DETAILED ACTION
The Applicant’s response, received 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 the Claims
Claims 1-12, 16, 20-25, 155, 159, and 161-163 are pending.
Claims 1-12, 16, 20-25, 155, 159, and 161-163 are rejected.
Claim 23 is objected to.
Priority
This application claims benefit of 62/881,845, filed 01 August 2019,
and claims benefit of 62/931,600, filed 06 November 2019,
and claims benefit of 62/978,130, filed 18 February 2020.
Therefore, the effective filing date of the claimed invention is 01 August 2019.
Information Disclosure Statement
The information disclosure statements (IDSs) received 15 October 2025, 19 December 2025, 03 February 2026, 30 April 2026, and 29 May 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Interpretation
The claim interpretation regarding claim 1 at step (D) in the Office action mailed 25 September 2025 is maintained in view of the amendment received 25 March 2026, as noted below.
Claim 1 at step (D) is interpreted as reciting a product-by-process limitation with the product being the data of respective microsatellite loci obtained from biological samples of a cohort of at least 200 subjects, wherein the cohort consists of healthy subjects or subjects with stable microsatellite cancer. The claim is further interpreted to not require the processing steps of producing the product.
The amendment received 25 March 2026 has been fully considered, however after further consideration, new grounds of interpretation are raised in view of the amendment, as noted below.
Claim 1 at step (H) is interpreted as reciting a product-by-process limitation with the product being a trained classifier, and further interpreted to not require the active steps of performing the process of producing the product, i.e., steps of training the classifier.
Claim Objections
The objections to claims 5, 10, 21, and 23 in the Office action mailed 25 September 2025 are withdrawn in view of the amendment received 25 March 2026.
The amendment received 25 March 2026 has been fully considered, however after further consideration, new grounds of objection are raised in view of the amendment.
Claim 23 is objected to because of the following informalities: The claim recites “and the the test subject is…” in line three. The claim should be amended to recite “and the test subject is…” in line three.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The rejection of claims 2 and 161 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 25 September 2025 are withdrawn in view of the amendment received 25 March 2026.
The amendment received 25 March 2026 has been fully considered, however after further consideration, the rejection of claim 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 25 September 2025 is maintained in view of the amendment, as noted below.
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.
Claim 21 is 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.
Claim 21 is indefinite for reciting the limitation “wherein the biological samples from the cohort further include (iii) solid tumor samples from training subjects with unstable microsatellite cancer” because claim 1 at step (D) recites “wherein the cohort consists of heathy subjects or subjects with stable microsatellite cancer” (emphasis added) and therefore claim 1 is closed to other types of subjects, i.e., subjects with unstable microsatellite cancer, and thus, it is unclear as to whether claim 21 is referencing the same cohort as recited at step (D) of claim 1, or else a different cohort altogether, or else the cohort at step (D) does not actually consist of heathy subjects or subjects with stable microsatellite cancer.
The rejection of claim 154 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, in the Office action mailed 25 September 2025 is withdrawn in view of the amendment received 25 March 2026.
The amendment received 25 March 2026 has been fully considered, however after further consideration, the rejection of claim 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, in the Office action mailed 25 September 2025 is maintained in view of the amendment, as noted below.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 recites “wherein the biological samples from the cohort further include (iii) solid tumor samples from training subjects with unstable microsatellite cancer,” and therefore is of improper dependent form for no longer requiring that the cohort at step (D) of claim 1 “consists of heathy subjects or subjects with stable microsatellite cancer” (emphasis added), because claim 21 is requiring that the cohort also includes subjects with unstable microsatellite cancer.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
The Applicant’s arguments/remarks received 25 March 2026 have been fully considered but are not persuasive in part, to the extent noted below.
The Applicant states on pages 10/18 and 11/18 of the Remarks that although the Applicant disagrees with the rejection of claim 21 under 35 U.S.C. 112(b) and 35 U.S.C. 112(d), the Applicant has amended claim 21 to recite subject matter in accordance with 112(b) and 35 U.S.C. 112(d).
These arguments are not persuasive, at least because it does not appear that the Applicant’s amendment of claim 21 was an attempt to remedy the rejection as made in the Office action mailed 25 September 2025.
Claim Rejections - 35 USC § 101
The rejection of claims 1-12, 16, 19-25, 154, 155, 159, and 161-163 under 35 U.S.C. 101 in the Office action mailed 25 September 2025 is maintained with modification in view of the amendment received 25 March 2026, as noted below.
The rejection of claims 19 and 154 under 35 U.S.C. 101 in the Office action mailed 25 September 2025 is withdrawn in view of these claims having been cancelled in the amendment 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 1-12, 16, 20-25, 155, 159, and 161-163 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a law of nature without significantly more. The claims recite: (a) mathematical concepts, (e.g., mathematical relationships, formulas or equations, mathematical calculations); (b) mental processes, i.e., concepts performed in the human mind, (e.g., observation, evaluation, judgement, opinion); and (c) a law of nature (naturally occurring relationship).
