
Claims 2, 4, and 54, and claims dependent therefrom, are indefinite for recitation of “(E) normalize features of each of the first, second, and third compendium of reads after artefactual noise suppression”. However, claims 2 and 4 do not recite any steps of artefactual noise suppression. As a result, it is unclear if the step of normalizing is intended to be contingent upon artefactual noise suppression being performed, or if the claims intend to require performing artefactual noise suppression. Clarification is requested.
Claim 4, and claims dependent therefrom, are indefinite for recitation of “(D)…a tumor-associated genome-wide representation of the genetic markers…detecting reads, within the third compendium of reads, corresponding to the filtered genetic markers”. First, it is unclear which genetic markers, “the genetic markers” is referring to in lines 3-4 of step “(D)” because claim 4 previously recites “(D)…a third compendium of genetic markers from a third biological sample” and “(A)…a first compendium of reads associated with genetic markers”. Furthermore, claim 4 then recites “the third compendium of reads, corresponding to the filtered genetic markers” in lines 4-5, which refers to filtered markers from the genetic markers associated with the first compendium of reads. Therefore, it is further unclear if Applicant intends for the “third compendium of genetic markers” to be a separate set of markers, or if these are intended to the same genetic markers associated with the first and second compendium of reads.
Claim 4, and claims dependent therefrom, are indefinite for recitation of “(F)…wherein the tumor fraction is calculated by estimating…..detected from the tumor sample”. Claim 4 previously recites “(A)…wherein the baseline sample comprises a tumor sample or a plasma sample”. Therefore, it is not clear if claim 4 intends to require that the baseline sample is actually a tumor sample, as suggested by step (F), or if Applicant intends for step (F) to be contingent on the baseline sample being a tumor sample. For purpose of examination, the baseline sample will be interpreted to be a tumor sample.
Claim 30 is indefinite for recitation of “…wherein the tumor fraction is calculated by checking a linear dilution ratio between a cumulative signal…and a cumulative signal from the tumor sample”. Claim 2, from which claim 30 depends, recites “..the baseline sample comprises a tumor sample or a plasma sample”. Therefore, it is not clear if claim 30 intends to require that the baseline sample is actually a tumor sample, or if Applicant intends for the limitation of claim 30 to be contingent on the baseline sample being a tumor sample. For purpose of examination, the baseline sample will be interpreted to be a tumor sample.
Claims 37-38, and claims dependent therefrom, are indefinite for recitation of “…a second compendium of reads…corresponding to the filtered genetic markers….to generate a tumor-associated genome-wide representation of the genetic markers…” in steps (C) and (c), respectively, for the same reasons discussed above with respect to claims 2 and 54 in para. [013] above regarding the filtered markers and the markers for the third biological sample.
Claim 41 is indefinite for recitation of (a) calculating…for each candidate mutation in the first and second compendium of reads” because claim 37 does not recite any “candidate mutations”. As a result it is not clear what set of mutations, “each candidate mutation is referring to”.
Response to Arguments
Applicant's arguments filed 25 March 2026 regarding 35 U.S.C. 112(b) have been fully considered but they are not persuasive because they do not pertain to the new grounds of rejection set forth above.
Claim Rejections - 35 USC § 101
The rejection of claim 41 under 35 U.S.C. 101 in the Office action mailed 29 Dec. 2025 has been withdrawn in view of the cancellation of this claim received 25 March 2026.
