DETAILED ACTION
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 1-21 are pending and examined herein.
No claims are canceled.
Priority
As detailed on the 26 February 2025 filing receipt, the application claims priority as early as 05 August 2021 to provisional application 63/229,797. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Withdrawn Objections and Rejections
The objection to claim 21 is withdrawn in view of amendment adding commas.
The rejection of claim 19 under 35 USC 112(a) is withdrawn in view of persuasive argument, where applicant remarks state instructions to perform methylation sequencing (pg. 15, second paragraph). Instructions to perform sequencing is output and not sequencing itself, which cannot be performed by the recited computing system comprising processors and memory in parent claim 11.
The rejections of claims 12 and 21 are withdrawn in view of amending antecedence for computer elements in claim 12 and amending numeration of element claims in claim 21.
The rejection under 35 USC 102 is withdrawn in view of amendment reciting co-occurrence of methylation status and sequence data from the same liquid biological sample.
The following rejections are either maintained or newly applied, and constitute the complete set of rejections for the instant claims.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites enrichment of somatic variants. However, the recited active steps are obtaining sequence and methylation data, using the data to assign to a reference, and applying the model to obtain an indication of variant being somatic or germline. An enriching step or prior teaching of enrichment is not taught, rendering the claim unclear. Claims 11 and 20-21 recite a similar element. All claims dependent on claims 1, 11, and 20-21 are rejected on similar grounds.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-21 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of identifying a variant allele as somatic or germline.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to methods (claims 1-10 and 21), a computer system (claims 11-19), and a non-transitory computer-readable medium (claim 20), each of which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
The recited claim element of using the reference genetic information to assign each fragment to a reference subset (claims 1, 11, and 20-21) is a mental step as the step of matching or aligning the sequences, where such a step is matching patterns of nucleotides and thus a step practically performed by the human mind.
The recited claim element of using the variant genetic information to assign each fragment to a variant subset (claims 1, 11, and 20-21) is a mental step as the step of matching or aligning the sequences, where such a step is matching patterns of nucleotides and thus a step practically performed by the human mind.
The recited claim element of applying a trained binary classifier to identify a variant as a somatic or germline variant (claims 1, 11, and 20-21) is interpreted as a mental step of identifying a variant based on a classification where such a step is data evaluation or judgment, which the human mind is practically equipped to perform, and is facilitated by a trained binary classifier. Given its broadest reasonable interpretation in light of the specification, a binary classifier is disclosed as generated by a mathematical step exemplified as a logistic regression model trained through backpropagation and error minimization (pg. 95-96, paragraph [342]), all of which are interpreted as verbal descriptions of mathematical processes. A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation (MPEP 2106.04(a)(2)).
The recited claim element of leveraging co-occurrence between abnormal methylation and somatic variants is considered to be further description of the data thus an abstract idea. Furthermore, such a relationship is a natural phenomenon (MPEP 2106.04(b)(I)).
The recited claim element of using the methylation state, sequences with a variant, and orthogonal calls to train a classifier (claim 21) is interpreted as a mathematical step because training is disclosed as updating parameters through backpropagation ((pg. 95, paragraph [342]), which is a method of computing predictions and calculating loss.
Claims 3 and 13 recite additional information about the nucleic acid fragment sequences, where the additional information is abstract, and determining the p-value, which is a mathematical calculation.
Claim 4 recites additional information about the type of variation the allele is, where the additional information is abstract.
Claims 5 and 14 recite determining a cancer risk of the test subject and predicting an ethnicity of the test subject, which are data evaluation steps and thus a mental process based on evaluation of the data, and determining a tumor fraction of the test subject, where a tumor fraction is a mathematical concept defined as the fraction of nucleic acid molecules in a sample that originates from a cancerous tissue of the subject, rather than from a noncancerous tissue (pg. 30, paragraph [102]). These values may also be understood as a mental process.
Claims 6-7 and 15-16 recite mathematical concepts in the form of calculation of measure of central tendency, minima, maxima, and spread of p-values.
Claims 8 and 17 recite the applying, to the trained binary classifier, further applies one of one or more additional parameters, where parameterization of the classifier is interpreted as additional information about the mathematical concept.
Claims 9 and 18 recite data interpretation supporting a variant call and thus a mental process based on data evaluation, which the human mind is practically equipped to perform.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Because the claims recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they recite elements in addition to the abstract ideas which integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)).
