DETAILED ACTION
Applicant’s response, filed 26 May 2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 5, 8-9, 22-27, 36, and 39-53 are canceled.
Claims 56-57 are newly added.
Claims 1-4, 6-7, 10-21, 28-35, 37-38, and 54-57 are pending.
Claims 15-17, 28, and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 Dec. 2022.
Claims 1-4, 6-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-57 are rejected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08 Dec. 2025, 06 Feb. 2026, 16 April 2026, and 12 June 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, cited references were considered by the examiner.
Claim Interpretation
Claims 1, 11, 21, and 56 recite “…at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences”, which is interpreted to mean that both sides of each DNA fragment of the portion is blunt-ended, given a fragment with an overhang is not a blunt-ended fragment as understood by one of ordinary skill in the art.
Claims 1, 11, 21, and 56 recite a “sequence motif”, which is defined at Applicant’s specification at para. [0062] to mean a recurring pattern of bases in DNA fragments that occurs at an end of a fragment and thus be part of or include an ending sequence.
Claims 1 ,11, 21, and 56 recite an “end motif”, which is defined at Applicant’s specification to refer to a sequence motif for an ending sequence which can occur just before or just after ends of a fragment.
Claims 1, 11, 21, and 56 recite “to determine… a collective property of the end motif pattern…”. Applicant’s specification at para. [0059] defines an aggregate value to refer to a collective property of a set of end motifs, such as a mean, median, etc. Applicants specification does not mention a collective property elsewhere in the specification, and thus the “collective property” is considered synonymous to an aggregate value as defined.
Claim 2 recites “…filtering the cell-free DNA to identify the plurality of cell-free DNA fragments.”. In light of Applicant’s specification at para. [0228]-[0232], which describes various ways the DNA fragments can be filtered based on information determined after sequencing (e.g. read location, methylation metrics, sequence variations), the filtering step is interpreted to be an in-silico filtering of the cell-free DNA fragments.
Response to Arguments
Applicant's arguments filed 26 May 2026 regarding claim interpretation have been fully considered but they are not persuasive.
Applicant remarks that claim 1 has been amended such that both sides of the at least some cfDNA fragments do not have to be blunt-ended (Applicant’s remarks at pg. 10, para. 2).
This argument is not persuasive. Claim 1 recites “wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences”. The limitation states that the portion of “cell-free DNA fragment are blunt-ended at ends…” (i.e. blunt-ended is describing the cell-free DNA fragment), such that the fragments themselves are blunt-ended at ends including the ending sequences. A cell-free DNA fragment with an overhang on one end of the fragment and a blunt-end on the other side of the fragment, is not considered a blunt-ended DNA fragment, as understood by one of ordinary skill in the art. A blunt-ended DNA fragment is a DNA fragment with blunt-ends, and does not contain overhangs. A DNA fragment with an overhang on one end is not a blunt-ended fragment. Furthermore, the only support for this limitation is in Applicant’s specification at para. [0090], which states “the DNA fragments may be blunt-ended”, consistent with this interpretation. There does not appear to be support for specifying that one end of a cell-free DNA fragment has a blunt-end while the other end of the cell-free DNA fragment has an overhang. Regardless, if Applicant intends to only require that one end is blunt-ended, the claims can be amended to specify that “at least a portion of the plurality of cell-free DNA fragments contain at least one blunt-end…”, or a similar amendment.
Examiner comment: It is further noted that if the claims were amended to remove the requirement that the cell-free DNA fragments are blunt-ended, in favor of a claim limitation only requiring one end of the fragment has a blunt-end, then this may raise prior art issues as previously applied in the Office action mailed 10 June 2024, given the claims would encompass determining and analyzing a sequence motif on fragments with overhangs as described in Kincaid (US 2021/0054366 A1; previously cited); the claims would encompass analyzing “one or more ending sequences of the cell-free DNA” (i.e. any end, such as the overhang end) in determining the sequence motifs.
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.
Claims 56-57 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 56, and dependent claim 57, are indefinite for recitation of “A cancer monitoring device…comprising: a sequencing device….; and a logic system configured to perform:…determining, by a computer system…”. Claim 56 recites that the device includes a “logic system” that is configured to perform various steps, “by a computer system”. As a result, it is not clear if the logic system is intended to be the computer system, or if the logic system is a separate system than the computer system. If the logic system is separate from the computer system, it is further unclear if the computer system is also intended to be part of the claimed device. Clarification is requested. For purpose of examination, the logic system is interpreted to be the computer system. If Applicant agrees, the device can be amended to recite “a computer system configured to perform…determining ,.
Claim Rejections - 35 USC § 101
The rejection of claim 5 under 35 U.S.C. 101 in the Office action mailed 24 Nov. 2025 has been withdrawn in view of claim amendments received 26 May 2026.
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4, 6-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-57 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and law of nature without significantly more. Any newly recited portion is necessitated by claim amendment.
The Supreme Court has established a two-step framework for this analysis, wherein a claim does not satisfy § 101 if (1) it is “directed to” a patent-ineligible concept, i.e., a law of nature, natural phenomenon, or abstract idea, and (2), if so, the particular elements of the claim, considered “both individually and as an ordered combination,” do not add enough to “transform the nature of the claim into a patent-eligible application.” Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016) (quoting Alice, 134 S. Ct. at 2355). Applicant is also directed to MPEP 2106.