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 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 2, 4, 37-38, and 54 being representative) is directed to a method and system for detecting residual disease. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claims 2, 4, and 54 recite the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
filtering/filter recurring sites and germ line mutations from the genetic markers associated with the first compendium of reads, wherein the recurring sites are based on a cohort of reference samples, and wherein the germline mutations are identified using the PBMCs;
detecting/detect, within a third compendium of reads from a third biological sample from the subject, reds corresponding to the filtered genetic markers to generate a tumor-associated genome-wide representation of the genetic markers in the third biological sample (claims 2 and 54 only)/ receive… a third compendium of genetic markers from a third biological sample of the subject to generate a tumor-associated genome-wide representation of the genetic markers in the third biological sample by detecting reads, within the third compendium of reads corresponding to the filtered genetic markers, wherein the third compendium of reads is subject-specific and genome wide, and wherein the third biological sample comprises a follow-up plasma sample (claim 4);
normalizing/normalize features each of the first, second and third compendium of reads after artefactual noise supression to produce a first filtered read set based on and spanning the first compendium of reads, a second filtered read set based on and spanning the second compendium of reads, and a third filtered read set based on and spanning the third compendium of reads;
the following steps of “applying one or more models”:
applying one or more models integrating genome coverage, mutation load, and detected mutations to the first, second, and third filtered read sets to calculate a tumor fraction and detect residual disease (claim 2);
applying one or more models integrating genome coverage, mutation load, and detected mutations to the first, second, and third filtered read sets to estimate a tumorm fraction and detect residual disease, (ii) inferring the tumor fraction based on a correlation between depth of coverage skew and fragment size skew within tumor-associated CNV or SV segments, wherein the tumor fraction is calculated by estimating a linear dilution ratio between a cumulative signal detected from the follow-up plasma sample and a cumulative signal detected from the tumor sample (claim 4); and
applying one or more models, wherein the one or more models (a) integrates genome coverage, mutation load, and detected mutations to the first, second, and third filtered read sets to calculate a tumor fraction and detect residual disease, wherein the tumor fraction is calculated by estimating a linear dilution ratio between a cumulative signal detected from the follow-up plasma sample and a cumulative signal detected from the tumor sample, and/or (b) infers the tumor fraction based on a correlation between depth of coverage skew and fragment size skew within tumor-associated CNV or SV segments (claim 54);
determining/determine an administration of an adjuvant therapy to the subject based on the detected residual disease.
Claims 37 and 38 recite the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
filtering/filter recurring sites and/or germline mutations from the genetic markers associated with the first compendium of reads, wherein the recurring sites based on a cohort of reference samples, and wherein the germline mutations are identified using the PBMCs
detecting/detect, within a second compendium of reads from a second biological sample from the subject, reads corresponding to the filtered genetic markers to generate a tumor-associated genome-wide representation of the genetic markers in the second biological sample, wherein the second compendium of reads is subject-specific and genome-wide;
filtering/filter noise from the first and second compendium of reads using at least one error suppression protocol to produce a first filtered read set based on and spanning the first compendium of reads and a second filtered read set based on and spanning the second compendium of reads;
applying one or more models integrating genome coverage, mutation load, detected mutations, and tumor fraction, to the first and second filtered read sets to estimate a tumor fraction and detect residual disease; and
generating an output indicative of presence or absence of the residual disease in the subject.
The identified claim limitations falls into one of the groups of abstract ideas of mental processes, for the following reasons. In this case, filtering recurring sites and germ line mutations encompasses identifying mutations (CNVs or SVs) present multiple times in a cohort of reference healthy samples and removing these mutations from the first and second compendium of reads, which amounts to a mere analysis of data. Detecting reads corresponding to genetic markers within a compendium of reads encompasses analyzing aligned sequencing data to identify reads corresponding to markers of interest, which can be practically performed in the mind aided with pen and paper. Filtering noise, as recited in claims 37-38 can be performed mentally by using discordant testing by analyzing reads, to remove artefactual mutations that are only present in a single test. Normalizing each of the first, second, and third reads to produce respective filtered reads can be practically performed in the mind by dividing counts of reads in each read set by a normalization factor. Detecting residual disease by using one or more models integrating various types of numerical information and analyses can be practically performed in the mind by performing addition and multiplication to estimate a tumor fraction, determining a linear dilution ratio (e.g. performing division), and correlating information as discussed in Applicant’s specification (see FIG. 1D), and then comparing the estimated tumor fraction to a threshold, which is a mental process. Generating an output indicative of the presence or absence of the disease encompasses determining whether the tumor fraction is above some threshold and writing if the disease is present, which can be practically performed in the mind aided with pen and paper. Last, determining an administration of adjuvant therapy a encompasses analyzing the result of the detection to determine an appropriate therapy which is a mental process. That is other, than reciting the limitations are performed by a processor in claims 4 and 38, nothing in the claims precludes the step from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
The steps of normalizing each of the first, second, and third compendium of reads and applying one or more models integrating genome coverage, mutation load, detected mutations, and tumor fraction to filtered read sets, estimating a linear dilution ratio between a cumulative signal detected from the follow-up plasma sample and a cumulative signal detected from the tumor sample, and inferring the tumor fraction based on a correlation between depth of coverage skew and fragment size skew within CNV or SV segments further recite a mathematical concept. The claim limitations amount to a textual equivalent to performing mathematical calculations. First the step of normalizing reads requires the use of division and/or multiplication to perform the normalization, as discussed in Applicant’s specification at para. [0034] and [00159]. Similarly applying one or more models integrating various types of information to detect residual disease encompasses, in light of Applicant’s specification (see FIG. 1D), estimating tumor fraction by performing addition and multiplication to perform the calculation. Similarly, calculating ratios and correlations also amounts to a textual equivalent to performing mathematical calculations (e.g. division and calculating R values). Therefore, these limitations recite a mathematical concept. Last, the claims recite the law of nature of a natural correlation between the presence of genetic markers and residual disease. See MPEP 2106.04(b).