Additional elements that are not abstract ideas recited in the instant claims are: obtaining an identification of a reference allele at the genomic position (claims 1, 11, and 20-21); obtaining an identification of the variant allele at the genomic position claims 1, 11, and 20-21; obtaining a methylation state and a respective sequence of each nucleic acid fragment sequence in a respective plurality of nucleic acid fragment sequences in a sequencing dataset derived from a liquid biological sample obtained from the test subject that map onto the genomic position, wherein the sequencing dataset comprises at least 1 x 106 nucleic acid fragment sequences (claims 1, 11, and 20-21); inputting a reference genome and aligning to the reference genome (claim 2); obtaining an orthogonal call for the variant allele as somatic or germline for the respective subject (claim 21); a computer system (claims 2 and 11-12); one or more processors (claims 2 and 11-12); memory storing program(s) (claim 11); a non-transitory computer-readable medium (claims 2, 12, and 20); inputting and mapping to a genomic reference (claims 2 and 12); performing methylation sequencing (claim 10); and outputting instructions to perform methylation sequencing (claim 19).
Claim elements reciting obtaining data, mapping sequences, aligning sequences, and methylation sequencing are interpreted as data gathering steps required to perform the abstract steps concluding in classifying the variant allele as somatic or germline. Therefore, these steps are interpreted as insignificant extra-solution activity (MPEP 2106.05(g)). Outputting instructions to perform sequencing is a data transmitting step similarly related to gathering data. Claim elements reciting computer systems or components are interpreted as a generic computer performing the functions that constitute the abstract idea. Hence, these are mere instructions to apply the abstract idea using a computer, and therefore the claim does not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
Because the claims recite an abstract idea, and do not integrate that abstract idea into a practical application, the claims are directed to that abstract idea. Claims that are directed to abstract ideas must be examined further to determine whether the additional elements besides the abstract idea render the claims significantly more than the abstract idea. Claims that are directed to abstract ideas and that raise a concern of preemption of those abstract ideas must be examined to determine what elements, if any, they recite besides the abstract idea, and whether these additional elements constitute inventive concepts that are sufficient to render the claims significantly more than the abstract idea (MPEP 2106.05). [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Additional elements that are not abstract ideas recited in the instant claims are: obtaining an identification of a reference allele at the genomic position (claims 1, 11, and 20-21); obtaining an identification of the variant allele at the genomic position claims 1, 11, and 20-21; obtaining a methylation state and a respective sequence of each nucleic acid fragment sequence in a respective plurality of nucleic acid fragment sequences in a sequencing dataset derived from a liquid biological sample obtained from the test subject that map onto the genomic position, wherein the sequencing dataset comprises at least 1 x 106 nucleic acid fragment sequences (claims 1, 11, and 20-21); inputting a reference genome and aligning to the reference genome (claim 2); obtaining an orthogonal call for the variant allele as somatic or germline for the respective subject (claim 21); a computer system (claims 2 and 11-12); one or more processors (claims 2 and 11-12); memory storing program(s) (claim 11); a non-transitory computer-readable medium (claims 2, 12, and 20); inputting and mapping to a genomic reference (claims 2 and 12); performing methylation sequencing (claim 10); and outputting instructions to perform methylation sequencing (claim 19).
The courts have found that receiving and outputting data are well-understood, routine, and conventional functions of a computer when claimed in a merely generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(II)(i)).
Borchiellini (Cells 8: 15 pgs., 2019; previously cited 25 March 2026) teaches DNA methylation changes in somatic cells linked to cancer (abstract) and bisulfite sequencing for gene locus specific DNA methylation detection (pg. 4, first paragraph). Furthermore, alignment of sequences to a reference genome is a well-known step of bioinformatic pipelines, such as those taught in the review by Li (Briefings in Bioinformatics 11(5): 473-483, 2010; newly cited), including those involving methylation, such as those found in the view by Krueger (Nature Methods 9: 145-151, 2012; newly cited).
Therefore, the recited additional elements, alone or in combination with the judicial exceptions, do not appear to provide an inventive concept. [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Response to the 17 August 2026 Applicant Remarks
Applicant remarks state, regarding Step 2A Prong One, that identifying variants as somatic or germline and their methylation state is beyond what is practically performable by the human mind because it requires at least one million fragment sequences (pg. 17, second paragraph). This argument is not persuasive. While identifying one million sequences would take a long time, the individual comparisons are each within the scope of what the human mind can do. While it is acknowledged that such computations performed mentally, or with paper and pencil, would take considerable time and effort, this does not graduate the entire process from being many mental steps into a non-abstract step.