Step 1: The instantly claimed invention (claims 1, 11, 21, and 56 being representative) is directed to a method and system. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claims 1, 11, 21, and 56 recite the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
for each of the plurality of cell-free DNA fragments, determining…. a sequence motif for each of one or more ending sequences of the cell-free DNA fragment;
determining….an end motif pattern of a set of one or more sequence motifs corresponding to the ending sequences of the ends of the plurality of cell-free DNA fragments, wherein the end motif pattern is determined using a respective plurality of cell-free DNA fragments that have an ending sequence corresponding to each sequence motif of the set;
training a machine learning model using reference end motif patterns of reference samples having known classifications of the level of the pathology, wherein the pathology is cancer (claims 1 and 56);
training a machine learning model using reference end motif patterns of reference samples having known gestational ages (claim 21);
training a machine learning model using reference end motif patterns of reference samples whose classifications of clinically relevant DNA are known (claim 11);
processing, using the machine learning model, the end motif pattern to determine a collective property of the end motif pattern of the set of one or more sequence motifs; and
determining a classification of the level of the pathology/cancer for the subject based on a comparison of the collective property of the end motif pattern to a reference value (claims 1 and 56); and
determining a classification of the clinically-relevant DNA in the biological sample by comparing the collective property of the end motif pattern to one or more calibration values determined from one or more calibration samples whose fractional concentration of clinically-relevant DNA are known (claim 11);
Claim 21 further recites the following steps which fall under the mental processes groupings of abstract ideas:
obtaining one or more calibration data points, wherein each calibration data point specifies a calibration gestational age corresponding to a calibration collective property, and wherein the one or more calibration data points are determined from a plurality of calibration samples with known gestational ages and including cell-free DNA molecules;
comparing the collective property of the end motif pattern to the calibration value of at least one calibration data point; and
estimating the gestational age of the fetus based on the comparing.
The identified claim limitations falls into the group of abstract ideas mental processes for the following reasons. In this case, the steps of determining a sequence motif for each of 100,000 cell-free DNA fragments encompasses reading each fragment read to determine the last N number of bases of each read, which is a mental process. Furthermore, determining an end motif pattern of a set of one or more sequence motifs can be practically performed in the mind by summing a number of reads with the respective motif by the total number of reads. Determining a collective property of the end motif pattern can be performed mentally by summing relative frequencies of the one or more sequence motifs. With respect to claim 21, obtaining calibration data points for calibration samples, encompasses repeating the above operations of determining an end sequence motif pattern and collective property for samples with known gestational ages, which can be performed mentally as discussed above. Last, determining a classification by comparing a collective property to a calibration, or reference value, or estimating a gestational age of a fetus based on the comparing encompasses merely performing data comparisons which can be practically performed in the mind. That is, other than reciting the limitations are performed by a computer system, nothing in the claims precludes the steps from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
The steps of training a machine learning model using reference end motif patterns of reference samples having known classifications of the level of the pathology/cancer or known gestational ages and determining a collective property using the machine learning model further recite a mathematical concept. Training a machine learning model using end motif patterns (e.g. numerical values) encompasses training a logistic regression model, which amounts to a textual equivalent to inputting numbers into a regression model, performing mathematical calculations (e.g. multiplication, division, addition) to calculate a model output, calculating a loss function, adjusting model parameters and repeating the process. Similarly, applying a trained machine learning model encompasses simply inputting numerical values of the end motif pattern into the regression model and performing mathematical calculations to determine the output of a collective property, which encompasses a mathematical aggregate value of a probability as disclosed in the specification (see Applicant’s specification at para. [0066] and [0233]). Therefore, these limitations further recite a mathematical concept. See MPEP 2106.04(a)(2) I.
Last, claims 1, 11, and 56 further recite a law of nature of a natural correlation between frequencies of end sequence motifs and a level of cancer or clinically-relevant DNA (i.e. an amount of disease). Similarly, claim 21 recites the law of nature of a natural correlation between a frequency of end motifs and gestational age. See MPEP 2106.04(b).
Dependent claims 2-4, 6-7, 10, 12-14, 18-20, 29, 31-35, 37-38, 54-55, and 57 further recite an abstract idea and/or are part of the judicial exception. Dependent claim 2 further recites the mental process of filtering fragments. Dependent claim 3 further recites the mental process of filtering based on a size of, or a region from which the DNA fragment is derived. Dependent claim 4 further recites the mental process of filtering the DNA fragments for open chromatin regions of a particular tissue. Dependent claim 6 further limits the classification of the pathology to be for a cancer from the group of cancers in claim 6. Dependent claim 7 further limits the classification to be determined from a plurality of levels of cancer. Dependent claim 10 further limits the classification to be for a fractional concentration of clinically-relevant DNA. Dependent claim 12 further limits the classification to be for a fractional concentration of fetal DNA, tumor DNA, DNA from a transplanted organ, or a tissue type. Dependent claims 13-14 further limit the classification to be for clinically relevant DNA of a particular tissue type of liver or hematopoietic. Dependent claim 18 further limits the comparison to be with one or more aggregative values of relative frequencies from one or more calibration samples. Dependent claim 19 further recites the abstract idea of measuring fractional concentrations of clinically relevant DNA in the calibration sample and determining an aggregate value of relative frequencies by analyzing cell-free DNA fragments from the calibration sample. Dependent claim 20 further limits the mental process of claim 19 to determine the fractional concentration using an allele specific to the clinically relevant DNA. Dependent claims 29 and 31 further limit the step of determining relative frequencies to be for a set of one a top M sequence motifs with a largest difference between two reference samples having different classifications for the level of pathology. Dependent claim 32 further limits the step of determining relative frequencies to be a top M most frequent sequence motifs. Dependent claims 33-34 further limit the step of determining relative frequencies to be for a plurality of sequence motifs and the aggregative value to be a weighted sum of the relative frequencies of the set, and thus additionally recite a mathematical concept of determining a weighted sum. Dependent claim 35 further limits the aggregate value to include an entropy term which includes a sum of terms multiplied by a logarithm of the relative frequency, and thus also further recites a mathematical concept. Dependent claims 37-38 further limit the abstract idea of determining the aggregate value to be from a machine learning model of clustering, support vector machines, or logistic regression, which also recites a mathematical concept. Dependent claim 54 further limits the set of one or more sequence motifs to be 7 bases or less, and thus is part of the mental process of claim 1. Dependent claim 55 further limits the mental process of performing classification to indicate a presence of cancer and recites the mental process of determining to perform imaging based on the classification indicating the presence of cancer. Dependent claim 57 further limits the abstract idea determining a sequence motif of each cell-free DNA fragment of claim 56 to determine motifs with 2, 3, or 4 bases.
