DETAILED ACTION
Applicant’s response, filed 06 Nov. 2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 17, 22, and 27 are cancelled.
Claims 1-16, 18-21, 23-26, and 28-34 are pending.
Claims 3, 8, 19-21, and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06 Feb. 2024.
Claims 1-2, 4-7, 9-16, 18, 24-26, 28-31, and 33-34 are rejected.
Claim 32 is objected to.
Priority
The effective filing date of the claimed invention is 07 Feb. 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06 Nov. 2025 and 10 Sept. 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Claim Interpretation
Claim 2 recites “wherein the first set of sites hypomethylated for the first tissue type and the second set of sites hypermethylated for the first tissue type are identified using a sample of the first tissue type that has…”. Claim 1, from which claim 2 depends, recites “(a) obtaining, from the biological sample, a plurality of cell-free DNA molecules at at least 1,000 sites, including a first set of sites hypomethylated…and a second set of sites hypermethylated for the first tissue type”. Therefore, claim 2 is interpreted to be a product by process limitation that defines the process in which the first and second set of sites were previously identified. However, the claims do not require a step of identifying the first and second set of sites from a sample of the first tissue type. See MPEP 2113 I.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 2 under 35 U.S.C. 112(d) in the Office action mailed 06 Aug. 2025 has been withdrawn in view of claim amendments received 06 Nov. 2025.
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 1-2, 4-7, 9-16, 18, 24-26, 28-31, and 33-34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portion herein is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1 and 30 being representative) is directed to a method and product. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 1 recites the following steps which fall under the mental processes grouping of abstract ideas:
(c) analyzing…using the sequence reads, the plurality of cell-free DNA molecules from the biological sample of the subject, wherein analyzing a cell-free DNA molecule includes:
(i) aligning the sequence reads to a human reference genome to determine a location of the cell-free DNA molecule in the human reference genome, wherein the plurality of cell-free DNA molecules are located in a first set of regions of the human reference genome that includes the at least 1,000 sites, and wherein a first subset of the first set of regions is hypomethylated in the first tissue type and includes the first set of sites, and wherein a second subset of the first set of regions is hypermethylated in the first tissue type and includes the second set of sites;
(ii) determining an end sequence motif of at least one end of the cell-free DNA molecule, wherein an end of the cell-free DNA molecule has a first position at an outermost position, a second position that is next to the first position, and a third position that is next to the second position;
(d) determining a first set of amounts of a first set of end sequence motifs of the plurality of cell-free DNA molecules, wherein: each of the first set of one or more end sequence motifs has C at the first position and G at the second position, or each of the first set of end sequence motifs has C at the second position and G at the third position, wherein the first set of amounts are generated using end sequence motifs only selected from a group consisting of (1) end sequence motifs having C at the first position and G at the second position and (2) end sequence motifs having C at the second position and G at the third position; and
(e) determining a classification of the level of the cancer in the first tissue type for the subject based on the first set of amounts, wherein the classification is determined based on amounts of end sequence motifs only from the group, wherein the classification indicates that the cancer is present.
Claim 30 recites the following steps which fall under the mental processes grouping of abstract ideas:
(a) analyzing a plurality of cell-free DNA molecules from the biological sample of the subject, wherein analyzing a cell-free DNA molecule includes:
determining a location of the cell-free DNA molecule in a reference genome, wherein the plurality of cell-free DNA molecules are located in a first set of one or more regions of the reference genome, and wherein each of the first set of one or more regions is hypomethylated or each is hypermethylated in a first tissue type; and
determining an end sequence motif of at least one end of the cell-free DNA molecule, wherein an end of the cell-free DNA molecule has a first position at an outermost position, a second position that is next to the first position, and a third position that is next to the second position, wherein analyzing the plurality of cell-free DNA molecules includes analyzing at least 1,000 cell-free DNA molecules;
b) training a machine learning model using a feature vector, the feature vector
generated using a fragmentation pattern of a first set of end sequence motifs of the plurality of cell-free DNA molecules, wherein: each of the first set of end sequence motifs has C at the second position and G at the third position, wherein the fragmentation pattern is generated using end sequence motifs only selected from a group consisting of (1) end sequence motifs having C at the first position and G at the second position and (2) end sequence motifs having C at the second position and G at the third position, wherein the machine learning model includes at least one selected from a group consisting of a neural network or support vector machine, wherein training the machine learning model includes:
determining a classification of the level of the cancer in the first tissue type for the subject based on the output of the machine learning model, wherein the classification is determined using end sequence motifs only from the group; and
updating the machine learning model using the classification and a known label for the level of the cancer in the subject.