Applicant remarks state the binary classification is not a mental step because it requires at least ten parameters (pg. 17). Using ten parameters in a decision does not necessarily preclude a decision on identification of a variant allele from being a mental process. Furthermore, given its broadest reasonable interpretation in light of the specification, binary classifiers are mathematical concepts. A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation (MPEP 2106.04(a)(2)). If the classification cannot be performed mentally and does not require mathematical steps, then it is unclear how the classification is being performed.
At Step 2A Prong Two, applicant remarks state that leveraging a co-occurrence of abnormal methylation and enrichment of somatic variants represents an improvement over other variant classification techniques (pg. 19, last paragraph). At Step 2A Prong Two, the claims must be examined further to determine whether they recite elements in addition to the abstract ideas which integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)). The additional elements in the instant claims include data input, alignment, sequencing, and general purpose computer components. These elements are considered to be data gathering steps (insignificant extra-solution activity) or invoking a computer to perform the abstract steps, neither of which integrate the abstract idea into a practical application. The steps culminate in an identification, which is an abstract step. It is also noted that obtaining data.
Applicant remarks further state that the combination of methylation sequencing, binning, extraction of methylation state, and the classifier enable accurate variant identification. The steps of binning, extraction of methylation state, and the classifier are abstract steps that rely on the sequencing steps, which is only actively required in claim 10 and within the state of the art. Therefore, the argument that the additional elements integrate the abstract ideas into a practical application in the form of an improvement is unpersuasive. Similarly, analogy to Desjardins is unpersuasive because the improvement therein is to a computer system solving a problem rooted in computational analysis, whereas the instant claims are directed to a biological question of identifying variants based on methylation.
At Step 2B, applicant remarks state the analytical pipeline including obtaining data, assigning fragments to bins, extracting methylation state from the subsets, and applying them to a trained classifier represents an unconventional arrangement of elements and thus significantly more than the abstract ideas is provided (pg. 20, second paragraph). At Step 2B, the elements in addition to the abstract ideas are analyzed for conventionality. Here, those steps of data input, alignment, sequencing, and general purpose computer components. These steps were determined to be conventional in view of Berkheimer evidence provided and steps explained as conventional in MPEP 2106.05(d)(II)(i)). The arrangement of additional elements is considered conventional and thus does not provide significantly more than the abstract idea.
The rejection under 35 USC 101 is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 8-12, and 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Gross (US 20200340064 A1; previously cited on the 04 August 2022 IDS form) in view of Luo (Trends in Molecular Medicine 27(5): 482-500, 2021; newly cited).
Claim 1 recites obtaining an identification of a reference allele at the genomic position and obtaining an identification of the variant allele at the genomic position.
Gross teaches obtaining reference and variant alleles from genomic positions (paragraph [175]).
Claim 1 recites obtaining a methylation state and a respective sequence of each nucleic acid fragment sequence in a respective plurality of nucleic acid fragment sequences in a sequencing dataset derived from a liquid biological sample obtained from the test subject that map onto the genomic position, wherein the sequencing dataset comprises at least 1 x 106 nucleic acid fragment sequences.
Gross teaches determining a methylation pattern in an allele position (paragraph [48]) and sequencing millions of fragments (paragraph [156]) and deriving the sample from a liquid biopsy (paragraph [231]). Gross does not clearly teach deriving both sequence data and methylation status data from the same liquid sample.
Claim 1 recites using (i) the identification of the reference allele at the genomic position and (ii) the respective sequence of each nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences to assign each nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences that has the reference allele, at the genomic position, to a reference subset, and using (i) the identification of the variant allele at the genomic position and (ii) the respective sequence of each nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences to assign each nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences that has the variant allele, at the genomic position, to a variant subset.
Gross teaches determining counts of fragments with an alternative allele, interpreted as a variant allele, and those with a reference allele (pg. 20, paragraph [205]), where these counts are interpreted as generating subsets of those with a variant and reference allele.