Dependent claims 20, 24, 27-36, 39, 41-43, 45-48, 51, and 53 further recite an abstract idea and/or further limit the abstract idea identified above. Dependent claim 20 further limits the abstract idea of filtering to comprise generating a panel or normal blacklist or mask. Dependent claim 24 further recites the mental process of binning a region of interest containing genomic segments, estimating a depth of coverage in each window (i.e. counting reads), and the mental process and mathematical concept of calculating median depth of coverage per window. Dependent claims 27-28 further limit the abstract idea of performing normalization to use a robust z-score normalization to each sample, by calculating a median and MAD based on neutral regions of each sample and performing the normalizing by subtracting and dividing. Dependent claim 29 further recites the mental process and mathematical concept of calculating depth of coverage skew and/or fragment size center-of mass skew (i.e. calculations using mathematical distributions, as discussed at FIG. 11C, para. [0050] and [00166]) in the third sample compared to a panel of normal healthy plasma samples. Dependent claim 30 further recites the mental process and mathematical concept of checking a linear dilution ratio between two signals, which in light of Applicant’s specification at para. [00167]-[00169] encompasses performing mathematical calculations. Dependent claims 31-32 further recite the mathematical concept and mental process of using a background noise model to calculate expected noise distributions and provide an estimated mean and standard-deviation of artefactual mutation detection rate, respectively. Dependent claim 33 further limits the abstract idea of claim 2 to utilize a secondary feature of fragment size shift. Dependent claim 34 further recites the mental process and mathematical concept of analyzing correlation between depth of coverage skew and fragment size skew in CNV segments to infer tumor fraction. Dependent claim 39 further limits the mental process of filtering sites. Dependent claim 41 further limits the abstract idea of the error suppression protocol to recite a mental process and mathematical concept of calculating probabilities using features, the mental process of identifying discordant mutations, and the mental process and mathematical concept of employing a trained machine learning model (e.g. linear regression model) to identify artefactual mutations (e.g. calculate a probability of artefactual mutation). Dependent claims 42-43 further limit the abstract idea of the filtering artefactual sites to include particular data analysis protocols. Dependent claims 45-46 further recite the mental process and mathematical concept of applying a background model to calculate an expected noise distribution and to provide an estimate of a mean and standard deviation. Dependent claim 47 further limits the abstract idea of using the mathematical model to be based on a fragment size shift. Dependent claim 48 further recites the mental process and mathematical of analyzing intra-subject fragment size shifts and random markers using statistical methods. Dependent claim 51 further limits the step of filtering artefactual sties to be from a cohort of healthy samples. Dependent claim 53 further limits the determination of adjuvant therapy to be based on an estimated tumor fraction.
The claims additionally recite the law of nature of a natural correlation between coverage, mutation load, detected mutations, and residual disease (tumor fraction), analogous to the natural correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). See MPEP 2106.04(b).
Therefore, claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 20, 24, 27-34, 39, 41-43, 45-48, 50-51, and 53 do not recite any elements in addition to the judicial exception and thus are part of the judicial exception.