The identified claim limitations falls into the group of abstract ideas of mental processes for the following reasons. In this case, analyzing a plurality of cell-free DNA molecules by aligning reads to a reference genome to determine a location of the cell-free DNA molecule in a first set of one or more hypomethylated or hypermethylated regions encompasses anyway of performing data comparisons between two sequences to determine a location of each read, similar to the claims in Ambry Genetics, where the courts found claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. See MPEP 2106.04(a)(2) III. A. Determining an end sequence motif of the DNA molecules can be practically performed in the mind by reading the last three nucleotides at an end of each DNA molecule. Furthermore, the above mental process of determining can be repeated for each of 100,000 cell-free DNA molecules, with the end sequence motif of each molecule recorded via pen and paper. The step of (b) determining a first amount of a first set of end sequence motifs with a C and G at the first and second position or the second and third position, respectively, can be practically performed in the mind by counting a number of end sequence motifs that include CGN or NCG. For claim 1, determining a classification of the level of the pathology can be practically performed in the mind by comparing the determined first amount to a reference value, and making a determination of the classification of the cancer based on how high the first amount is above the reference value. Further regarding claim 30, determining an output using a machine learning model of a support vector machine and a feature vector generated using a fragmentation pattern and then determining a classification of the level of the cancer in the first tissue type encompasses inputting numerical values of the feature vector into the support vector machine, performing mathematical calculations to calculate an output, and then simply analyzing the output to determine the classification of the cancer, which can be practically performed in the mind. That is, other than reciting the limitations are carried out by a computer system in claim 1 or a processor in claim 30, nothing in the claims precludes the steps from being practically performed in the mind.
Additionally, the step of determining an output using a machine learning model, including a support vector machine, and a feature vector further recites a mathematical concept because the claim amounts to a textual equivalent to performing mathematical calculations. Similarly, training a machine learning model using the feature vector including determining the classification and updating the model using the classification encompass iteratively fitting a support vector machine, calculating the difference between the model output and known label in a cost function, and adjusting the value of a parameter of the model, which simply uses words to describe mathematical calculations. See MPEP 2106.04(a)(2) I., stating 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.
Dependent claims 2, 4-7, 9-16, 18, 24-26, 28-29, and 33-34 additionally recite an abstract idea and/or are part of the abstract idea. Dependent claim 2 further recites the mental process of determining the classification for a level of the pathology for a cancer tissue type. Dependent claim 4 further limits the analyzing step of claim 1 to involve analyzing cell-free DNA molecules obtained from plasma or serum, and recites the mental process of determining the classification for a level of the pathology for a liver cancer tissue type. Dependent claim 5 further recites the mental process of determining the classification using differentially methylated regions for a plurality of tissue types, and analyzing other sets of cell-free DNA molecules from the biological sample located in a respective set of one or more regions of the reference genome, wherein each respective set of one or more regions are hypomethylated or hypermethylated in a respective tissue type of the plurality of tissue types. Dependent claims 6-7 further recite the mental process of analyzing sets of cell-free DNA molecules from the recited first region type, the recited second region type, and the recited another particular set of one or more regions of a plurality of regions types. Dependent claim 9 further recites the mental process and mathematical concept of determining the classification using a multiclass machine learning model to provide a probability of each of the plurality of tissue types having the pathology. Dependent claim 10 further recites the mental process of determining the classification using differentially methylated regions for a plurality of tissue types that include cancer tissue types and non-cancer tissue types. Dependent claim 11 further recites the mental process of identifying a second set of CpG sites, determining a second amount of cell-free DNA molecules ending in a window around any one of the second set of CpG sites, and the mental process and mathematical concept of normalizing the first amount with the second amount to obtain a normalized first amount that is compared to the reference value. Dependent claim 12 further recites the mental process of, for each of at least two positions within a window around any one of the first set of one or more CpG sites defined by the first set of one or more end sequence motifs, determining a respective amount of cell-free DNA molecules ending at the position, thereby determining respective amounts and generating a feature vector including the respective amounts and the first amount. Dependent claim 12 further recites the mental process and/or mathematical concept of inputting the feature vector into a trained machine learning model to determine the classification of the level of the pathology. Dependent claim 13 further recites the mental process of generating a second feature vector using a second set of one or more CpG sites that are all hypermethylated and the mental process and mathematical concept of inputting the second feature vector and the first feature vector into the machine learning model as part of determining the classification