Claim 1 recites applying, to a trained binary classifier, at least (i) one or more indications of
methylation state across the methylation state of each nucleic acid fragment sequence in the variant subset and (ii) an indication of a number of nucleic acid fragment sequences in the reference subset versus a number of nucleic acid fragment sequences in the variant subset, wherein the trained binary classifier comprises at least 10 parameters, thereby obtaining from the trained binary classifier an identification of the variant allele at the genomic position in the test subject as somatic or germline.
Gross teaches a ratio including alternative allele fragments and reference allele fragments (pg. 20, paragraph [205]) and using methylation state to determine a variant (pg. 28, paragraph [267]).
Gross teaches application of a classifier using a neural network (pg. 26, paragraph [250]) and a number of hyperparameter (pg. 22, paragraph [226]). While at least ten is not taught, the Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. The presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process. Here, number of parameters is interpreted as a result-effective variable and thus a person having ordinary skill in the art would be experimented with optimizing a classifier. MPEP 2144.05 pertains.
Gross teaches a classifier for determining the presence of cancer in a subject (pg. 13, paragraph [133]). The instant claim recites determining an identification of a somatic or germline mutation at a genomic position, and a somatic mutation may be indicative of cancer. Gross teaches a training population to be applied to the classifier.
Luo teaches liquid biopsy to determine ctDNA methylation by methylation sequencing (pg. 482, first paragraph), where methylation sequencing results in methylation information and sequence information.
Claim 11 recites a computer system performing the steps of claim 1, the computing system comprising one or more processors and memory storing one or more programs to be executed by the one or more processor.
Gross teaches performing the above recited steps using processors and memory (pg. 4, paragraph [65]).
Claim 20 recites a non-transitory computer readable storage medium storing one or more programs for performing the steps of claim 1.
Gross teaches performing the above recited steps using non-transitory computer-readable storage media (pg. 5, paragraph [68]).
Claims 2 and 12 recite inputting a reference genome into a computer system comprising a processor coupled to a non-transitory memory, and using the computer system to determine that each respective nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences maps to the genomic position by aligning the respective nucleic acid fragment sequence to the reference genome.
Gross teaches a reference genome that is used to map nucleic acid fragment sequences obtained
from sequencing a sample from the subject (pg. 9, paragraph [101]).
Claim 4 recites the variant allele is an insertion, a deletion, or a single nucleotide polymorphism.
Gross teaches the variant can arise through a single nucleotide variation, insertion, or deletion (pg. 13, paragraph [132]).
Claims 8 and 17 recite the applying, to the trained binary classifier, further applies one of one or more CpG site indications across the variant subset, one or more indications of methylation state across the reference subset, or one or more CpG site indications across the reference subset.
Gross teaches methylation state at nucleotide positions (pg. 7, paragraph [92]) and classifying reference and variant fragments (pg. 20, paragraph [205]), and therefore it is considered to be known if the fragments in either subset are methylated based on the analysis.
Luo further teaches CpG indications of cancer versus a normal reference where hypermethylation islands suggest cancer (pg. 483, Glossary).
Claims 9 and 18 recite the obtaining an identification of the variant allele at the genomic position comprises determining that the respective plurality of nucleic acid fragments support a variant allele call at the genomic position.
Gross teaches determine a variant allele position with a given fraction and coverage (pg. 13, paragraph [136]), where coverage indicates a presence of an allele in multiple fragments.
Claims 10 and 19 recite performing methylation sequencing to obtain the methylation state and the respective sequence of each nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences.
Gross teaches methylation sequencing to obtain fragments (pg. 20, paragraph [198]) and Luo teaches methylation sequencing applied to cell-free DNA determined from liquid biopsy (abstract).
Claim 21 recites a method of training a classifier to identify a variant allele at a genomic position in a test subject as somatic or germline, the method comprising the steps of claim 1 applied to more than one subject.
Gross teaches cohorts of multiple subjects (pg. 4, paragraph [54]).
Combining Gross and Luo
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Gross and Luo because Gross teaches a liquid biopsy for sequencing and a solid sample for tumor methylation for comparison (pg. 25, paragraph [246]), but Luo teaches cfDNA methylation analysis because it can be used for early detection, monitoring minimal residual disease, predicting treatment response and prognosis, and tracing issue of origin (abstract). Both the Gross and Luo are directed to the shared field of endeavor of using methylation status to predict cancer, and their combination is considered to be prima facie obvious.
Claims 3, 6-7, 13, and 15-16
Claims 3, 6-7, 13, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Gross and Luo as applied to claims 1-2, 4, 8-12, and 17-21 above and further in view of Zhao (Genetic Epidemiology 39(2): 53-64, 2015; previously cited on the 25 March 2026 PTO-892 form).