Subject matter eligibility evaluation in accordance with MPEP 2106.
Eligibility Step 1: Step 1 of the eligibility analysis asks: Is the claim to a process, machine, manufacture or composition of matter?
Claims 1-12, 16, 20-25, 155, 159, and 161-163 are directed to a method (i.e., a process) of determining a microsatellite instability (MSI) status of a test subject.
Therefore, the claims are encompassed by the categories of statutory subject matter, and thus satisfy subject matter eligibility requirements under Eligibility Step 1.
[Step 1: YES]
Eligibility Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two whether the recited judicial exception is integrated into a practical application of that exception.
Eligibility Step 2A Prong One: In determining whether a claim is directed to a judicial exception, examination is performed that analyzes whether the claim recites a judicial exception, i.e., whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim.
Independent claim 1 recites the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas:
at step (C) generating a mapping of the set of raw sequence reads to a reference genome for the species of the test subject, thereby obtaining a plurality of aligned nucleotide sequences, wherein the plurality of aligned nucleotide sequences comprises at least 15,000 nucleotide sequences mapped to a respective predetermined microsatellite loci in the plurality of predetermined microsatellite loci and wherein the plurality of aligned nucleotide sequences has an average length of at least 50 nucleotides (i.e., mental processes);
at step (D) generating, for each respective microsatellite locus in the plurality of predetermined microsatellite loci, a corresponding density estimate of a number of repeat units in the respective microsatellite locus using a number of repeat units in each nucleotide sequence in a corresponding plurality of nucleotide sequences that map to the respective microsatellite locus obtained from biological samples of a cohort of at least 200 subjects, wherein the cohort consists of heathy subjects or subjects with stable microsatellite cancer, thereby determining at least 30 density estimates (i.e., mental processes and mathematical concepts);
at step (E) generating, for each corresponding nucleotide sequence in the plurality of aligned nucleotide sequences, a likelihood score using (i) the corresponding density estimate of a number of repeat units in the respective microsatellite locus, which the corresponding nucleotide sequence maps to, from among the at least 30 density estimates and (ii) a number of repeat units in the corresponding nucleotide sequence, thereby generating a plurality of likelihood scores, each likelihood score in the plurality of likelihood scores associated with a corresponding microsatellite locus in the plurality of predetermined microsatellite loci (i.e., mental processes and mathematical concepts);
at step (F) determining a central tendency value characterizing a central tendency of those likelihood scores in the plurality of likelihood scores that are associated with each respective microsatellite locus in the plurality of predetermined microsatellite loci and generating a respective value for a likelihood of microsatellite locus stability for each respective microsatellite locus in the plurality of predetermined microsatellite loci based on the corresponding central tendency value (i.e., mental processes and mathematical concepts); and
at step (H) inputting the corresponding metric value for each of the one or more metrics to a trained classifier to generate the MSI status of the test subject, wherein the classifier is trained with training data to distinguish between stable and unstable microsatellite loci and generate the MSI status based on a proportion of the plurality of predetermined microsatellite loci that are unstable, and wherein the training data comprises metric values for the one or more metrics (i.e., mental processes and mathematical concepts).
Independent claim 1, and those claims dependent therefrom, recites a law of nature by associating an individual’s genomic data (microsatellites, i.e., short, repeated sequences of DNA) with a phenotype (microsatellite instability), i.e., a genotype-phenotype correlation (MPEP 2106.04(b)).
Dependent claims 2-12, 16, 20-25, 161, and 162 recite the following steps which fall within the mental processes and/or mathematical concepts groupings of abstract ideas, as noted below.
Dependent claim 2 further recites:
wherein the mapping at step (C) comprises:
aligning each respective raw sequence read in the set of raw sequence reads to the reference genome for the test subject, thereby obtaining a corresponding set of aligned raw sequence reads for the respective DNA fragment (i.e., mental processes); and
collapsing the corresponding set of aligned raw sequence reads for the respective DNA fragment into a corresponding nucleotide sequence for the respective DNA fragment that has been aligned to a human reference genome, thereby obtaining the plurality of aligned nucleotide sequences (i.e., mental processes).
Dependent claim 3 further recites:
the plurality of aligned nucleotide sequences comprises at least 250,000 aligned nucleotide sequences (i.e., mental processes).
Dependent claim 4 further recites:
the one or more metrics further comprises a percentage score (i.e., mental processes and mathematical concepts); and
the corresponding metric value for the percentage score is the percentage of aligned nucleotide sequences, in the plurality of aligned nucleotides, encompassing the respective microsatellite locus that have a number of repeat units that is less than a reference number of repeat units representative of a stable construct at the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 5 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is a number of repeat units present in a reference genome for the species of the test subject (i.e., mental processes).
Dependent claim 6 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is a measure of central tendency of a plurality of reference values, wherein each respective reference value in the plurality of reference values is determined at least in part based on a distribution of the number of repeat units at the respective microsatellite locus in a respective reference sample in a plurality of reference standards (i.e., mental processes and mathematical concepts).