The additional elements of claims 1, 4, and 54 include:
one or more processors (claim 4);
receiving/receive a first compendium of reads associated with genetic markers from a first biological sample of the subject, wherein the first compendium of reads is subject-specific and genome-wide, wherein the genetic markers comprise copy number variations (CNVs) or structural variations (SVs), wherein the first biological sample comprises a baseline sample and a normal sample, and wherein the baseline sample comprises a tumor sample or a plasma sample (i.e. receiving data); and
receiving a second compendium of reads associated with the genetic markers from a second biological sample of the subject, wherein the second compendium of reads is subject-specific and genome wide, and wherein the second biological sample comprises a peripheral blood mononuclear cell (PBMC) sample, (i.e. receiving data);
The additional elements of claims 37 and 38 include:
one or more processors (claim 38 only);
receiving/receive a first compendium of reads associated with genetic markers from a first biological sample of a subject, wherein the first biological sample comprises a baseline sample and a normal cell sample, wherein the normal cell sample comprises PBMCs, and wherein the baseline sample comprises a tumor sample or a plasma sample;
Dependent claims 49-50 further limit the data received in claim 37.
First, the additional elements of a processor and receiving data are generic computer components and/or functions. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
Furthermore, the step of receiving genome-wide reads only serves to collect data for use by the abstract idea, which amounts to insignificant extra-solution that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Therefore, the additionally recited elements amount to insignificant extra-solution activity, and/or merely uses a computer as a tool, and, as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception for the following reasons.
First, dependent claims 20, 24, 27-34, 39, 41-43, 45-48, 50-51, and 53-54 do not recite any elements in addition to the judicial exception and thus are part of the judicial exception.
The additional elements of claims 1, 4, and 54 include:
one or more processors (claim 4);
receiving/receive a first compendium of reads associated with genetic markers from a first biological sample of the subject, wherein the first compendium of reads is subject-specific and genome-wide, wherein the genetic markers comprise copy number variations (CNVs) or structural variations (SVs), wherein the first biological sample comprises a baseline sample and a normal sample, and wherein the baseline sample comprises a tumor sample or a plasma sample (i.e. receiving data); and
receiving a second compendium of reads associated with the genetic markers from a second biological sample of the subject, wherein the second compendium of reads is subject-specific and genome wide, and wherein the second biological sample comprises a peripheral blood mononuclear cell (PBMC) sample, (i.e. receiving data);
The additional elements of claims 37 and 38 include:
one or more processors (claim 38 only);
receiving/receive a first compendium of reads associated with genetic markers from a first biological sample of a subject, wherein the first biological sample comprises a baseline sample and a normal cell sample, wherein the normal cell sample comprises PBMCs, and wherein the baseline sample comprises a tumor sample or a plasma sample;
Dependent claims 49-50 further limit the data received in claim 37.
The additional elements of a processor and receiving data are conventional computer components and/or functions. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Therefore, taken alone, the additional elements do not provide significantly more. Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 25 March 2026 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks the claims do not merely analyze existing data in the abstract, but recite a particularized data-gathering architecture that begins with the generation of subject-specific, genome-wide compendia of sequence reads from multiple biologically distinct samples, while prior to 2018, conventional cfDNA-based cancer monitoring relied on targeted panels or limited CNV calling pipelines (Applicant’s remarks at pg. 14, para. 4-6).
This argument is not persuasive because it is not commensurate with the scope of the claims. The claims do not require any steps of actually sequencing the various distinct samples using whole genome sequencing to produce the genome-wide compendia of sequence reads, such that these additional elements may potentially amount to significantly more than the judicial exception for being unconventional. Instead, the claims merely use a computer to receive already generated sequence reads. As discussed in the above rejection, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Applicant remarks the claims detect reads corresponding to filtered genetic markers within a follow-up dataset, rather than calling variants de novo, which is not a generic mental comparison but a data gathering constraint that requires preservation of genome-wide coverage while interrogating signal at previously defined loci, and such detection is inseparable from the way sequence data is generated and cannot be performed without the physical sequencing outputs (Applicant’s remarks at pg. 14, para. 6 to pg. 15, para. 1). Applicant further remarks the assertion that steps could be performed mentally ignores that the methods depend on biological measurements which cannot be perceived by humans (Applicant’s remarks at pg. 17, para. 2).
This argument is not persuasive. It is agreed that analyzing sequencing data does require a physical sequencing output was generated. However, a claim may still recite a mental process of analyzing data, even if the data is required to be generated by a physical process. See MPEP 2106.05(g) providing examples of insignificant extra-solution activity that were not sufficient to integrate a recited judicial exception into a practical application, including performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989). As discussed in the above rejection, the human mind is practically able to analyze and remove recurring sites generated over a cohort of reference samples and/or germline mutations (e.g. mutations present in both the tumor and PBMC sample).