of the level of the pathology in the first tissue type for the subject. Dependent claim 14 further recites the mental process of determining respective amounts of cell-free DNA molecules ending at each of the first set of CpG sites defined by the first set of one or more end sequence motifs, and comparing each of the respective amounts to a respective reference value. Dependent claim 15 further recites the mental process and mathematical concept of inputting the respective amounts as part of a feature vector into a machine learning model. Dependent claim 16 further recites the mental process of, for each CpG site of the first set of one or more CpG sites: for each position of at least two positions within a window around the CpG site, determining a respective amount of cell-free DNA molecules ending at the position, thereby determining respective amounts; and including the respective amounts for the at least two positions and the respective amount for the CpG site in the feature vector. Dependent claim 18 further recites the mental process of determining the amount of an end sequence motif including CGN. Dependent claim 24 further recites the mental process of repeating steps (a), (b), and (c) for one or more additional sets of one or more regions that are all hypomethylated or hypermethylated in one or more other tissue types, to determine a type of cancer. Dependent claim 25 further recites the mental process of determining the first amount for a first set of end sequence motifs including all sequence motifs having C at the first position and G at the second position, determining a respective amount of each 3-mer end sequence motifs that has a C at the first position and a G at the second position, thereby determining respective amounts, and generating a feature vector including the respective amounts. Dependent claim 25 further recites the mental process and mathematical concept of inputting the feature into a trained machine learning model to determine the classification of the level of the pathology. Dependent claim 26 further recites the mental process of determining a respective additional amount of each 3-mer end sequence motif with a C at the second position and a G at the third position, and including the respective additional amounts in the feature vector. Dependent claim 28 further recites the mental process of performing the classification using differentially-methylated regions for a plurality of tissue types, including the first tissue type, analyzing other sets of cell-free DNA molecules from the biological sample, each set located in a respective set of one or more regions of the reference genome, and forming a matrix with each row corresponding to a respective set of one or more regions and each column corresponding to a respective amount of each 3-mer end sequence motif. Dependent claim 28 further recites the mental process and mathematical concept of determining the classification by inputting the matrix into a convolution neural network. Dependent claim 29 further recites the mental process of determining a respective amount of each 3-mer end sequence motif with a C at the second position and G at the third position, thereby determining respective amounts and generating a feature vector of the respective mounts. Dependent claim 29 further recites the mental process and mathematical concept of inputting the feature vector into a trained machine learning model to determine the classification. Dependent claim 32 further limits the mental process of determining the classification to be that the cancer is present in the first tissue type. Dependent claim 33 further limits the mental process of determining the amounts to be for end sequence motifs including CGA, CGT, CGC, ACG, TCG, CCG, and GCG. Dependent claim 34 further limits the mental process of aligning the sequence reads to be performed within 7 days.
The claims further recite a natural correlation between the presence of cell-free DNA molecules with particular end motifs from hypomethylated and hypermethylated regions of a genome in a subject and the presence of cancer in the tissue type in the subject. This is similar to the law of nature of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). See MPEP 2106.04(b). Therefore, claims 1-2, 4-7, 9-16, 18, 24-26, 28-31, and 33-34 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Claims 2, 4-7, 9-16, 18, and 24-26, and 28-29 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements of claims 1, 30, and 33 include:
a cancer screening device including a sequencer and a computer system (claim 1);
a non-transitory computer readable medium (claim 30); and
outputting the classification of the level of the cancer (i.e. outputting data) (claim 33);
The above additional elements of a computer system, non-transitory computer readable medium, and outputting data are generic computer components and processes. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
The additional elements of claim 1 include:
a sequencer;
(a) obtaining a plurality of cell-free DNA molecules at least 1,000 sites including a first set of sites hypomethylated for a first tissue type and a second set of sites hypermethylated for the first tissue type;
(b) sequencing, using the sequencer of the cancer screening device, the plurality of cell-free DNA molecules from the biological sample to obtain sequence reads, the plurality of cell-free DNA molecules being at least 100,000 cell-free DNA molecules; and
(f)….performing one or more additional screening modalities on the subject for detection of the cancer, wherein the one or more additional screening modalities include at least one selected from a group consisting of imaging the subject or performing a biopsy of the first tissue type from the subject, wherein the imaging includes the first tissue type.
The additional elements of claim 31 and 34 include:
enriching the biological sample for cell-free DNA molecules at the at least 1,000 sites, including the first set of sites hypomethylated for the first tissue type and the second set of sites hypermethylated for the first tissue type (claim 31); and
wherein the sequencing comprises massively parallel sequencing (claim 34).