Dependent claim 7 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is the mode of the number of repeat units at the respective microsatellite locus in aligned nucleotide sequences, in the plurality of aligned nucleotide sequences, encompassing the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 8 further recites:
the one or more metrics further comprises a lower mean score (i.e., mental processes and mathematical concepts); and
the corresponding metric value for the lower mean score is determined at least in part by the mean number of repeat units in aligned nucleotide sequences, in the plurality of aligned nucleotides, mapping to the respective microsatellite locus that have a number of repeat units that is less than a reference number of repeat units representative of a stable construct at the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 9 further recites:
the mean number of repeat units is normalized by the reference number of repeat units representative of a stable construct at the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 10 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is a number of repeat units present in a reference genome for the species of the test subject (i.e., mental processes and mathematical concepts).
Dependent claim 11 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is a measure of central tendency of a plurality of reference values, wherein each respective reference value in the plurality of reference values is determined at least in part based on a distribution of the number of repeat units at the respective microsatellite locus in a respective reference sample in a plurality of reference samples (i.e., mental processes and mathematical concepts).
Dependent claim 12 further recites:
for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the reference number of repeat units representative of a stable construct is the mode of the number of repeat units at the respective microsatellite locus in aligned nucleotide sequences, in the plurality of aligned nucleotides, encompassing the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 16 further recites:
the one or more corresponding metric values further comprises a corresponding standard deviation of the number of repeat units in the aligned nucleotide sequences, in the plurality of aligned nucleotide sequences, mapping to the respective microsatellite locus (i.e., mental processes and mathematical concepts).
Dependent claim 20 further recites:
the biological samples from the cohort include both (i) solid tumor samples from training subjects with stable microsatellite cancer and (ii) normal tissue samples (i.e., mental processes).
Dependent claim 21 further recites:
the biological samples from the cohort further include (iii) solid tumor samples from training subjects with unstable microsatellite cancer (i.e., mental processes).
Dependent claim 22 further recites:
the trained classifier comprises a k-nearest neighbors classifier (i.e., mental processes and mathematical concepts).
Dependent claim 23 further recites:
the trained classifier assigns a stability status selected from unstable and stable to each respective microsatellite locus in the plurality of predetermined microsatellite loci (i.e., mental processes), and the test subject is classified as having a high level of microsatellite instability when at least a threshold proportion of microsatellite loci are assigned a status of unstable (i.e., mental processes and mathematical concepts).
Dependent claim 24 further recites:
the threshold proportion of microsatellite loci is at least 30% of the plurality of predetermined microsatellite loci (i.e., mental processes and mathematical concepts).
Dependent claim 25 further recites:
the threshold proportion of microsatellite loci is at least 50% of the plurality of predetermined microsatellite loci (i.e., mental processes and mathematical concepts).
Dependent claim 161 further recites:
the plurality of predetermined microsatellite loci comprises at least 10 human microsatellite loci selected from the group listed in the claim (i.e., mental processes).
Dependent claim 162 further recites:
the plurality of predetermined microsatellite loci comprises at least all of the human microsatellite loci from the group listed in the claim (i.e., mental processes).
The abstract ideas recited in the claims are evaluated under the broadest reasonable interpretation (BRI) of the claim limitations when read in light of and consistent with the specification. As noted in the foregoing section, the claims are determined to contain limitations that can practically be performed in the human mind with the aid of a pen and paper (e.g., mapping sequence data to a reference genome sequence; determining density estimations; and calculating likelihood scores; are steps that can be practically performed in the human mind with the aid of pen and paper), and therefore recite judicial exceptions from the mental process grouping of abstract ideas. Additionally, the recited limitations that are identified as judicial exceptions from the mathematical concepts grouping of abstract ideas (e.g., determining density estimations; generating likelihood scores; measuring central tendencies of the likelihood scores; and determining a proportion of loci that are unstable (e.g., Specification at para. [0397])) are abstract ideas irrespective of whether or not the limitations are practical to perform in the human mind. Furthermore, a law of nature correlating a genotype-phenotype association is identified at Eligibility Step 2A Prong One.
Therefore, claims 1-12, 16, 20-25, 155, 159, and 161-163 recite an abstract idea and a law of nature.
[Step 2A Prong One: YES]
Eligibility Step 2A Prong Two: In determining whether a claim is directed to a judicial exception, further examination is performed that analyzes if the claim recites additional elements that when examined as a whole integrates the judicial exception(s) into a practical application (MPEP 2106.04(d)). A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. The claimed additional elements are analyzed to determine if the abstract idea is integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the abstract idea, the claim fails to integrate the abstract idea into a practical application (MPEP 2106.04(d)(III)).
The judicial exceptions identified in Eligibility Step 2A Prong One are not integrated into a practical application because of the reasons noted below.