Applicant further remarks that the normalization of features, including depth of coverage skew and fragment-size center-of-mass skew across bins are not mathematical concepts but physical properties of cfDNA fragments arising from nucleosomal packaging and apoptotic fragmentation, which are phenomena not exploited in conventional CNV pipelines prior to 2018, and thus the claimed data is not pre-existing information but new measures extracted from sequencing reads (Applicant’s remarks at pg. 15, para. 2).
This argument is not persuasive. As discussed above, it is agreed that analyzing sequencing data to generate the recited features (e.g. size skew, coverage skew) does require a physical sequencing output was generated. However, this does not preclude the limitations from reciting a mathematical concept even if the mathematical calculations are being applied to numerical values derived from a physical process. For example, See MPEP 2106.04(a)(2) I, providing an example of a mathematical concept of a relationship between reaction rate and temperature, which relationship can be expressed in the form of a formula called the Arrhenius equation, Diamond v. Diehr; 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981).
Regarding Applicant’s argument that data are measures, the claimed features of coverage skew and fragment-size skew are part of the abstract idea as discussed above. These features are not being directly physically measured form nucleic acid, and instead are being inferred (by the abstract idea) from sequencing data generated by conventional methods. Whether an abstract idea is “new”, alone, is not sufficient to integrate a recited judicial exception into a practical application or provide significalty more. Nor can one patent "a novel and useful mathematical formula," Parker v. Flook, 437 U.S. 584, 585, 198 USPQ 193, 195 (1978).
Applicant remarks that accordingly, the claims are not directed to an abstract idea under Step 2A, Prong 1 because they are directed to a specific technical solution for acquiring and structuring biological measurement data that overcomes physical limitations of low tumor fraction DNA and then asserts the claimed steps cannot be practically performed in the mind (Applicant’s remarks at pg. 15, para. 3-4).
This argument is not persuasive. Applicant conflates Step 2A, Prong 2 (whether the claims are directed to an abstract idea) with step 2A, prong 1 (whether the claims recite a judicial exception). It is assumed Applicant intends to argue the claims do not recite an abstract idea. Applicant’s assertion that the claimed steps cannot be performed mentally is not persuasive because an explanation regarding why each limitation can be practically performed in the mind is provided in the explanation above, and Applicant does not provide an explanation regarding why these limitations cannot be performed in the mind.
Furthermore, Applicant’s argument for “acquiring and structuring biological measurement data” Is not persuasive. The claims do not require any steps of actually sequencing the various distinct samples using whole genome sequencing to produce the genome-wide compendia of sequence reads, such that these additional elements may potentially provide integration for how measurement data is acquired. Instead, the claims merely use a computer to receive already generated sequence reads, and then carry out the abstract idea of analyzing the sequencing reads. As discussed in the above rejection, the courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
Applicant remarks the methods and systems do not apply mathematics in the abstract, but only after a specific sequence of non-conventional data acquisition and condition steps, including germline subtraction, cohort-based filtering, noise suppression, and normalization, and the models operate on physically constrained datasets whose structure is dictated by the sequencing process (Applicant’s remarks at pg. 15, para. 5 to pg. 16, para. 1).
This argument is not persuasive. The data acquisition and condition steps of germline filtering, cohort-based recurring filtering, and artefactual noise suppression, normalization are all part of the abstract idea, as discussed in the above rejection. Furthermore, for the reasons already discussed above, simply because the data was generated by a physical assay does not preclude the claim from reciting an abstract idea.
It is further noted that this argument is provide under Applicant’s Step 2A, Prong 2 section. However, the above steps are part of the abstract idea, and thus cannot integrate themselves into a practical application.
Applicant remarks the output of the process is not merely a number, but a recommendation for adjuvant therapy, which effects a real-world medical decision that could be reliably made using conventional pre-2018 techniques (Applicant’s remarks at pg. 16, para. 2)
This argument is not persuasive. Generating an output of whether the subject has residual disease and determining administration of adjuvant therapy recites a mental process of determining an indication of whether a subject should take adjuvant therapy based on determining the tumor fraction exceeds a threshold, which is a simple data comparison. However, the claim does not recite any additional elements that affect a real-world medical decision, such as a step of treating the subject with an adjuvant therapy. As explained above, an improvement in the abstract idea is not an improvement to technology (see MPEP 2106.05(a)), and furthermore, the abstract idea cannot integrate itself into a practical application.