The above additional elements of obtaining cell-free DNA molecules by enriching the biological sample and performing massively parallel sequencing, using a sequencer, on the cell-free DNA molecules only serve to collect sequence data for use by the abstract idea, which amounts to insignificant extra-solution activity that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Last, the additional element of performing one or more screening modalities does not integrate the recited judicial exception into a practical application because it amounts to insignificant extra-solution activity. Here, a screening modality simply encompasses imaging the first tissue type of performing a biopsy of the first tissue type of the subject, which does not impose meaningful limits on the claim such that it is not nominally or tangentially related to the invention. See MPEP 2106.05(g). The abstract idea recited in the claims involves detecting the presence of cancer in the first tissue type, and the additional element merely serves to physically confirm the cancer identified by the abstract idea, but does not apply the identification of cancer in any meaningful way.
Therefore, the additionally recited elements amount to mere instructions to apply the exception and/or amount to insignificant extra-solution activity, and as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 1-2, 4-7, 9-16, 18, 24-26, 28-31, and 33-34 are directed to an abstract idea and law of nature. [Step 2A, Prong 2: NO]
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP § 2106.05.
The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception. Claims 1-2, 4-7, 9-16, 18, 24-26, and 28-29 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
Claims 1-2, 4-7, 9-16, 18, 24-26, and 28-29 do not recite any elements in addition to the judicial exception, and thus are part of the judicial exception.
The additional elements of claims 1, 30, and 33 include:
a cancer screening device including a sequencer and a computer system (claim 1);
a non-transitory computer readable medium (claim 30); and
outputting the classification of the level of the cancer (i.e. outputting data) (claim 33);
The additional element of a computer system, non-transitory computer readable medium, and outputting data are conventional computer components and processes. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
The additional elements of claim 1 include:
a sequencer;
(a) obtaining a plurality of cell-free DNA molecules at least 1,000 sites including a first set of sites hypomethylated for a first tissue type and a second set of sites hypermethylated for the first tissue type;
(b) sequencing, using the sequencer of the cancer screening device, the plurality of cell-free DNA molecules from the biological sample to obtain sequence reads, the plurality of cell-free DNA molecules being at least 100,000 cell-free DNA molecules; and
(f)….performing one or more additional screening modalities on the subject for detection of the cancer, wherein the one or more additional screening modalities include at least one selected from a group consisting of imaging the subject or performing a biopsy of the first tissue type from the subject, wherein the imaging includes the first tissue type.
The additional elements of claim 31 and 34 include:
enriching the biological sample for cell-free DNA molecules at the at least 1,000 sites, including the first set of sites hypomethylated for the first tissue type and the second set of sites hypermethylated for the first tissue type (claim 31); and
wherein the sequencing comprises massively parallel sequencing (claim 34).
The additional elements of obtaining cell-free DNA molecules at 1,000 sites by enriching the molecules at the at least 1,000 sites, and then performing massively parallel sequencing, using a cancer screening device including a sequencer and computer system, on the cell-free DNA molecules are well-understood, routine, and conventional. This position is supported by Applicant’s own specification, Ballester et al. (Advances in clinical next-generation sequencing: target enrichment and sequencing technologies, 2016, Expert Review of Molecular Diagnostics, 16(3), pg. 357-372; previously cited), and Illumina (An introduction to Next-Generation Sequencing Technology, 2017, pg. 1-16; newly cited).
First, Applicant’s specification at para. [0558] further discloses various known targeted sequencing techniques (enrichment followed by sequencing, as described at para. [0397]) that may be used, in a manner that indicates the element is so well-known that it need not be described in detail in the patent specification. Furthermore, Ballester reviews clinical next-generation sequencing technology (Abstract), and discloses traditional PCR has been used for many years to enrich single genes or regions followed by sequencing, and multiplex PCR allows for multiple regions being amplified (pg. 358, col. 1, para. 2 to col. 2, para. 1). Ballester discloses a plurality of widely used, commercially available sequencers for performing next-generation sequencing (pg. 364, col. 2, para. 1; pg. 365, col. 1, para. 3 to col. 2, para. 3; Table 4). Ballester further discloses other major enrichment strategies prior to next-generation sequencing, including capture-based methods (pg. 358, col. 2, para. 2; Table 2). Ballester further discloses numerous publications have recently focused on the utility of next generation sequencing applied to DNA isolated from plasma and circulating tumor cells, and its applicability to early cancer detection, demonstrating the conventionality of using such next-generation sequencing techniques on cell-free DNA (Applicant’s remarks at pg. 360, col. 2, para. 3). Last, Illumina discloses a plurality of commercially available next-generation sequencing systems that include a computer system that performs integrated data analysis (pg. 13, para. 2; Figure 10).