Dependent claims 2-12, 16, 20-25, 161, and 162 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements in independent claim 1 include:
step (A) hybridizing cell-free DNA fragments from a liquid biopsy sample from a test subject to a plurality of nucleic acid capture probes to generate a plurality of cell-free DNA fragments enriched, relative to all cell-free DNA fragments in the liquid biopsy sample, for a set of cell-free DNA fragments encompassing a plurality of predetermined microsatellite loci, wherein the plurality of nucleic acid capture probes collectively hybridize to at least 30 predetermined microsatellite loci and wherein a number of repeats within each microsatellite locus in the plurality of predetermined microsatellite loci in the germ line of the test subject is unknown (i.e., a step in the process of gathering data for use in the claimed method);
step (B) sequencing the plurality of cell-free DNA fragments to generate a set of raw sequence reads (i.e., a step in the process of gathering data for use in the claimed method); and
at least one processor communicatively coupled to a memory device with stored instructions;
at steps (D), (E) and (F), a database (i.e., a stored collection of data); and
at step (G) receiving, from the database, one or more corresponding metric values for one or more metrics for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the one or more metrics including the likelihood of microsatellite locus stability of the respective microsatellite locus (i.e., receiving data for use in the claimed process); and
at step (I) storing the MSI status within the database (i.e., a step of storing data).
The additional elements in dependent claims 155, 159, and 163 include:
the plurality of aligned sequence reads represents, on average, greater than 1000X sequence depth for each microsatellite locus in the plurality of predetermined microsatellite loci and the plurality of aligned nucleotide sequences comprises at least 30000 nucleotide sequences (i.e., data gathering) (claim 155);
the liquid biopsy sample is a blood or blood plasma sample (i.e., data gathering) (claim 159); and
the subject is a human (i.e., part of the data gathering process) (claim 163).
The additional element of at least one processor communicatively coupled to a memory device with stored instructions (claim 1) invokes a computer and/or computer-related components merely as tools for use in the claimed process, such that they amount to no more than mere instructions to apply the exceptions using a generic computer (MPEP 2106.05(f)), and therefore are not an improvement to computer functionality itself, or an improvement to any other technology or technical field, and thus, do not integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(1)).
The additional element of a database (claim 1) is merely a part of the pre-solution activities of gathering data for use in the claimed process – a nominal or tangential addition to the claims that does not meaningfully limit the claims, and therefore does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)). Furthermore, the additional element of a database invokes a computer and/or computer-related components merely as tools for use in the claimed process, such that they amount to no more than mere instructions to apply the exceptions using a generic computer (MPEP 2106.05(f)), and therefore are not an improvement to computer functionality itself, or an improvement to any other technology or technical field, and thus, do not integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(1)).
The additional element of receiving, from the database, one or more corresponding metric values for one or more metrics for each respective microsatellite locus in the plurality of predetermined microsatellite loci, the one or more metrics including the likelihood of microsatellite locus stability of the respective microsatellite locus (i.e., receiving data for use in the claimed process) (claim 1) is merely a pre-solution activity that is part of the process of gathering data for use in the claimed process – a nominal or tangential addition to the claims that does not meaningfully limit the claims, and therefore does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional element of storing the MSI status within the database (claim 1) is merely a post-solution activity of storing data – a nominal or tangential addition to the claims that does not meaningfully limit the claims, and therefore does not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
The additional elements of hybridizing cell-free DNA fragments from a liquid biopsy sample from a test subject to a plurality of nucleic acid capture probes to generate a plurality of cell-free DNA fragments enriched, relative to all cell-free DNA fragments in the liquid biopsy sample, for a set of cell-free DNA fragments encompassing a plurality of predetermined microsatellite loci (claim 1); sequencing the plurality of cell-free DNA fragments to generate a set of raw sequence reads (claim 1); the plurality of aligned sequence reads represents, on average, greater than 1000X sequence depth for each microsatellite locus in the plurality of predetermined microsatellite loci and the plurality of aligned nucleotide sequences comprises at least 30000 nucleotide sequences (claim 155); the liquid biopsy sample is a blood or blood plasma sample (claim 159); and the subject is a human (claim 163); are merely pre-solution activities that are part of the process of gathering data for use in the claimed process – nominal or tangential additions to the claims that do not meaningfully limit the claims, and therefore do not add more than insignificant extra-solution activity to the judicial exceptions (MPEP 2106.05(g)).
Thus, the additionally recited elements merely invoke a computer as a tool, and/or amount to insignificant extra-solution data gathering activity, and as such, when all limitations in claims 1-12, 16, 20-25, 155, 159, and 161-163 have been considered as a whole (i.e., the analysis takes into consideration all the claim limitations and how those limitations interact and impact each other when evaluating whether the exception is integrated into a practical application), the claims are deemed to not recite any additional elements that would integrate a judicial exception into a practical application, and therefore claims 1-12, 16, 20-25, 155, 159, and 161-163 are directed to an abstract idea (MPEP 2106.04(d)).
[Step 2A Prong Two: NO]
Eligibility Step 2B: Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are probed for a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). Identifying whether the additional elements beyond the abstract idea amount to such an inventive concept requires considering the additional elements individually and in combination to determine if they amount to significantly more than the judicial exception (MPEP 2106.05A i-vi).
