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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05 February 2026 has been entered.
Status of Claims
Claims 1-2, 4-9, 11-13, 16-19, 23, 34, 48, and 68 are pending and examined herein.
Claims 3, 10, 14-15, 20-22, 24-33, 35-47, and 49-67 are canceled.
Priority
As detailed on 17 March 2020 filing receipt, the application claims priority as early as 19 December 2018. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Claim Interpretation
Claim 1 recites accessing, upon processing of cfDNA from the subject, a sequence dataset from a physical assay. This is being interpreted as not requiring nucleotide sequencing as part of the process, including prior assays.
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 1-2, 4-9, 11-13, 16-19, 23, 34, 48, and 68 are rejected under 35 USC § 101 because the claimed inventions are directed to non-statutory subject matter 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 predicting cancer tissue source of origin.
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 a method (1-2, 4-9, 11-13, 16-19, 23, 34, and 48) and a non-transitory computer-readable medium (claim 68), 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)).
Mathematical concepts recited in the independent claims include "identifying feature values… and corresponding quality values based on an amount of noise," where identifying features to determine expected noise rates is described in the specification as using a model such as Bayesian hierarchical model, and thus is interpreted as a mathematical concept (pg. 45, paragraph [148]); "weighting the feature value;" and "processing… with a machine-learning prediction model" and “training” the regression(s), comprising application of a first and second sub-model, in which the models are described as binary and multinomial regression model. 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. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation (MPEP 2106.04(a)(2)).
Steps the human mind is practically equipped to perform that are recited in the independent claims 1 and 68. The claims recite aligning the sequence reads; read alignment is interpreted as recognizing patterns under a broadest reasonable interpretation and thus an evaluation that may be performed by the human mind. The claim recite collapsing aligned reads into a consensus; collapsing reads into a consensus is also interpreted as recognizing and acting on patterns discovered in the data and thus is a mental process. Generating a directed graph and compressing said directed graph by pruning based on comparison to a threshold are interpreted as mental processes; generating a directed graph for assembling the reads and pruning areas of the graph to compress it are both, under a broadest reasonable interpretation, steps that can be by the human mind. Classification of a subject’s data as indicating cancer or non-cancer is a judgment performable by the human mind. Predicting the origin of a cancer is also a judgment performable by the human mind. Identifying feature values is interpreted as data selection, which is performable by the human mind.
Claim 2 recites "generating a value of a confidence parameter," which is interpreted as a mathematical step. The step of "providing the prediction to an entity" is interpreted as organizing human activity, as it reads on telling a healthcare provider the result.
Claims 5-9, 11-13, 16-19, 23, and 34 recite details of the mathematical operations found in the independent claims.
Claims 48 recites lists of genes, which are the data to be analyzed.
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, Prong One: 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))?
Independent claims 1 and 68 recite "accessing" data from datasets, "identifying a set of small-variant features by aligning the directed graph to a reference genome," "accessing… training datasets," and "returning a prediction," and claim 68 further recites "a non-transitory computer-readable medium storing a plurality of instructions."
Steps including accessing a data, identifying variations between the directed graph and a reference genome, and returning a prediction appear to be necessary data gathering and output, and therefore are interpreted as insignificant extra-solution activity (MPEP 2106.05(g)). Regarding the computer-readable medium, the claims do not describe any specific computational steps by which the computer performs or carries out the abstract idea, nor do they provide any details of how specific structures of the computer are used to implement these functions. The claims state nothing more than that a generic computer performs 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)).
Dependent claim 4 recites "performing a reflex assay on a reserve sample." A reflex assay is interpreted as a repetition of previously conducted assay. That is, this is interpreted as a step to apply the abstract idea to confirm the results of the original assay and thus is the idea of a solution without details of how it is solved (MPEP 2106.05(f)). It may also be additional data for use in the abstract steps and thus insignificant extra-solution activity (MPEP 2106.05(g)).
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. [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). Independent claims 1 and 68 recite "accessing" data from datasets, "identifying a set of small-variant features by aligning the directed graph to a reference genome," "accessing… training datasets," and "returning a prediction," and claim 68 further recites "a non-transitory computer-readable medium storing a plurality of instructions." Accessing data (or receiving data) and returning a prediction (or retrieving information from memory) are interpreted as conventional (TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016); Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93; MPEP 2106.05(d)). Reflex assays as recited in claim 4 have been used in cancer diagnostics (e.g., Dietrich (pg. 825, col. 2, paragraph 1), Nikolaidis (pg. 5692, col. 2, paragraph 3), and van de Donk (pg. 1105, col. 2, paragraph 1). Regarding comparison using a reference genome and directed graph to detect variants, Paten (Genome Research 35(1): 665-676, 2017; previously cited on the 12 February 2025 PTO-892 form) teaches "reference-assisted variant calling" and "graph-based structures" (pg. 665, col. 2, last paragraph), including a "directed graph" (pg. 666, col. 2, last paragraph). Paten also teaches "resequencing" (pg. 665, col. 1, paragraph 1), which is interpreted as similar to a reflex assay, where the specification discloses generation of another prediction based on a reserve sample, which is interpreted as requiring sequencing.