Regarding the additional element of imaging the tissue type or performing a biopsy of the first tissue type, this additional element is well-understood, routine, and conventional, in combination with sequencing cell-free DNA of a sample in a liquid biopsy, as supported by Tay (Liquid Biopsy in Breast Cancer, 2021, Arch Pathol Lab Med, 145, pg. 678-686; previously cited). Tay reviews the role if liquid biopsy in cancer management (Abstract), and discloses breast cancer has a well-established screening test using mammography (i.e. imaging to detect cancer) (pg. 679, col. 2, para. 2), and further discloses a plurality of studies that involves combining liquid biopsies within imaging (see table on pg. 680-681; pg. 681, col. 2, para. 1-2). Tay discloses circulating tumor levels in the blood provide additional prognostic information on top of imaging results and analyzing circulating tumor cells in blood before imaging (pg. 681, col. 2, para. 1-2; pg. 683, col. 1, para. 3, pg. 684, col. 2, para. 3). Tay further discloses there is uncertainty regarding how to manage patients with extremely early stage disease with detectable ctDNA without a radiologically evident lesion (i.e. not detectable by imaging) (pg. 681, col. 1, para. 1), and that liquid biopsies are ancillary investigations that complement and build on results from conventional tissue biopsies, demonstrating liquid biopsies are not conventionally done without additional biopsies and/or imaging (pg. 685, col. 1, para. 1). Overall, Tay demonstrates the conventionality of using imaging to detect cancer in a patient, including after detecting cell-free DNA in blood. Last, Applicant’s specification at para. [0779] also generically discloses that based on any classification, the subject can be referred to screening such as using X ray, ultrasound, computed tomography, magnetic resonance imaging, or positron emission tomography, demonstrating various known imaging techniques well known by one of ordinary skill in the art.
Last, regarding the sequencing being massively parallel sequencing, in combination with the above additional elements, Gorgannezhad et al. (Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies, 2018, Lab Chip, 18, 1174-1196; newly cited). Gorgannezhad reviews detection technologies of circulating tumor DNA and liquid biopsies in diagnosis of cancer patients (Abstract), and discloses massively parallel sequencing has improved the sensitivity of ctDNA detection and quantification (pg. 1178, col. 2, para. 2; Fig. 4). Gorgannezhad discloses massively parallel sequencing, including deep sequencing and amplicon sequencing, have been used to analyze specified genomic regions in ctDNA and provided to be highly sensitive, citing a plurality of different strategies (pg. 1184, col. 1, para. 1). Gorgannezhad further discloses analysis of cell-free DNA allows for early diagnosis of cancer 5 months before being confirmed by imaging (Table 2), and that imaging studies are required to analyze clinical progression and/or therapeutic resistance in better detail (pg. 1193, col. 2, para. 2), demonstrating cell-free DNA is used for early detection while imaging is later used for studying clinical progression in detail in combination with sequencing the cell-free DNA using massively parallel sequencing.
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception(s). Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claims as a whole do not amount to significantly more than the exception itself. [Step 2B: NO]
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea and natural correlation without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Response to Arguments
Applicant's arguments filed 06 Nov. 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks that the alignment of a read to reference sequences cannot be performed mentally, and states that the Examiner’s position is not consistent with the guidelines because the guidelines are clear that training a neural network is not a mental step, given such training can be broken down into many multiplications but the procedure in totality cannot be performed mentally (Applicant’s remarks at pg. 13, para. 1-2). Applicant further remarks the alignment as well as other limitations are not directed to a mental step for a similar rational as SiRF Tech (Applicant’s remarks at pg. 14, para. 3).
This argument is not persuasive. The instant claims do not involve training a neural network, and simply because training a neural network may not be a mental process does not provide evidence that “aligning the sequence reads to a human reference genome” cannot be performed mentally. Aligning reads to a reference genome simply involves performing data comparisons between a read, and a table with subsequences and corresponding locations of a reference genome; the human mind is equipped to compare two words (e.g. two reads) and assess their similarity and repeating the process for large numbers of reads. The argument is also not persuasive for the reasons previously discussed at para. [059]-[061] of the previous Office action mailed 06 Aug. 2025.
Furthermore, the claims in SiRF Tech did not recite a mental process because they involved calculating an absolute position of a GPS receiver and an absolute time of reception of satellite signals, where the claimed GPS receiver calculated pseudoranges that estimated the distance from the GPS receiver to a plurality of satellites. None of the instant limitations require any particular special-purpose hardware, such as a GPS receiver, to carry out the various limitations that recite an abstract idea. Instead, the claims simply use “a computer system” to carry out steps that can be performed mentally, and therefore simply using a computer as a tool to perform the concept. In these cases, the claims still recite a mental process even if claimed as requiring a computer. See MPEP 2106.04(a)(2) III. C.