Therefore, claims 1-4, 6-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-57 recite an abstract idea and/or law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Dependent claims 2-4, 6-7, 10, 12-14, 18-20, 29, 31-35, 37-38, 54, and 57 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, 11, 21, and 56 include:
a computer system (claims 1, 11, 21);
a logic system (claim 56);
a sequencing device configured to perform sequencing on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences (claim 56);
performing an assay on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences (claims 1, 11, 21);
and wherein the plurality of cell-free DNA fragments include at least 100,000 cell free DNA fragments.
The additional element of claim 55 includes:
performing imaging of the subject to detect a presence of a tumor.
Regarding the computer system, 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).
Regarding the sequencing device configured to sequence cell-free DNA and the step of performing an assay on cell-free DNA fragments to produce sequence reads, including blunt-ended fragments, to obtain sequence reads (i.e. performing sequencing), these additional elements only serve to collect read information for use by the abstract idea, and thus amounts to insignificant extra-solution activity, which does not integrate the recited judicial exception into a practical application.
Last, performing imaging of the subject to detect the presence of a tumor amounts to insignificant extra-solution activity. Merely imaging the subject to detect the presence of a tumor after the judicial exception indicates the presence of cancer only serves to confirm the determination already made by the abstract idea, which amounts to an insignificant application that is nominally related to the invention, similar to printing or downloading generated menus in Ameranth, 842 F.3d at 1241-42, 120 USPQ2d at 1854-55. See MPEP 2106.05(g).
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 1-4, 6-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-57 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.
Dependent claims 2-4, 6-7, 10, 12-14, 18-20, 29, 31-35, 37-38, 54, and 57 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, 11, 21, and 56 include:
a computer system (claims 1, 11, 21);
a logic system (claim 56);
a sequencing device configured to perform sequencing on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences (claim 56);
performing an assay on a plurality of cell-free DNA fragments from the biological sample to obtain sequence reads, wherein performing the assay includes performing sequencing to obtain the sequence reads, wherein the sequence reads include ending sequences corresponding to ends of the plurality of cell-free DNA fragments, wherein at least a portion of the plurality of cell-free DNA fragments are blunt-ended at ends including the ending sequences (claims 1, 11, 21);
and wherein the plurality of cell-free DNA fragments include at least 100,000 cell free DNA fragments.
The additional element of claim 55 includes:
performing imaging of the subject to detect a presence of a tumor.
Regarding the computer system used to implement the abstract idea, 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).
Regarding the additional element of a sequencing device and sequencing cell-free DNA fragments including blunt-ended fragments, Grace et al. (Cell-free DNA Screening: Complexities and Challenges of Clinical Implementation, 2016, Obstet Gynecol Surv., 71(8), pg. 477-487; previously cited). Grace reviews screening using cell-free DNA (Abstract), and discloses commercial laboratories utilize whole genome sequencing of cell-free DNA in plasma samples (Abstract; pg. 11, para. 2; pg. 12, para. 3). Grace further discloses different commercial platforms that use different applications of next generation sequencing technologies (pg. 3, para. 2). Last, Applicant’s specification at para. [0158] further discloses the sequencing of cell-free DNA fragments, which may include blunt-end fragments, can be performed in a variety of ways and that skilled person will appreciate the variety of sequencing techniques that may be used, demonstrating the conventionality of the additional element. Therefore, the additional element is not sufficient to amount to significantly more than the judicial exception.