The claims do not include any additional elements that are sufficient to amount to significantly more than the judicial exception(s) because of the reasons noted below.
Dependent claims 2-12, 16, 20-25, 161, and 162 do not recite any elements in addition to the judicial exceptions.
The additional elements recited in independent claim 1 and dependent claims 155, 159, and 163 are identified above, and carried over from Step 2A: Prong Two along with their conclusions for analysis at Step 2B. Any additional element or combination of elements that was considered to be insignificant extra-solution activity at Step 2A: Prong Two was re-evaluated at Step 2B, because if such re-evaluation finds that the element is unconventional or otherwise more than what is well-understood, routine, conventional activity in the field, this finding may indicate that the additional element is no longer considered to be insignificant; and all additional elements and combination of elements were evaluated to determine whether any additional elements or combination of elements are other than what is well-understood, routine, conventional activity in the field, or simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, per MPEP 2106.05(d).
The additional elements of at least one processor communicatively coupled to a memory device with stored instructions (claim 1); a database (claim 1); receiving data (claim 1); and storing data (claim 1); are conventional (see MPEP at 2106.05(b) and 2106.05(d)(II) regarding conventionality of computer components and computer processes).
The additional element of hybridizing cell-free DNA fragments from a liquid biopsy sample from a test subject to a plurality of nucleic acid capture probes to generate a plurality of cell-free DNA fragments enriched, relative to all cell-free DNA fragments in the liquid biopsy sample (claim 1); is conventional. Evidence for the conventionality is shown by:
Osumi et al. (“Clinical utility of circulating tumor DNA for colorectal cancer.” Cancer Science, 2019 (First published 11 February 2019), Vol. 110, No. 4, pp. 1148-1155, as cited in the Office action mailed 25 September 2025).
Osumi et al. reviews the clinical utility of circulating tumor DNA (ctDNA) for colorectal cancer (Title) and provides an overview of the characteristics of ctDNA with a focus on detection methods for ctDNA, and the feasibility of use of ctDNA to monitor tumor dynamics for patients with colorectal cancer (Abstract). Osumi et al. further shows that the measurement of biomarkers before treatment is of importance in the optimum management of patients with colorectal cancer (CRC) and that tissue-based biomarkers such as RAS mutation, BRAF mutation, HER2 amplification, and microsatellite instability are used to determine prognosis and guide systemic therapy (page 1148, col. 1, Introduction). Osumi et al. further shows that compared with a classic biopsy, liquid biopsies are more convenient, and present minimal procedural risk to the patient, and that ctDNA has potential clinical utility as a key component of liquid biopsies (page 1148, col. 2, Introduction). Osumi et al. further shows that capture-based next generation sequencing (NGS) has the ability to enrich genomic regions of interest by hybridizing target genes/regions to antisense oligonucleotides before sequence, and that this approach allows for the agnostic analysis of large portions of the genome and can identify multiple mutations with increased sensitivity (page 1150, col. 1, para. 1) and further shows various technologies for detecting ctDNA using targeted sequencing approaches (Table 2).
The additional elements of sequencing the plurality of cell-free DNA fragments to generate a set of raw sequence reads (claim 1); the plurality of aligned sequence reads represents, on average, greater than 1000X sequence depth for each microsatellite locus in the plurality of predetermined microsatellite loci and the plurality of aligned nucleotide sequences comprises at least 30000 nucleotide sequences (claim 155); the liquid biopsy sample is a blood or blood plasma sample (claim 159); and the subject is a human (claim 163); are conventional. Evidence for the conventionality is shown by:
Morganti et al. (“Complexity of genome sequencing and reporting: Next generation sequencing (NGS) technologies and implementation of precision medicine in real life.” Critical Reviews in Oncology, 2019 (Published January 2019), Vol. 133, pp. 171-182, as cited in the Office action mailed 20 September 2023).
Morganti et al. reviews the complexity of genome sequencing and reporting, particularly focusing on next-generation sequencing (NGS) technologies and the implementation of precision medicine (Title; and Abstract). Morganti et al. shows that NGS technologies allow for the obtainment of extensive genetic information from liquid biopsies, and the obtainment of genetic material for sequencing from circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA; page 172, col. 2, para, 1; and page 177, col. 2, Section 4.3). Morganti et al. further reviews NGS sequencing (page 173, Section 2.2) and NGS methods (page 174, Section 3), and further still, reviews advantages of NGS methodology with regard to microsatellite instability analyses (page 177, col. 1, Section 4.2.2). Morganti et al. further shows that liquid biopsies are non-invasive blood tests (page 177, col. 2, Section 4.3); next-generation sequencing platforms that produce at least 30,000 reads per run (Table 2); and genome analysis by targeted sequencing, in which specific regions of interest are isolated and sequenced, and gene panels allowing selected genes to be sequence with a 500-1000X coverage (page 174, col. 2, para. 2).