Applicant remarks as legal basis for “practical” meaning that if a mental process talks a long time, the limitation cannot be practically performed in the mind, the USPTO made the Ex parte DESJARDINS precedential where training a model was recited and found eligible even whilst the basic building block is multiplying numbers over and over again, and if there were not requirement about a mental process taking a long time, DESJARDINS would have been found directed to mental steps (Applicant’s remarks at pg. 13, para. 3). Applicant further remarks that CardioNet referred to monitoring capabilities as “real-time monitoring”, which has a time constraint for the output to be useful, and the screening device has a timeframe to be useful (Applicant’s remarks at pg. 13, para. 4 to pg. 14, para. 1).
This argument is not persuasive. Applicant appears to conflate the considerations under Step 2A, Prong 1 (whether the claims recite a judicial exception) with the considerations under Step 2A, Prong 2 (whether the claims recite additional elements that integrate the judicial exception into a practical application). The claims in Desjardins were not found patent eligible for not reciting an abstract idea, but because the claims were found to not be directed to the recited judicial exception under Step 2A, Prong 2. The same is true for the claims in CardioNet. Therefore it is not persuasive that Dejsardins or CardioNet, indicates that mental process steps that are time consuming cannot recite a mental process.
Applicant further remarks that the Office has the burden of proof, not the Applicant, and states that Bancorp Serves does not relate to the issue of the term “practically” and rather that if a computer is the preferred implementation, a claim can still recite a mental process (Applicant’s remarks at pg. 14, para. 2).
This argument is not persuasive. The Office’s position and prima facie case regarding why the claims recite an abstract idea have been thoroughly explained in the rejection above and also at para. [065]-[066] in the previous Office action.
Applicant remarks that the Office is skirting the issue with regard to Example 48, where the Office stated it is not practical for the human mind to synthesize speech waveforms, regardless of the number of operations required”, and that the steps in example 48 are all manipulations of data that can be broken down into building blocks as is alleged here, and that a person can synthesize a speech waveform using measured values and applying basic rules, and while the result will be inaccurate and slow, and further remarks the Office appears to make a distinction between data comparisons and multiplication of values but no rationale has been provided for this distinction (Applicant’s remarks at pg. 14, para. 4 to pg. 15, para. 1).
This argument is not persuasive. Applicant appears to argue that because synthesizing a speech waveform in example 48 is classified as an additional element, then the limitations in the instant claim must also be an additional element. Applicant’s explanation for why the synthesis of a speech waveform being classified as an additional element is not provided by the Example, and appears to be speculation by Applicant. Instead, Example 48 simply states that “Synthesizing speech waveforms…is not a process a process that can be practically performed in the mind”. The reasons for why the instant claims recite an abstract idea are explained in detail in the above rejection, and in previous responses to Applicant’s argument. In particular, MPEP 2106.04(a)(2) III. A. states that comparing known information can be performed mentally.
Applicant also points to the Aug. 4 memo and reminds Examiner’s that the rejection under 101 should only be made when it is more likely than not the claim is ineligible (Applicant’s remarks at pg. 15, para. 2).
This argument is not persuasive for the reasons discussed above.
Applicant remarks that para. [074] appears to contradict the Aug. 4 memo and example 39, and requests the Office to make a reasoned distinction that determining, using an ML model, is directed to mathematical concepts, and the PTO guidance that using machine learning is not directed to math unless specific mathematical calculations are required such as backpropagation algorithm or gradient descent (Applicant’s remarks at pg. 15, para. 3-4).
This argument is not persuasive. Para. [074] of the previous Office action simply contains a citation of MPEP 2106.04(a)(2) I. C explaining why calculating a level of cancer using a mathematical algorithm does not simply involve math. As stated in the memo, this memorandum is not intended to announce any new USPTO practice or procedure and is meant to be consistent with existing USPTO guidance. The cited portion of the memo noted by Applicant pertains to training a neural network, rather than any machine learning algorithm or support vector machine. As discussed in MPEP 2106.04(a)(2) I., a claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the "mathematical concepts" grouping. 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. See MPEP 2106.04(a)(2) I. C.
Applicant remarks that PTO guidance should be interpreted using the standard meaning of “prophylaxis”, instead of using a definition only limited to a treatment or a vaccine (Applicant’s remarks at pg. 16, para. 2).