The additional element of imaging the subject to detect a presence of a tumor after/based on cancer being detected by performing an assay on cell-free DNA fragments to obtain sequence reads is well-understood, routine, and conventional. This position is supported by Zhang et al. (Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes, 2017, 41, pg. 755-768; previously cited), Cheng et al. (Circulating cell-free DNA and circulating tumor cells, the “liquid biopsies” in ovarian cancer, 2017, Journal of Ovarian Research, 10:75, pg. 1-10; previously cited), Gorgannezhad et al. (Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies, March 2018, Lab Chip, 18, pg. 1174-1196; previously cited), and Heitzer et al. (Circulating tumor DNA as a liquid biopsy for cancer, 2015, Clinical Chemistry, pg. 112-123; previously cited), and
First, Zhang reviews liquid biopsies for analyzing cell-free DNA in cancer (Abstract) and discloses traditional biomarkers and imaging techniques play important roles in tumor diagnosis (pg. 755, para. 1), and that imaging, including ultrasound, CT, or MRI, remains the gold standard in solid tumor screening and monitoring (pg. 759, para. 3). Zhang further discloses a combination of circulating tumor cell detection with imaging is a better choice than either alone (pg. 759, para. 3). Zhang discloses that liquid biopsy has been increasingly considered for early tumor diagnosis due to increased sensitivity, and discloses subsequent CT scans, surgical resection, and pathological examination are used to diagnose early-stage lung cancer (pg. 755, para. 1; pg. 759, para. 3). Cheng reviews the use of serial monitoring of tumor genotypes with circulating cell-free (cf) DNA (Abstract), and that for ovarian cancer, cf-DNA may be used as an adjuvant diagnostic method for ovarian cancer, and the use of cf-DNA as a combination application tool along with ultrasound imaging to diagnose ovarian cancer. Gorgannezhad reviews detection technologies of circulating tumor DNA and liquid biopsies in diagnosis of cancer patients (Abstract), and discloses analysis of cell-free DNA allows for early diagnosis of cancer 5 months before being confirmed by imaging (Table 2). Gorgannezhad further discloses that because it is not obvious ctDNA represents all metastatic cell clones placed at various sites or represents ctDNA from distinct subclones, imaging studies are required to analyze clinical progression and/or therapeutic resistance in better detail (pg. 1193, col. 2, para. 2). Last, Heitzer similarly reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses quantification of cfDNA might not be useful for diagnosis, monitoring tumor-specific changes may be used for early cancer detection (pg. 117, col. 1, para. 3 to col. 2, para. 2). Heitzer discloses sequencing analysis of plasma DNA and biopsies in combination with imaging studies are needed to assess clinical progression because it is not clear whether ctDNA represents all relevant metastatic clones at different locations, such that further imaging studies are required. Therefore, the use liquid biopsies for early cancer detection in combination with subsequent imaging to further analyze and characterize a tumor (e.g. metastatic locations or early stage diagnosis) is well-understood, routine, and conventional.
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 26 May 2026 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Step 2A, Prong 1:
Applicant remarks the Office is reading out “practically” from the guidelines, and instead is using the rule that such steps, even if done incorrectly over the span of 10+ years, still qualify as being practically performed in the mind (Applicant’s remarks at pg. 11, para. 1-2). Applicant further remarks that summing relative frequencies does not constitute a machine learning model (Applicant’s remarks at pg. 11, para. 3).
This argument is not persuasive. First, it is not clear where the Office applied a rule regarding a step being done “incorrectly” and a rule pertaining the time to perform steps taking “10+ years”. The claims only require analyzing 100,000 DNA fragments, and determining a sequence motif of an end sequence of the cell-free DNA fragments, which encompassing reading 100,000 “words” (each DNA fragment is a word) to obtain 100,000 motifs, and then counting the 100,000 motifs to obtain an end motif pattern (i.e. determining a count of “AAG” and “GGC” ends). Humans practically and often read books that are over 100,000 words, and do so easily within 10 years.
Furthermore as previously discussed, the amount of data, in and of itself is not a limitation which takes a process out of the realm of the human mind. Although a general-purpose computer can perform calculations at a rate and accuracy that can far outstrip the mental performance of a skilled artisan, the nature of the activity is essentially the same, and constitutes an abstract idea. See Bancorp Serves., L.L. C. v. Sun Life Assur. Co. of Canada (U.S.) (holding that “the fact that the required calculations could be performed more efficiently via a computer does not materially alter the patent eligibility of the claimed subject matter”); see also SiRF Tech., Inc. v. Int’l Trade Comm ’n, (Fed. Cir. 2010) (holding that: In order for the addition of a machine to impose a meaningful limit on the scope of a claim, it must play a significant part in permitting the claimed method to be performed, rather than function solely as an obvious mechanism for permitting a solution to be achieved more quickly, i.e., through the utilization of a computer for performing calculations).
Regarding the argument pertaining to summing relative frequencies, the “machine learning model” determining the collective property is addressed in the above rejection as a mathematical concept. However, the human mind is also practically able to sum relative frequencies to determine a collective property (e.g. such as in linear regression). Applicant is also directed to the 2024 AI-related subject-matter eligibility examples, which provides claim examples in which a step recites a mental process despite being implemented by a machine learning model (see example 47, claim 2). Therefore, simply reciting a step as being performed by a “machine learning model” does not preclude a step from reciting a mental process.
Applicant remarks the claims only involve math but do not recite math, and thus the Office mistakenly characterizes the claimed step of processing the end motif pattern using machine learning as summing or a textual equivalent to math, which ignores the structural requirement of the claim (Applicant’s remarks at pg. 11, para. 4 to pg. 12, para. 1). Applicant further remarks that training an algorithm on complex multi-dimensional reference data of different sequence motifs to recognize underlying high-dimensional fragmentation patterns cannot be mapped to a human mind executing mental addition, and while machine learning models rely fundamentally on underlying mathematical operations, the hardware-implemented process of automated parameter adjustment across hundreds of thousands of distinct biological fragment is an architectural data processing pipeline and not math (Applicant’s remarks at pg. 12, para. 1).
This argument is not persuasive. As discussed in the previous rejection, MPEP 2106.04(a)(2) I. C. explains 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. The instant claims merely recite “processing, using the machine learning model the end motif pattern to determine a collective property…”, which encompasses inputting numbers into a linear regression model to determine the collective property (i.e. aggregate value, as defined above). Similarly, training a machine learning model using end motif patterns (e.g. numerical values) encompasses training a logistic regression model, which amounts to a textual equivalent to inputting numbers into a regression model, performing mathematical calculations (e.g. multiplication, division, addition) to calculate a model output, calculating a loss function, adjusting model parameters and repeating the process.