Therefore, when taken alone (i.e., individually), all additional elements in claims 1-12, 16, 20-25, 155, 159, and 161-163 do not amount to significantly more than the above-identified judicial exception(s). Even when evaluated as an ordered combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 1-12, 16, 20-25, 155, 159, and 161-163 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) (MPEP 2106.05(II)).
[Step 2B: NO]
Response to Arguments
The Applicant’s arguments/remarks received 25 March 2026 have been fully considered, but are not persuasive.
The Applicant provides the claim language of amended claim 1 on pages 11-12 of the Remarks, and states on page 12 (bottom) that when properly considered under the revised MPEP (as revised by the December 5, 2025 Memorandum by Charles Kim, Deputy Commissioner for Patents (hereinafter the “December Memorandum”), as well as the 2019 Revised Patent Subject Matter Eligibility Guidance (hereinafter the “2019 Guidance”), independent claim 1 is not directed to an abstract idea and, in any event, integrates any alleged abstract idea into a practical application, and thus claim 1 recites patentable subject matter. The Applicant further states on page 12 (bottom) that as an initial point, the December Memorandum provides updates to the Manual of Patent Examining Procedure (MPEP) that took effect immediately, and that the December Memorandum updates MPEP 2106.05(a) subsection I, to list as an example:
xiv. Improvements to computer component or system performance based upon adjustments to parameters of a machine learning model associated with tasks or workstreams; Ex Parte Desjardins, Appeal No. 2024-000567 (PTAB September 26, 2025, Appeals Review Panel Decision) (precedential).
The Applicant further states on page 13 (para. 2) that here, among other features, independent claim 1 recites “inputting the corresponding metric value for each of the one or more metrics to a trained classifier to generate the MSI status of the test subject, wherein the classifier is trained with training data to distinguish between stable and unstable microsatellite loci and generate the MSI status based on a proportion of the plurality of predetermined microsatellite loci that are unstable, and wherein the training data comprises metric values for the one or more metrics,” and as such, claim 1 not only recites using a trained classifier to generate the MSI status, but also recites that the trained classifier is trained with training data that comprises metric values for the one or more metrics that allows the classifier to distinguish between stable and unstable microsatellite loci. The Applicant further states that thus, in accordance with the Desjardins Appeals Review Panel Decision, which the USPTO designated precedential on November 4, 2025, claim 1 recites subject matter that improves computer functionality, and thus is not directed to an abstract idea.
These arguments are not persuasive, because first, with regard to the Applicant’s attempt to analogize the instant claims to the claims in Desjardins, these arguments are not persuasive at least because the fact patterns differ between the claims at issue in Desjardins (i.e., a method of training a machine learning model) and the instant claims (i.e., a method using a trained classifier), not least in that the “ARP” in Desjardins notes that the Federal Circuit held that the eligibility determination should turn on whether “the claims are directed to an improvement to computer functionality versus being directed to an abstract idea” (citing Enfish), prior to the “ARP” finding that the improvement to how the machine learning model operates allows artificial intelligence (AI) systems to use less of their storage capacity and enables reduced system complexity, as supported by the Specification – i.e., the improvement to the model provided an improvement to computer functionality itself. This fact pattern contrasts with the fact pattern recited in the instant claims, i.e., steps of using a trained classifier to analyze data and generate a data output representing a classification of the data and then storing the classification within a database. Therefore, claims should be interpreted based on the fact patterns set forth in a particular claim, as other claims with different fact patterns may have different eligibility outcomes, as evidenced in the rejection of the instant claims above.
The Applicant states on page 13 (para. 3) of the Remarks that moreover, the Memorandum dated August 4, 2025, by Charles Kim, Deputy Commissioner for Patents (hereinafter the “Aug. Memorandum”) offered a helpful reminder “to distinguish claims that recite an exception… from claims that merely involve an exception.” The Applicant further states that the Aug. Memorandum notes that “[a]n important consideration in determining whether a claim improves technology or a technical field is the extent to which the claim covers a particular solution to a problem or a particular way to achieve a desired outcome, as opposed to merely claiming the idea of a solution or outcome,” and further “cautioned not to oversimplify claim limitations.” The Applicant further states (para. 4) that here, rather than merely claiming any mental process, any mathematical concept, or any law of nature, the claims recite, among other things, how the plurality of cell-free DNA fragments are generated, how the set of raw sequence reads are generated, how the plurality of aligned nucleotide sequences are generated, how the density estimates and likelihood scores are generated, and how the MSI status is generated with a trained classifier, among other things, and as such, any allegation that the claims merely recite a mental process, any mathematical concept, or merely a law of nature appear to be, at best, an oversimplification of the claimed subject matter. The Applicant further states on page 14 (para. 2) that indeed, the Aug. Memorandum distinguishes features that “involve or rely on” mathematical concepts from those that “set forth or describe mathematical relationships, calculations, formulas, or equations using words or mathematical symbols.” The Applicant further states that here, the Office action alleges that the steps at (D), (E), (F), (G), and (H) all recite mathematical concepts, yet nowhere does claim 1 “set forth or describe any mathematical relationships, calculations, formulas, or equations using words or mathematical symbols.” The Applicant further states that as such, at best, claim 1 may “involve or rely on” mathematical concepts, but does not “set forth” any such alleged abstract idea.