This argument is not persuasive. The meaning of “prophylaxis” is interpreted in light of MPEP 2106.04(d)(2). MPEP 2106.04(d)(2) states examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient.
Simply performing a biopsy or imaging a tissue to detect cancer does not prevent the cancer or stop the cancer from getting worse, and this this step clearly does not “recite an action that effects…prophylaxis for a disease or medical condition”. Therefore, unlike the claims in Classen Immunotherapies, the instant claims do not affect the prophylaxis of a disease or condition.
Applicant remarks that screening all subjects would require all subjects to be imaged or a surgical resection, and instead subjects can undergo an initial screening using a blood sample, and as a basic matter, a blood draw takes only a few minutes, much shorter than imaging or a tissue biopsy, and only positively identified subjects using cell-free sample would undergo additional screening, and thus there is a savings in time (Applicant’s remarks at pg. 16, para. 3).
This argument is not persuasive. MPEP 2106.05(a) explains an indication that the claimed invention provides an improvement can include a discussion in the specification that identifies a technical problem and explains the details of an unconventional technical solution expressed in the claim, or identifies technical improvements realized by the claim over the prior art.
First, it is not clear an otherwise healthy subject is routinely being screened via imaging or a biopsy for a cancer for any tissue type (e.g. liver) in the first place, such that the instant claims are reducing a number of imaging or biopsy screenings for a subject, and thus saving time. The claims are not limited to monitoring residual cancer in a subject after treatment, and instead encompass testing a healthy subject for cancer.
Furthermore, performing analyzing blood or plasma on a subject suspected to have a condition is standard in the medical field. For example, each of Tay and Gorgannezhad describe cell-free DNA monitoring as being used for early disease detection prior to imaging, with imaging being required for staging disease (Tay: pg. 681, col. 2, para. 1-2; pg. 683, col. 1, para. 3, pg. 684, col. 2, para. 3; Gorgannezhad: pg. 1193, col. 2, para. 2). Therefore, the use of analyzing cell-free DNA in plasma for early disease detection is already standard, such that there does not appear to be an unconventional technical solution or an improvement over the prior art.
As explained in the above rejection, the additional element of screening the subject only serves to confirm the detection already predicted by the abstract idea after screening the subject via sequencing cell-free DNA in plasma, which amounts to insignificant extra-solution activity for the reasons discussed in the above rejection.
Applicant remarks the claims improve a cancer screening device just as the device in CardioNet includes detectors and logic, and increased accuracy in biological measurements, used for a diagnostic, are an improvement to a technical field (Applicant’s remarks at pg. 16, para. 4-5).
This argument is not persuasive for the same reasons already extensively discussed (see at least para. [075]-[081] of the previous Office action. While Applicant has amended the claim to recite a cancer screening device comprising a sequencing machine that performs the sequencing, and a computer system that carries out the analysis of the reads, any improved analysis of already generated sequencing reads by a computer system amounts to an improved abstract idea as previously discussed, which is not an improvement to technology. MPEP 2106.05(1) I further explains that in computer-related technologies, the examiner should determine whether the claim purports to improve computer capabilities or, instead, invokes computers merely as a tool. Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, 1336, 118 USPQ2d 1684, 1689 (Fed. Cir. 2016). Here, the claims merely use the computer system as a tool to carry out the abstract idea, rather than improving computer capabilities or any other devices capability (such as the sequencer).
The claims of cardionet reflected an improved cardiac monitoring device, due to better accuracy. The instant claims still do not improve a particular device such as a cardiac monitoring device, and instead just uses a “sequencer” to perform the sequencing to gather the necessary data for the abstract idea and then a “computer system” to carry out the analysis of the data. MPEP 2106.05(a) makes clear that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology.
Applicant’s remarks about CardioNet II (Applicant’s remarks at pg. 16, para. 6) are noted but do not appear to present an argument regarding the rejection of the claims.
Applicant remarks, regarding 2106.05(a), that whether an improvement is in the abstract idea is not a separate test (loophole) as is used by the Office, and the test is whether the claims as a whole provide a practical application (Applicant’s remarks at pg. 17, para. 1). Applicant remarks the claims provide an improvement to medical technology and more specifically medical diagnostics, which CardioNet identified as a technical field (Applicant’s remarks at pg. 17, para. 2).
This argument is not persuasive. It is agreed that whether the improvement is in the abstract idea is “not a separate test”, but it is not clear why Applicant believes this to be a “loophole”. Part of considering whether the claims recite additional elements that integrate the recited judicial exception into the practical application of an improvement to technological is whether the improvement is in the abstract idea, as discussed in MPEP 2106.05(a). In the instant case, the alleged improvement is in the abstract idea (i.e. a better analysis of sequencing reads to classify cancer), which is not a technology. Furthermore, the claims of cardionet reflected an improved cardiac monitoring device, as already discussed above.