Furthermore, Applicant’s arguments are not commensurate with the scope of the claims. Applicant alleges the claims require “multi-dimensional reference data”, and train data on “hundreds of thousands of distinct biological fragment inputs”. However, the claims only require training a machine learning model “using reference end motif patterns of reference samples”, which encompasses simply using a count of two end motifs per sample (i.e. a one dimensional vector of two numbers for each of two reference samples) as input into the model.
Step 2A, Prong 2:
1. Constellation Designs LLC vs. LG Electronics Inc.
Applicant remarks the claims integrate the recited judicial exception into a practical application under step 2A, Prong 2, because the pending claims are structurally analogous to patent-eligible “constellation claims” in Constellation Designs, LLC. V. LG Electronics Inc (Applicant’s remarks at pg. 12, para. 2 to pg. 13, para. 2). Applicant remarks the pending claims do not attempt to pre-empt or monopolize the broad mathematical or natural laws governing cell-free DNA fragmentation, and instead, the structural architecture of the claims map directly to the distinction drawn by the Federal Circuit in Constellation (Applicant’s remarks at pg. 13, para. 3). Applicant remarks that instead of evaluating an entire sequence read, the computational and physical steps of the claim are confined to isolating a highly specific localized sub-population by determining a sequence motif for each of one or more ending sequences of the cell-free DNA, instead of analyzing the entire read, which provides a technical focus on terminal boundaries like the specific overlapping point constraints in Constellation, which serve as a filter that isolates high-fidelity biological signal from background noise (Applicant’s remarks at pg. 13, para. 4 to pg. 14, para. 2).
This argument is not persuasive. While preemption is the concern underlying the judicial exceptions, it is not a standalone test for determining eligibility. Rapid Litig. Mgmt. v. CellzDirect, Inc., 827 F.3d 1042, 1052, 119 USPQ2d 1370, 1376 (Fed. Cir. 2016). Instead, questions of preemption are inherent in and resolved by the two-part framework from Alice Corp. and Mayo (the Alice/Mayo test referred to by the Office as Steps 2A and 2B). It is necessary to evaluate eligibility using the Alice/Mayo test, because while a preemptive claim may be ineligible, the absence of complete preemption does not demonstrate that a claim is eligible. Diamond v. Diehr, 450 U.S. 175, 191-92 n.14, 209 USPQ 1, 10-11 n.14 (1981) ("We rejected in Flook the argument that because all possible uses of the mathematical formula were not pre-empted, the claim should be eligible for patent protection").
Therefore, simply because the claims do not preempt all methods of analyzing a cell-free DNA fragment, and instead only analyze ends of the fragment, is not sufficient to demonstrate eligibility. Furthermore, Applicant has not provided an explanation regarding how the additional element(s) in the claim, integrate the judicial exception into a practical application. Instead, Applicant only discusses that the judicial exception (i.e. the analysis of the fragment ends) provides better data (e.g. isolates high-fidelity signal).
2. Reduced sample size
Applicant remarks that para. [0086] and FIG. 28 of the specification demonstrates that by evaluating end motifs, the method achieves better statistical clustering, and vastly more sequence reads are collected per motif feature, which creates a more robust signal to noise ratio, and therefore, the technology requires significantly less absolute volume of input circulating cell-free DNA fragments to achieve clinical accuracy compared to the same feature depth as would be obtained using depth at positions across the human genome (Applicant’s remarks at pg. 14, para. 3 to pg. 15, para. 1). Applicant further remarks this represents a tangible physical improvement in testing efficiency and patient sample management, and if the Examiner disagrees, a scientific explanation is requested (Applicant’s remarks at pg. 15, para. 2).
This argument is not persuasive. First, para. [0086] of the specification states “as the number of end motifs may be smaller than the number of preferred end positions in a reference genome, greater statistics can be gathered for each end motif, potentially increasing accuracy”. This appears to be a general allegation of increasing accuracy, but is not evidence. As previously, discussed arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). Furthermore, in FIG. 28 cited by Applicant, discussed at para. [0218] of the specification, various methods for analyzing cell-free DNA including a MDS (motif diversity score), orientation-aware plasma cell-free DNA fragment signals (OCF), fragment size analysis, and fragment preferred ends. The preferred end motif method, has the lowest AUC of the presented methods in FIG. 28; furthermore, there does not appear to be a comparison to methods that analyze cell-free DNA using absolute genomic coordinates, as discussed by Applicant above. Overall, the improvement is not apparent.
However, even if the above statements regarding the improvement in sensitivity are assumed true, the above argument is not sufficient to overcome thee rejection. It is important to note, the judicial exception alone cannot provide the improvement. Furthermore, it is important to keep in mind that an improvement in the abstract idea itself (e.g. a recited fundamental economic concept) is not an improvement in technology. See MPEP 2106.05(a). As previously discussed, Applicant’s explanation provides purported benefits of the abstract idea, but does not provide an explanation regarding how the additional element(s), contribute to the improvement in using less input DNA. See MPEP 2106.05(a) regarding improvements, cited above.
Last, Applicant’s arguments are not commensurate with the scope of the claims. The claim must be evaluated to ensure the claim itself reflects the disclosed improvement in technology. Intellectual Ventures I LLC v. Symantec Corp., 838 F.3d 1307, 1316, 120 USPQ2d 1353, 1359 (Fed. Cir. 2016). The full scope of the claim under the BRI should be considered to determine if the claim reflects an improvement in technology. See MPEP 2106.05(a). Applicant argues the alleged improvement is provided by using a particular sample size or sample with a concentration of DNA. However, the claims encompass using a sample with any amount of DNA, and thus the alleged improvement is not reflected in the claims.