Thus, none of the claims recite additional elements which would amount to significantly more than the abstract ideas. [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 05 February 2026 Applicant Remarks
Applicant remarks state the following limitations cannot be characterized as directed to any abstract idea at Step 2A Prong One: classifying a subject into a cancerous or non-cancerous group by applying a machine learning prediction model; predicting the tissue of origin by applying a multinomial regression model; identifying feature values, and training binary regression models (pg. 20, third paragraph). In particular, applicant remarks state these steps rely on but do not expressly state mathematical principles, akin to a computer.
This argument is not persuasive. At least the step of classifying, predicting, and identifying are mental steps of evaluating data, particularly the output of the first and second sub-models, where data evaluation is a step practically performed by the human mind (MPEP 2106.04(a)(2)(III)).
The sub-models themselves are interpreted as 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. That is, a claim does not have to recite the word "calculating" in order to be considered a mathematical calculation. For example, a step of "determining" a variable or number using mathematical methods or "performing" a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation (MPEP 2106.04(a)(2)). Here, a binary or multinomial regression is interpreted as a mathematical relationship. For instance, the specification discloses the binary classification model can include an alpha parameter that tunes between regression modes and adjust for coefficient values which affect likelihood of classification (pg. 49, paragraph [155]), which is considered a verbal description of mathematical principles. This is considered to differ from a computer, which is a physical structure which may use mathematical concepts to perform similar to how a teeter-totter comprises physical structures which involves mathematical principles to operate but is not directed to a judicial exception. MPEP 2106.04(II)(A)(1) pertains.
Further regarding Step 2A Prong One, applicant remarks point to the improvement to a machine learning model in Ex Parte Desjardins is analogous to the improvement in the instant claims, where optimizing a second task while protecting a first task is analogous to a model determining the presence of cancer or not followed by a second model which determines the tissue of origin when cancer is determined (pg. 3, second and third paragraphs), but these elements are considered to the judicial exceptions in the instant claims for the reasons outlined above.
At Step 2A Prong Two, applicant remarks state the particular architecture of the two-stage learning model is an improvement in the field of machine learning (pg. 21, penultimate paragraph), where it is asserted that separating the first and second sub-models prevent unnecessary expenditure of computation on the second sub-model when the first sub-model does not determine the presence of cancer (pg. 22, third paragraph), and the second sub-model is a multinomial regression model (pg. 22, fourth paragraph). The sub-models are regression models, which are mathematical concepts and thus abstract. An inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05). Furthermore, the alleged improvement is not considered to be directed to machine learning; instead, the improvement appears to be use of coefficients associated with genetic features for cancer diagnosis and tissue of origin prediction. The specification discloses an improvement in analysis of cfDNA in cancer prediction (pg. 1-2, paragraph [3]). Therefore, the improvement to machine learning, which was relevant to the analysis of Ex Parte Desjardins, is not analogous to the improvement of cancer diagnosis here.
At Step 2B, applicant remarks state the additional elements are not conventional (pg. 23, second and fourth paragraphs). Independent claims 1 and 68 recite "accessing" data from datasets, "aligning the directed graph to a reference genome," "accessing… training datasets," and "returning a prediction," and claim 68 further recites "a non-transitory computer-readable medium storing a plurality of instructions." Accessing data (or receiving data) and returning a prediction (or retrieving information from memory) are interpreted as conventional (TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016); Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93; MPEP 2106.05(d)). Reflex assays as recited in claim 4 have been used in cancer diagnostics (e.g., Dietrich (pg. 825, col. 2, paragraph 1), Nikolaidis (pg. 5692, col. 2, paragraph 3), and van de Donk (pg. 1105, col. 2, paragraph 1). Regarding comparison using a reference genome and directed graph to detect variants, Paten (Genome Research 35(1): 665-676, 2017; previously cited on the 12 February 2025 PTO-892 form) teaches "reference-assisted variant calling" and "graph-based structures" (pg. 665, col. 2, last paragraph), including a "directed graph" (pg. 666, col. 2, last paragraph). Paten also teaches "resequencing" (pg. 665, col. 1, paragraph 1), which is interpreted as similar to a reflex assay, where the specification discloses generation of another prediction based on a reserve sample, which is interpreted as requiring sequencing. Therefore, the additional elements are considered to be well-known and conventional in the field. The architecture of the machine learning model is understood to be a binomial regression model followed by a multinomial regression model, where regression models are mathematical concepts and thus abstract ideas, which are not evaluated for conventionality.
Thus, the amended claims are similarly rejected under 35 USC 101.
Conclusion
No claims are allowed. All claims are identical to or patentably indistinct from the claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/R.J.K./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685