Claims 3 and 13 recite a first nucleic acid fragment sequence in the respective plurality of nucleic acid fragment sequences has a plurality of CpG sites, wherein the first nucleic acid fragment sequence has a corresponding methylation pattern across the plurality of CpG sites and wherein the methylation state of the first nucleic acid fragment sequence is a p-value.
The claims recite determining the p-value of the first nucleic acid fragment sequence, at least in
part, by comparison of the corresponding methylation pattern of the first nucleic acid fragment sequence to a corresponding distribution of methylation patterns of those nucleic acid fragment sequences in a healthy noncancer cohort dataset that each have the respective plurality of CpG sites.
Gross teaches methylation patterns in terms of CpG sites (pg. 17, paragraph [172]) and healthy controls as a comparison for methylation anomalies associated with cancer (pg. 9, paragraph [105]), but not a p-value comparing methylation patterns in a healthy, non-cancer cohort.
Zhao teaches using p-values in methylation analysis (abstract), and specifically between healthy and cancer tissues (pg. 13, second paragraph).
Claims 6 and 15 recite each indication in the one or more indications of methylation state across the variant subset is a measure of central tendency of a methylation state p-value across the variant subset,
a minimum methylation state p-value across the variant subset, a maximum methylation state p-value across the variant subset, or a measure of spread of a methylation state p-value across the variant subset.
Zhao teaches p-value related to density (Table 1), where a measure of spread is interpreted as reading on a spread.
Claims 7 and 16 recite the one or more indications of methylation state across the variant subset is a plurality of indications of methylation state across the variant subset comprising at least 2, at least 3, or all four of: (1) a measure of central tendency of a methylation state p-value across the variant subset, (2) a minimum methylation state p-value across the variant subset, (3) a maximum methylation state p-value across the variant subset, and (4) a measure of spread of a methylation state p-value across the variant subset.
Zhao teaches p-value related to density (Table 1), where a measure of spread is interpreted as reading on a spread, and average methylation levels (Figure 3), where average is measure of central tendency.
Combining Gross, Luo, and Zhao
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Zhao with Gross and Luo because Zhao teaches applying p-values of significance to methylation (pg. 2, first paragraph), which is beneficial as such a metric is widespread indicator of significant relationships and applicable to Gross as Gross teaches comparison of properties of nucleic acids (pg. 7, paragraph [93]), and thus desirable for comparison. Both the previously combined art and Zhao are directed to the shared field of endeavor of using methylation status to predict cancer, and their combination is considered to be prima facie obvious.
Claims 5 and 14
Claims 5 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Gross and Luo as applied to claims 1-2, 4, 8-12, and 17-21 above and further in view of Liu (bioRxiv 428633: 40 pgs., 2021; previously cited on the 25 March 2026 PTO-892 form).
Claims 5 and 14 recite when the variant allele at the genomic position is determined by the trained binary classifier to be germline, the method further comprises using the variant allele in the test subject to perform an action selected from the group consisting of: determining a cancer risk of the test subject, predicting an ethnicity of the test subject, and determining a tumor fraction of the test subject.
Gross teaches calculating a tumor fraction (pg. 16, paragraph [162]) but not further steps based on determination of a germline classification.
Liu teaches an association between germline mutations and cancer burden (pg. 2, second paragraph).
Combining Gross, Luo, and Liu
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Liu with Gross because Liu teaches the importance of germline genetic risk factors for cancer (pg. 4, second paragraph) while Gross focuses on somatic indicators of cancer, and thus together Liu and Gross cover both germline and somatic mutations as cancer indications. Both the previously combined art and Liu are directed to the shared field of endeavor of using genetic predictors of cancer, and their combination is considered to be prima facie obvious.
Response to the 17 August 2026 Applicant Remarks
Applicant remarks dispute the validity of Gross under 35 USC 102(a)(1) because Gross was published within the one year grace period and under 35 USC 102(a)(2) because it is commonly owned. These arguments are not persuasive because Gross includes inventors in addition to those from the instant application. The involvement of Gross, Newman, Melton, and Hubbell as non-joint inventors in the applied prior art precludes it from being an exception. Therefore, given Gross is not excepted, the rejections including Gross are applied.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia M. Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/R.J.K./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