3. Improvement to the abstract idea
Applicant remarks that the Examiner does not assert what abstract idea is supposedly being improved, and that the claims do not provide an improved way to think or an improved mathematical concept, and instead provide an improvement to the measurement of a pathology signal in a sample in the technical fields of biology and medicine (Applicant’s remarks at pg. 15, para. 3 to pg. 16, para. 1).
This argument is not persuasive. As discussed repeatedly above and in the previous Office actions, MPEP 2106.05(a) makes clear that (1) the judicial exception alone cannot provide the improvement and (2) an improvement in the abstract idea itself is not an improvement in technology. Above, Applicant argues that the analysis of end motifs of cell-free DNA fragments results in higher sensitivity in cancer detection and provides a better data signal that removes background noise. The analysis of cell-free DNA end motifs is clearly identified as part of the abstract idea in the above rejection, corresponding to the limitations of “determining…a sequence motif”, “determining…an end motif pattern…”, “training a machine learning model…”, processing, using the machine learning model… to determine a collective property…”, and “determining classification” (i.e. the analysis of the end motifs). The improvement argued by Applicant is not provided by the assay being performed on the cell-free DNA, which is a conventional sequencing assay as discussed in the above rejection, and instead is being provided by the above analysis steps that are part of the abstract idea. This reflects an improvement in the abstract idea, which is not a technology.
As previously mentioned in the last Office action, Applicant is directed to the July 2024 Updated Subject Matter eligibility guidance, specifically claim 1 of Example 49, which was found ineligible and states “At best, the claimed combination amounts to an improvement to the abstract idea of determining patient risk rather than to any technology. See MPEP 2106.05(a)”. Simply because a patient risk was being determined using genotyping data did not mean that the improvement was in the technical field of “biology and medicine”. Applicant is further directed to the discussion of In re Board of Trustees of Leland Stanford Junior University, 989 F.3d 1367, 1370, 1373, in the 2024 Updated Subject Matter eligibility guidance, which explains that an improvement in the judicial exception is not an improvement to technology.
4. CardioNet
Applicant remarks the Examiner objects to claims not covering a monitoring device, and that new claim 56 recites a “cancer monitoring device” and thus parallels the device claim in CardioNet (Applicant’s remarks at pg. 16, para. 2).
This argument is not persuasive. The “cancer monitoring device” of claim 56 comprises a “sequencing device” and a “logic system” that is a computer system (see the 112(b) rejection above). MPEP 2106.05(a) states in computer-related technologies, the examiner should determine whether the claim purports to improve computer capabilities or, instead, invokes computers merely as a tool. In the instant case, the logic system is merely used as a tool to carry out the abstract idea, which does not reflect an improvement to computer technology. This is not analogous to the claims in CardioNet, which involved improving the function of a cardiac monitoring device.
5. Claim 55
Applicant remarks claim 55 integrates the judicial exception into a practical application of providing a prophylaxis because “prophylaxis” includes steps to detect a condition or disease, e.g. cancer according to the standard meaning of “prophylaxis” of preventative care (Applicant’s remarks at pg. 16, para. 3-5).
This argument is not persuasive. MPEP 2106.04(d)(2) states examples of "treatment" and prophylaxis" limitations encompass limitations that treat or prevent a disease or medical condition, including, e.g., acupuncture, administration of medication, dialysis, organ transplants, phototherapy, physiotherapy, radiation therapy, surgery, and the like. MPEP 2106.04(d)(2) further states 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. 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.
In the instant case, simply imaging a subject to detect a tumor after predicting the subject has cancer, is not a prophylaxis that prevents a disease or medication condition. Imaging a subject and detecting a tumor in that subject does not serve to prevent the cancer, unlike the various examples of a “prophylaxis” provided by the MPEP above (e.g. dialysis, acupuncture, etc.). Therefore, in view of the MPEP, simply imaging a subject to detect cancer does not provide integration by providing a prophylaxis for a disease or medication condition.
Applicant remarks that the imaging is a physical procedure applied to the subject and not simply creating printed material, and just because a physical act occurs after the judicial exception does not make the acts ineligible as insignificant extra-solution activity (Applicant’s remarks at pg. 16, para. 6 to pg. 17, para. 1). Applicant remarks that the assertion that claim 55 covers “any solution” is unclear in its relevance (Applicant’s remarks at pg. 17, para. 3).
This argument is not persuasive. It was not alleged that simply because a physical act occurs after the judicial exception automatically means a claim is ineligible. As explained in the above rejection, the additional element is considered insignificant extra-solution activity because the imaging step to detect the presence of a tumor after the judicial exception indicates the presence of cancer only serves to confirm the determination already made by the abstract idea. This is considered an “insignificant application” in view of MPEP 2106.05(g), similar to simply cutting hair after first determining the hair style in In re Brown, 645 Fed. App'x 1014, 1016-1017 (Fed. Cir. 2016) (non-precedential) and printing or downloading generated menus, in Ameranth, 842 F.3d at 1241-42, 120 USPQ2d at 1854-55.
Regarding Applicant’s arguments regarding the limitation being mere instructions to apply the exception, it is noted the reasoning regarding mere instructions to apply has been removed from the above rejection in view of the claim amendment.