These arguments are not persuasive, because first, the August 4, 2025 memorandum regarding reminders on evaluating subject matter eligibility of claims under 35 U.S.C. 101 clearly states (page 1) that the memorandum is not intended to announce any new USPTO practice or procedure and is meant to be consistent with existing USPTO guidance, and further states that Examiners should consult the specific MPEP sections for more thorough information. Second, the rejection above and the rejections of record have been raised in accordance with the eligibility analysis framework provided at MPEP 2106. Third, with regard to the Applicant’s argument that the claims are not directed toward a mathematical concept, and that the August 4, 2025 memorandum draws a distinction between claims that recite a mathematical relationship vs. claims that merely involve a mathematical relationship, it is noted that the MPEP at 2106.04 II.A.1. is instructive, describing an example of a claim that merely involves, or is based on, an exception is a claim to "A teeter-totter comprising an elongated member pivotably attached to a base member, having seats and handles attached at opposing sides of the elongated member." This claim is based on the concept of a lever pivoting on a fulcrum, which involves the natural principles of mechanical advantage and the law of the lever. However, this claim does not recite (i.e., set forth or describe) these natural principles and therefore is not directed to a judicial exception. In contrast, a claim that recites (i.e., sets forth or describes) a step of determining a central tendency value characterizing a central tendency of those likelihood scores in the plurality of likelihood scores that are associated with each respective microsatellite locus in the plurality of predetermined microsatellite loci and generating, within the database, a respective value for a likelihood of microsatellite locus stability for each respective microsatellite locus in the plurality of predetermined microsatellite loci based on the corresponding central tendency value, recites a mathematical concept because the step at least describes performing mathematical operations on data.
The Applicant states on page 14 (para. 3) of the Remarks that moreover, the Office action states that the “additional element of a computer system comprising at least one processor and a memory for storing (claim 1) invokes a computer merely as a tool for use in the claimed process, i.e., performing the abstract ideas, and therefore is not an improvement to computer functionality itself, or an improvement to any other technology or technical field” and concludes that claim 1 “does not integrate the judicial exceptions into a practical application.” The Applicant further states (para. 4) that the Applicant’s specification, however, demonstrates to one of ordinary skill in the art that, at least as amended, claim 1 provides a technical improvement that uses trained classifiers to generate the MSI status of a cancer in a test subject in a non-invasive fashion (e.g., see Specification, paras. [0008] – [0013]), and as such, rather than merely reciting any alleged abstract idea, including any mental process, mathematical concept, or law of nature, claim 1, in amended form, recites the above quoted features, which provides technological improvements to MSI status generation processes and thus integrates any alleged abstract idea into a practical application. The Applicant further states on page 15 (para. 1) that indeed, the Applicant also notes that on December 31, 2025, the PTAB issued an opinion in Ex Parte Carmody, Appeal 2025-002843, and further states that, relying on Ex Parte Desjardins, the PTAB stated that because “the claims recite an improvement in training of models for use by [a] recommendation engine to generate useful orchestrations,” the claims are patent eligible. The Applicant further states that in reaching that conclusion, the PTAB relied on the claimed features of “train at least one of a plurality of modular plug-and-play tactic-specific models using machine learning with a second training dataset comprising labeled feature vectors, wherein each of the labeled feature vectors comprises a set of orchestration features labeled with an indication of whether or not an engagement resulted within a defined time period.” The Applicant further states that similarly, the claims here recite, among other things, the features of “inputting the corresponding metric value for each of the one or more metrics to a trained classifier to generate the MSI status of the test subject, wherein the classifier is trained with training data to distinguish between stable and unstable microsatellite loci and generate the MSI status based on a proportion of the plurality of predetermined microsatellite loci that are unstable, and wherein the training data comprises metric values for the one or more metrics,” thereby similarly reciting an improvement in the training of machine learning models (specifically, training a classifier using specific training data to generate MSI status for test subjects), and thus are similarly patent eligible. The Applicant further states on page 15 (para. 2) that the claimed subject matter cannot be performed mentally, or with pen and paper, and that indeed, claim 1 recites, among other things, “executing, by at least one processor communicatively coupled to a memory device, instructions stored in the memory, wherein executing the instructions causes the at least one processor to perform … operations” including steps (E), (F), (G), (H), and (I) of claim 1, and further states on page 16 that these features simply cannot be performed mentally and, instead, provide a technical solution that allows for the automatic generation of MSI status of a cancer in a test subject in a non-invasive fashion, and further states that therefore, the quoted elements recited similarly by Applicant’s independent claim, at least in amended form, represent meaningful limitations that integrate any alleged abstract idea into a practical application.