Applicant remarks the claims improve the technical operation of sequencing-based diagnostics by combining subject-specific genome-wide CNV structure, fragment-size behavior, and dilution-based tumor fraction estimation, the present disclosure enables detection in regimes previously considered technically inaccessible due to sampling noise and physical fragment limits, which is an improvement to a technical field (Applicant’s remarks at pg. 16, para. 3-4).
This argument is not persuasive. MPEP 2106.05(a) explains it is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements. See the discussion of Diamond v. Diehr, 450 U.S. 175, 187 and 191-92, 209 USPQ 1, 10 (1981)) in subsection II, below. In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception. Furthermore, 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.
In the instant case, the steps of identifying markers, analyzing fragment size behavior, and dilution-based tumor fraction estimation, are part of the abstract idea and thus cannot provide integration. Furthermore, an improved in the diagnosis of residual disease based on the claimed analysis of data amounts to an improved abstract idea, which is not a technology.
As presently, recited, the only additional elements in the claims are generic computer components and steps of receiving data for use by the abstract idea, which do not integrate the judicial exception into a practical application. See MPEP 2106.05(f) and 2106.05(g), discussed above.
Applicant remarks that conventional cfDNA cancer detection predominantly relied on targeted sequencing, molecular barcoding, or hotspot mutation tracking rather than using genome-wide detection, and there was no routine practice of combining genome-wide CNV profiles from the various tissues followed by dilution-based tumor fraction estimation as claimed (Applicant’s remarks at pg. 16, para. 5-6).
This argument is not persuasive. As discussed above, the claims do not require any steps of actually sequencing the various distinct samples using whole genome sequencing to produce the genome-wide compendia of sequence reads, such that these additional elements may potentially amount to significantly more than the judicial exception for being unconventional. Instead, the claims merely use a computer to receive already generated sequence reads, which amount to conventional computer components and processes as discussed in the above rejection. In, addition the analysis of CNV profiles and dilution-based tumor fraction estimation are also part of the abstract idea, and thus their conventionality is not evaluated under Step 2B.
Applicant remarks the use of PBMC-derived germline CNVs to define subject-specific reference structure, coupled with follow-up plasma interrogation without de novo CNV calling as claimed is not conventional, nor was the use of fragment size center of mass skew as a quantitative signal integrated with coverage skew, and these techniques exploit physical properties of cfDNA that were not routinely measured or modeled together (Applicant’s remarks at pg. 16, para. 7 to pg. 18, para. 1). Applicant further remarks the inventive concept lies in how the data are gathered, condition, and constrained (Applicant’s remarks at pg. 18, para. 2).
This argument is not persuasive. The recited limitations relating to analyzing CNVs to define subject-specific reference structure, analyzing sequence reads from a follow-up plasma sample, analyzing fragment size center of mass skew and coverage skew are all part of the abstract idea. Similarly how the data is conditioned and constrained is part of the abstract idea. The conventionality of the abstract idea is not evaluated under step 2B.
Furthermore, the claims only recite “receiving” already generated reads and do not recite any unconventional combination of assays for gathering data that may provide an inventive concept. As presently recited the only additional elements in the claims are generic computer components and steps of receiving data for use by the abstract idea, which do not integrate the judicial exception into a practical application. See MPEP 2106.05(f) and 2106.05(g), discussed above.
Claim Rejections - 35 USC § 103
The rejection of claims 2, 4, 20, 29, 31-32, 37-43, 45-46, 49-51 and 53 under 35 U.S.C. 103 as being unpatentable over Newman (2016) in view of Diehn (2014), as evidenced by Bratman (2014) in the Office action mailed 29 Dec. 2025 has been withdrawn in view of claim amendments and cancellations received 25 March 2026.
The rejection of claim 24 under 35 U.S.C. 103 as being unpatentable over Newman in view of Diehn, as evidenced by Bratman, as applied to claim 2 above, further in view of Talevich (2016) in the Office action mailed 29 Dec. 2025 has been withdrawn in view of claim amendments received 25 March 2026.
The rejection of claims 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Newman in view of Diehn, as evidenced by Bratman, as applied to claim 2 above, further in view of Stumm (2014) in the Office action mailed 29 Dec. 2025 has been withdrawn in view of claim amendments received 25 March 2026.