Step 2B:
Claim 1
Applicant remarks that training a machine learning model using end motif patterns was unconventional, and also the determining a sequence motif and determining an end motif pattern steps are unconventional, particular in combination with the other additional limitations (Applicant’s remarks at pg. 17, para. 5 to pg. 18, para. 1-2).
This argument is not persuasive. Under Step 2B, only the additional elements are evaluated for conventionality. The training step, determining a sequence motif step, and determining an end motif pattern step are part of the abstract idea, as discussed in the above rejection, and therefore are not considered under Step 2B.
Claim 55
Applicant remarks that the Examiner addresses the “performing an assay…” and “performing imaging…” steps separately, but completely ignores the combination, simply stating, “Even when viewed as a combination, the additional element….” (Applicant’s remarks at pg. 18, para. 3-5).
This argument is not persuasive. Applicant alleges the combination of performing an assay on cell-free DNA and the imaging steps was ignored. However, this is not the case. In the previous Office action mailed 24 Nov. 2025, para. [028]-[029] specifically addressed the combination of performing liquid biopsies on cell-free DNA in combination with imaging techniques for diagnosing cancer. The brief conclusion statement cited by Applicant is in para. [030] of the previous Office action after this explanation. A similar explanation regarding the combination is provided above in para. [050]-[051]. The prior art demonstrates the conventionality of performing liquid biopsies on cell-free DNA for early cancer detection, followed by imaging for further evaluation of the tumor such as metastatic locations.
Double Patenting
The provisional rejections of claims 5, on the ground of nonstatutory double patenting in the Office action mailed 24 Nov. 2025 has been withdrawn in view of the cancellation of this claim filed 26 May 2026.
A nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-7, 10-14, 18-19, 29, 31-35, 37, and 56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-12, 23, 25-26, 29-30, and 47-49 of copending Application No. 17/144,021 (reference application). This rejection is previously recited. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1 and 56, reference claim 1 discloses the limitations of instant claim 1, except for that a portion of the DNA fragments are blunt ended, and further differs in scope due to the using motifs corresponding to both ending sequences of a fragment. Reference claim 6 discloses the pathology is cancer.
However, reference claim 1 discloses sequencing a plurality of cell-free DNA fragments in a biological sample to obtain sequence reads, and then determining end sequence motifs of the plurality of DNA fragments in the sample, regardless of whether the fragments are blunt ended or not. Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have determined the end motifs of blunt ended fragments in the sample according to the method of reference claim 1, and such a modification would have been obvious to try, given the biological sample finitely includes blunt ended DNA and/or non-blunt ended DNA, and reference claim 1 determines end sequence motifs of any DNA fragments of the sample.
Reference claim 2 discloses the limitations of instant claim 2.
Reference claim 6 discloses the limitations of instant claim 5.
Reference claim 7 discloses the limitations of instant claim 6.
Reference claim 8 discloses the limitation of instant claim 7.
Reference claim 12 discloses the limitation of instant claim 10.
Regarding instant claim 11, reference claim 12 discloses the limitations of instant claim 12 except for the cell-free DNA fragments including blunt ended DNA fragments, and differs in scope for the same reason discussed for instant claim 1. However, instant claim 11 is obvious over reference claim 12 for the same reasons discussed above for instant claim 1 with respect to the blunt ended fragments.
Reference claims 6-7 disclose the limitations of instant claims 12-14.
Reference claims 6 and 11-12 disclose the limitation of instant claim 18.
Reference claims 10-12 disclose the limitations of instant claim 19.
Reference claim 23 discloses the limitations of instant claim 29.
Reference claims 1, 25-26 and 29 discloses the limitations of instant claims 31-35.
Reference claim 30 discloses the limitations of instant claim 37.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3-4, 38, 54, and 57 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-12, 23, 25-26, 29-30, and 47-49 of copending Application No. 17/144,021 (reference application) in view of Kincaid (2018). Any newly recited portion is necessitated by claim amendment.
Cited reference: Kincaid (US 2021/0054366 A1; effectively filed 20 Nov. 2018; previously cited).
The reference claims disclose the limitations of instant claims 1-2 as applied above.
Further regarding instant claims 3-4, the reference claims do not disclose the filtering is based on a size or a region from which the DNA fragment is derived, wherein the cell-free DNA is filtered from open chromatin regions of a particular tissue.
Further regarding instant claim 38, the reference claims do not disclose the machine learning model uses clustering, supporting vector machines, or logistic regression.
Further regarding instant claim 54, the reference claims do not disclose each of the set of one or more end sequence motifs is 7 bases or less.
Further regarding instant claim 57, the reference claims do not disclose each sequence motif consists of two, three, or four bases.
However, Kincaid discloses a method of classifying a level of a medical condition (pathology) in a subject (Abstract; [0021]), which comprises determining percentages (i.e. relative frequencies) dinucleotides (motifs consisting of two bases, which is less than 7 bases, as recited in instant claims 54 and 57) in overhang (i.e. ending) sequences of cell-free DNA fragments ([0374]; FIG. 21), wherein a percentage is a proportion/percentage of the cell-free DNA fragments that have an ending sequence including (i.e. corresponding to) the overhang sequence (FIG. 21; [0374]). Kincaid further discloses the cell-free DNA is filtered for overhangs contained in open chromatin regions of healthy or cancer tissues (i.e. the cell-free DNA is filtered for DNA fragments of an open chromatin region) (Table 7; [0374]; [0050]), as recited in instant claims 3-4. Kincaid further discloses using the overhang features in a support vector machine to classify a subject with cancer ([0213]; [0379]), as recited in instant claim 38.