These arguments are not persuasive, because first, with regard to Applicant’s attempt to analogize the instant claims to a recent PTAB decision, i.e., Ex parte Carmody, (applying the Desjardins rationale finding patent eligibility for the claimed subject matter), it is noted that Carmody is not precedential, and further noted that every application should be interpreted based on the fact patterns set forth in a particular claim set, as other fact patterns may have different eligibility outcomes, as evidenced in the rejection of the instant claims above. Furthermore, to the extent that the Applicant intends to compare the claim set and adopt the logic of the PTAB, it appears that the cited Carmody is just a general example and does not necessarily represent all sides or all fact patterns presented to the PTAB and their decisions related to 35 U.S.C. 101. Second, with regard to the Applicant’s argument that the claims cannot be performed mentally, it is noted that claims can recite a judicial exception even if they are claimed as being performed on a computer (MPEP 2106.04(a)(2)(III)(C)), i.e., the use of a computer to perform the claimed method at a rate and accuracy that can far outstrip the mental performance of a skilled artisan does not change the nature of the activity being performed (i.e., an abstract idea), and therefore does not materially alter the patent eligibility of the claimed subject matter. Third, regarding the Applicant’s argument that the quoted elements above represent meaningful limitations that integrate any alleged abstract idea into a practical application, it is noted that the quoted elements recite limitations that comprise the judicial exceptions identified at Step 2A Prong One in the above rejection, and therefore cannot represent meaningful limitations for the purpose of integrating judicial exceptions into practical application, because the phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole (MPEP 2106.05(e)).
The Applicant states on page 16 (bottom) of the Remarks that when determining patent eligibility, the MPEP notes that consideration should be given as to “whether the claim ‘purport(s) to improve the functioning of the computer itself” or “any other technology or technical field,” which has been referred to as “the search for a technological solution to a technological problem.” (MPEP 2106.05(a)). The Applicant further states that moreover, the Office’s current examination guidelines state that “a claim that does not ‘integrate’ a recited judicial exception [may] nonetheless [be] patent eligible” when “the additional elements recited in the claims provid[e] ‘significantly more’ than the [alleged] recited judicial exception,” and requires that “the additional elements [should be evaluated] individually and in combination under Step 2B to determine whether they provide an inventive concept.” The Applicant further states on page 17 (para. 2) that here, at least as amended, the claims recite significantly more than any processes that can be performed in the mind, and mathematical concept, or any law of nature, and indeed, the claims recite “specific limitation[s] other than what is well-understood, routine, conventional activity in the field,” and “add[] unconventional steps that confine the claim to a particular useful application,” as the prior art fails to teach or suggest the claimed subject matter. The Applicant further states that moreover, the claimed subject matter is confined to a “particular useful application” that includes using a trained classifier to generate MSI status of cancer in test subjects in a non-invasive fashion, as described above. The Applicant further points to Alice Corp. v. CLS Bank International, noting that the Supreme Court explained that claims reciting an “inventive concept” are patent eligible under 35 U.S.C. 101, and the Applicant further states that the Applicant’s independent claim involves an “inventive concept” under 35 U.S.C. 101, at least because the claim recites features that exceed “well-understood, routine, conventional activities” already known in the industry, and accordingly, claim 1 qualifies as eligible subject matter under 35 U.S.C. 101.
These arguments are not persuasive, because first, regarding the Applicant’s argument that the claims recite significantly more than the judicial exceptions and the claims recite “specific limitation[s] other than what is well-understood, routine, conventional activity in the field,” and “add[] unconventional steps that confine the claim to a particular useful application,” as the prior art fails to teach or suggest the claimed subject matter, it is noted that when taken alone (i.e., individually), the additional elements in claims 1-12, 16, 20-25, 155, 159, and 161-163 do not amount to significantly more than the above-identified judicial exception(s), and even when these additional elements are evaluated as an ordered combination, the additional elements fail to transform the exception(s) into a patent-eligible application of that exception. Thus, claims 1-12, 16, 20-25, 155, 159, and 161-163 are deemed to not contribute an inventive concept, i.e., amount to significantly more than the judicial exception(s) at Step 2B (MPEP 2106.05(II)). Second, the search for an inventive concept is different from an anticipation analysis under 35 U.S.C. 102 or an obviousness analysis under 35 U.S.C. 103, and because there are separate and distinct requirements from eligibility, patentability of the claimed invention under 35 U.S.C. 102 and 103 with respect to the prior art is neither required for, nor a guarantee of, patent eligibility under 35 U.S.C. 101 (MPEP 2106.05(I)). Third, using a trained classifier to generate MSI status of a cancer in test subjects in a non-invasive fashion invokes a computer merely as a tool for performing the recited abstract ideas, and therefore any purported improvement is in the abstract idea itself (i.e., analyzing and classifying data), and not an improvement in the functioning of a computer itself, or an improvement to any other technology or technical field, as noted and discussed in the above rejection.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.W.B./Examiner, Art Unit 1687
/Joseph Woitach/Primary Examiner, Art Unit 1687
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