The rejection of claims 33 and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Newman in view of Diehn, as evidenced by Bratman, as applied to claims 2 and 37 above, further in view of Soo (2017) in the Office action mailed 29 Dec. 2025 has been withdrawn in view of claim amendments received 25 March 2026.
Double Patenting
The provisional rejection of claim 41 on the grounds of non-statutory double patenting in the Office action mailed 29 Dec. 2025 has been withdrawn in view of the cancellation of this claim received 25 March 2026.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 11-13, 15-18, 20-21, 24, and 26-37 of copending Application No. 18/133,524 (reference application). Any newly recited portion herein is necessitated by claim amendment. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Reference claims 2 and 4 disclose the limitations of instant claims 2, 4, 37-38, and 54, except the step of determining administration of a therapy, which is disclosed by reference claims 1 and 3, and details on the one or more models. Reference claim 14 discloses the model integrating the recited information. Reference claim 1 requires reads spanning the whole genome, which reads on the reads being derived from whole-genome sequencing. Reference claims 18 and 29-30 discloses the limitation of analyzing fragment size shifts, depth of coverage-skew, fragment size skew, and a linear dilution ratio in the one or more models.
Reference claims 20, 24, and 27-24, disclose the limitations of instant claims 20, 24, and 27-34.
Reference claims 1 and 6 disclose the limitations of instant claim 39.
Reference claims 11-13 disclose the limitations of instant claims 41-43.
Reference claims 15-18 discloses the limitations of instant claims 45-48, respectively.
Reference claim 2 discloses the compendium of reads comprises a coy number variation determined from a tumor sample, disclosing the limitation of instant claim 49.
Reference claim 2 discloses identifying germline mutations from the first and second compendium of reads, as recited in claim 50.
Reference claims 2 and 6 disclose the cohort can be of healthy samples, as recited in claim 51.
Reference claim 1 recites determining administering an adjuvant therapy (cancer therapy) to the subject based on the detection of residual disease, as recited in claim 53.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 25 March 2026 have been fully considered but they do not present any arguments regarding the double patenting rejection.
Conclusion
No claims are allowed.
Claims 2, 4, 20, 24, 27-34, 37-39, 41-43, 45-51, and 53-54 are free of the prior art because the prior art does not disclose the specifically claimed process for detecting residual disease that includes one or more mathematical models integrating “genome coverage” in addition to mutation load and detected mutations from the filtered read sets as recited in independent claims 2 and 37-38.
The closest prior art of record, Newman et al., Integrated digital error suppression for improved detection of circulating tumor DNA, 2016, nature biotechnology, 34(5), pg. 547-555 and supplementary (previously cited), discloses a method for detecting circulating tumor DNA (ctDNA) in a subject (Abstract) as previously discussed. Newman discloses computing a circulating tumor DNA (ctDNA) percentage (i.e. an estimated tumor fraction) using reads for each of a baseline and later blood draw and tumor biopsy (i.e. the first, second, and third read sets) (fig. 1, e.g. reads from blood draws at different time points; FIG. 5(c)-(d), e.g. estimated %ctDNA for both plasma and tumor; eONLINE methods, statistical methods for ctDNA detection based on detected tumor reporters in reads; Suppl. Fig. 14). Newman discloses the ctDNA percent at each time point for each sample (i.e. for the first, second, and third read sets) is calculated by a mathematical model integrating a relationship between a number of SNVs with an alelle fraction > 0 (i.e. mutation load and detected mutations), a mean SNV fraction of k tumor-associated SNVs (i.e. based on coverage, given an SNV fraction is a count of reads with a variant divided by the coverage at the locus), and the probability of observing a single tumor reporter (i.e. a number of detected mutations) (ONLINE methods, statistical methods for ctDNA detection, para. 1-4). However, Newman does not disclose the model integrates “genome coverage”, nor would it have been obvious to introduce the new genome coverage into the specifically recited probabilistic model of Newman with any reasonable expectation of success.
Claims 4 and 54 are free of the prior art for the same reasons discussed regarding claims 30 and 34 in the Office action mailed 17 Sept. 2024 regarding the linear dilution ratio and/or inferring tumor fraction based on a correlation between depth of coverage skew and fragment size skew.
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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAITLYN L MINCHELLA whose telephone number is (571)272-6485. The examiner can normally be reached 7:00 - 4:00 M-Th.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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