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Kincaid, thus arriving at the inventions of instant claims 3-4, 38, and 54. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Kincaid to facilitate the prediction of cancer in a subject, as shown by Kincaid ([0213]; [0379]), given the reference claims also use end motif frequencies for disease classification. This modification would have had a reasonable expectation of success given both the reference claims and Kincaid utilize end sequence counts to predict disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 55 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-12, 23, 25-26, 29-30, and 47-49 of copending Application No. 17/144,021 (reference application) in view of Heitzer (2015). This rejection is previously cited.
Cited reference: Heitzer et al. (Circulating tumor DNA as a liquid biopsy for cancer, 2015, Clinical Chemistry, pg. 112-123; newly cited).
Regarding instant claim 55, the reference claims disclose the limitations of instant claim 1 as applied above.
Regarding instant claim 55, The reference claims do not disclose performing imagine of the subject to detect presence of a tumor.
Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses sequencing analysis of plasma DNA and biopsies in combination with imaging studies are needed to assess clinical progression (pg. 121, col. 1, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the method of the reference claims to have further performed imaging of the subject to detect presence of a tumor, as shown by Heitzer, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Heitzer to assess clinical progression in more detail, as shown by Heitzer (pg. 121, col. 1, para. 2). This modification would have had a reasonable expectation of success given the reference claims use cell-free DNA to detect cancer, and thus the imaging of Heitzer is applicable to the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 6, and 54-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 18-21, 23-26, and 28-36 of copending Application No. 18/118,024 (reference application).Any newly recited portion is necessitated by claim amendment.
Although the claims at issue are not identical, they are not patentably distinct from each other because
Regarding instant claims 1 and 56, reference claims 1, 12, and 25 discloses the limitations of instant claim 1 except for determining relative frequencies of a second end motif and determining an aggregate value. However, reference claims 11 and 19 disclose obtaining a normalized value (i.e. aggregate value) by normalizing the first amount to a second amount of second set of end sequence motifs.
Furthermore, the reference claims do not disclose the cell-free DNA includes blunt-ended fragments.
However, reference claim 1 discloses sequencing a plurality of cell-free DNA fragments in a biological sample to obtain sequence reads, and then determining end sequence motifs of the plurality of DNA fragments in the sample, regardless of whether the fragments are blunt ended or not. Therefore, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have determined the end motifs of blunt ended fragments in the sample according to the method of reference claim 1, and such a modification would have been obvious to try, given the biological sample finitely includes blunt ended DNA and/or non-blunt ended DNA, and reference claim 1 determines end sequence motifs of any DNA fragments of the sample.
Reference claim 5-6 involves analyzing cell-free DNA from particular genomic regions, which shows the limitations of instant claims 2-3
Reference claims 4 and 22 discloses the limitation of instant claim 5.
Reference claim 4 discloses the limitation of instant claim 6.
Reference claim 1 discloses each of the set of end motifs is two bases, which is 7 bases or less as in instant claim 54.
Reference claim 1 discloses the limitation of instant claim 55.
Reference claim 29 discloses the end motifs have 3 bases, as recited in instant claim 57.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, 18-21, 23-26, and 28-36 of copending Application No. 18/118,024 (reference application) in view of Kincaid (2018). This rejection is previously recited.
Cited reference: Kincaid (US 2021/0054366 A1; effectively filed 20 Nov. 2018; previously cited).
The reference claims disclose the limitations of instant claims 1-2 as applied above.
Further regarding instant claim 4, the reference claims do not disclose the filtering is based on a size or a region from which the DNA fragment is derived, wherein the cell-free DNA is filtered from open chromatin regions of a particular tissue.
However, Kincaid discloses a method of classifying a level of a medical condition (pathology) in a subject (Abstract; [0021]), which comprises determining percentages (i.e. relative frequencies) dinucleotides in overhang (i.e. ending) sequences of cell-free DNA fragments ([0374]; FIG. 21), wherein a percentage is a proportion/percentage of the cell-free DNA fragments that have an ending sequence including (i.e. corresponding to) the overhang sequence (FIG. 21; [0374]). Kincaid further discloses the cell-free DNA is filtered for overhangs contained in open chromatin regions of healthy or cancer tissues (i.e. the cell-free DNA is filtered for DNA fragments of an open chromatin region) (Table 7; [0374]; [0050]), as recited in instant claims 4. Kincaid further discloses using the overhang features in a support vector machine to classify a subject with cancer ([0213]; [0379]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of the reference claims with the method of Kincaid, thus arriving at the inventions of instant claim 4. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Kincaid to facilitate the prediction of cancer in a subject, as shown by Kincaid ([0213]; [0379]), given the reference claims also use end motif frequencies for disease classification. This modification would have had a reasonable expectation of success given both the reference claims and Kincaid utilize end sequence counts to predict disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 26 May 2026 regarding the double patenting rejections have been fully considered but they do not present any arguments.
Applicant requests that the Office hold this rejection in abeyance until this application is otherwise in condition for allowance (Applicant’s remarks at pg. 19, para. 1-2).
As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. See MPEP 804 I.
Conclusion
No claims are allowed.
Claims 1-4, 6-7, 10-14, 18-21, 29, 31-35, 37-38, and 54-57 are free of the prior art for the reasons discussed in the Office action mailed 04 Nov. 2024.
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.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAITLYN L MINCHELLA whose telephone number is (571)272-6485. The examiner can normally be reached 7:00 - 4:00 M-Th.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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