Applicant remarks that steps (a), (b), and (f) are unconventional, and that Tay does not use imaging for diagnostics in response to an initial diagnosis using the liquid biopsy, and thus the actual feature of (f) Is not described as being routine (Applicant’s remarks at pg. 18, para. 2).
This argument is not persuasive. First, steps (a) and (b) are conventional, even in combination, as explained in the above rejection. Applicant does not make any specific arguments regarding steps (a) and (b) with respect to the references relied upon for these steps, and instead only provides arguments for (f) alone.
Regarding (f), this step only requires that imaging or a biopsy is performed “responsive to the classification”, or after the detection of cancer from the cell-free DNA analysis of the sequenced biological sample. The claims do not require any specific timing of when the imaging occurs after detection of cancer in a liquid biopsy (e.g. the cell-free DNA). Tay provides a plurality of studies that analyze circulating tumor cells (CTCs) in a liquid biopsy prior to performing imaging in order to correlate the CTCs with radiological progression (Table on pg. 680-681; pg. 682, col. 2, para. 2-3). It is noted that the claims use the transitional phrase comprising, and thus the claims do not preclude performing imaging prior to analyzing cell-free DNA of a sample. Gorgannezhad additionally reviews detection technologies of circulating tumor DNA and liquid biopsies in diagnosis of cancer patients using massively parallel seuqencing (Abstract), and discloses analysis of cell-free DNA allows for early diagnosis of cancer 5 months before being confirmed by imaging (Table 2), and that imaging studies are required to analyze clinical progression and/or therapeutic resistance in better detail (pg. 1193, col. 2, para. 2), demonstrating cell-free DNA is used for early detection while imaging is later used for studying clinical progression in detail. Both Tay and Gorgannezhad provide early detection of disease using liquid biopsies and confirm, or correlate these findings with imaging or radiological progression. Imaging is also used to analyze clinical progression after detection, as discussed above by Gorgannezhad. Even considered in combination, Ballester discloses how liquid biopsies are analyzed via sequencing (i.e. steps (a)-(b)), while Tay and Gorgannezhad disclose how liquid biopsies are used with imaging, in addition to using massively parallel sequencing. Thus the additional elements are well-understood, routine, and conventional, even when considered in combination.
Applicant remarks that aligning the sequence reads to a human reference genome is additional and is part of the unconventional combination (Applicant’s remarks at pg. 19, para. 1).
This argument is not persuasive for the reasons discussed above. That is, the step of aligning is part of the abstract idea, rather than an additional element, and thus is not considered under Step 2B.
Applicant remarks, regarding claim 31, that the Office appears to ignore that the 1,000 sites are for a first set of hypomethylated sites and a second set of hypermethylated sites for a first tissue type and Applicant could not identify an argument that such a limitation is conventional (Applicant’s remarks at pg. 19, para. 3).
This argument is not persuasive. This limitation was explicitly addressed in the previous response to arguments at para. [088]-[091] of the Office action mailed 06 Aug. 2025, and is described by Ballester in the above rejection. See also, Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 115 USPQ2d 1152. Whether a natural correlation is well-understood, routine, and conventional is not considered under Step 2B.
Applicant remarks that the combination of additional elements of “training…a machine learning model using a feature vector…” is not well-understood, routine, and conventional, and thus claim 30 and dependent claims are patent eligible (Applicant’s remarks at pg. 19, para. 5 to pg. 20, para. 2).
This argument is not persuasive because the above limitations are not additional elements. Applicant is also directed to the Examples 47-48, which make clear that generally linking an abstract idea to a technological environment of neural networks does not integrate the abstract idea into a practical application or provide significantly more. While the instant claims do not require a neural network, even if the claims were amended to require a neural network, this would not overcome the rejection.
Terminal Disclaimer
The instant Application is subject to a Terminal disclaimer with copending App. No. 18/117,992, now U.S. Patent US 12258634 B2. See the terminal disclaimer filed and approved 30 Step. 2024 in the ‘992 Application.
Allowable Subject Matter
Claim 32 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Claims 1-2, 4-7, 9-16, 18, 24-26, and 28-34 are free of the prior art for the reasons discussed in the Office action mailed 06 Aug. 2025 at para. [092]-[094].
Claim 32 is patent eligible for the reasons discussed in the Office action mailed 06 Nov. 2025 at para. [023].
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685