DETAILED ACTION
Applicant' s response, filed 23 December 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 23 December 2025 has been entered.
Claim Status
Claims 1-14 and 16 are pending and examined herein.
Claims 1-14 and 16 are rejected.
Claims 8 and 14 are objected to.
Priority
Claims 1-14 and 16 are granted the claim to the benefit of priority to U.S. Provisional application 62/517820 filed 09 June 2017. Thus, the effective filling date of claims 1-14 and 16 is 09 June 2017.
Drawings
The drawings are objected to because Fig. 1 provides improper labeling of partial views. The MPEP sets out the standards for drawings at 608.02(V) which states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter” (37 C.F.R. 1.84(u)(1)). Therefore, the partial views of (a) and (b) should be labeled Fig. 1A and Fig. 1B. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 8 and 14 are objected to because of the following informalities: claim 8 recites “The method of either claim 1” but should read “The method of claim 1”. Claim 14 recites “The method any of claim 1” but should read “The method of claim 1”. Appropriate correction is required.
Claim Interpretation
Claim 1 recites “determining the type of cancer in the subject as: i. the first cancer if the at least one first probability score is higher than… or ii. The second cancer if the at least one second probability score is higher than…”. Claim 3 recites “determining the disease or physiological condition in the subject as i. the first disease or physiological condition if the at least one first probability score is higher than… ii. the second disease or physiological condition if the at least one second probability score is higher than…”. The steps of determining the type of cancer (or the disease or physiological condition) in the subject are contingent upon the conditions of i. or ii. being met. There exists an embodiment where the first probability score may be equal to the second probability score, therefore neither i. or ii. are required to be met and the cancer (or physiological condition) type is not required to be determined. Further, the limitations in dependent claims 2, 7, and 14 which are dependent on this determination are also not required.
Claim 3 recites “the first disease or physiological condition” and “the second disease or physiological condition” which are interpreted as referring to the “first physiological state” and the “second physiological state”.
Claim 8 recites “wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound” and claim 9 recites “wherein the upper bound is 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, or 50 base pairs and the lower bound is 20, 25, 30, 35, 36, 40, 45, 50, 60, 70, 80, 90, 100, 110, or 120 base pairs” are interpreted as further limiting the positively recited steps of isolating cfDNA from biological sample(s) in claim 1. The instant disclosure provides a disclosure of size selection as a part of isolating cfDNA (instant disclosure [0045]).
Claim 10 recites “wherein a subset of isolated cfDNA fragments from the subject are targeted to a genomic location” which is interpreted as furthering limiting the positively recited steps of constructing a sequencing library in claim 1. The instant disclosure provides a disclosure of a subset of isolated cfDNA fragments from the subject are targeted to a genomic location as part of library construction (instant disclosure [0047]).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-14 and 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
These rejections are newly recited.
Claims 1 and 3 recite “the subject” in step k of the claims and claim 10 recites “the subject” in line 2 of the claim which renders the metes and bounds of the claims indefinite. The indefiniteness arises because it is unclear if “the subject” is referring to “a subject in need thereof” or one of the “one or more subjects with a first cancer” (or one or more subjects with at least one first physiological state in claim 3) or one of the “one or more subjects with a second cancer” (or one or more subjects with at least one second physiological state in claim 3). Dependent claims 2-14 and 16 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, “the subject” in step k of claims 1 and 3 and “the subject” in claim 10 will be interpreted as referring to the “subject in need thereof”.
Claims 1 and 3 recite “each of the sample fragment endpoints a sample vector corresponding to the number of sample cfDNA fragment endpoints observed at the genomic location” in step of o. of the claim and then recites “the sample vector” in step p. of the claim which renders the metes and bounds of the claim indefinite. The indefiniteness arises because step o. provides that there are more than one sample vector (i.e., one for each sample fragment endpoints) while step p. suggests that there is only one sample vector. It is further unclear what genomic location “the genomic location” is referring to. Dependent claims 2-14 and 16 are rejected by virtue of their dependency on a rejected claim without alleviating the indefiniteness. For the sake of furthering examination, the “sample vector” will be interpreted as a vector corresponding to the number of sample fragment endpoints observed at each respective genomic location (i.e., one vector which has the number of fragments aligned to each genomic location) (which is similar to the training vectors of steps e. and j. of the claims).
Claim 16 recites “the biological sample” which renders the metes and bounds of the claim indefinite. The indefiniteness arises because it is unclear if “the biological sample” is referring to the “biological sample” in step a, step f, or step k of the independent claim. For the sake of furthering examination “the biological sample” is interpreted as referring to the “biological sample” in step k of independent claim 1.
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 1-14 and 16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
This rejection was previously recited but has been modified based on claim interpretations above.
(Step 1)
Claims 1-14 and 16 fall under the statutory category of a process.
(Step 2A Prong 1)
Under the BRI, the instant claims recite judicial exceptions that are an abstract idea of the type that is in the grouping of a “mental process”, such as procedures for evaluating, analyzing or organizing information, and forming judgement or an opinion. Along with abstract ideas of the type that is in the grouping of a “mathematical concept”, such as mathematical relationships and mathematical equations. Along with judicial exceptions of the type that is in the grouping of a “law of nature”.
Independent claim 1 recites a mental process of using data of cell free DNA from a biological sample from a subject with a first cancer, “determining genomic locations of the first fragment endpoints within a reference genome…”, “determining at least one first training sample for the first fragment endpoints…”, “determining genomic locations of the second fragment endpoints within the reference genome…”, “determining at least one second training sample for the second fragment endpoints…”, “determining genomic locations of the sample fragment endpoints within the reference genome…”, “assigning to each of the sample fragment endpoints a sample vector…”, and “determining type of cancer in the subject as…”.
Independent claim 3 recites a mental process of “determining genomic locations of the first fragment endpoints within a reference genome…”, “determining at least one first training sample for the first fragment endpoints…”, “determining genomic locations of the second fragment endpoints within the reference genome…”, “determining at least one second training sample for the second fragment endpoints…”, “determining genomic locations of the sample fragment endpoints within the reference genome…”, “assigning to each of the sample fragment endpoints a sample vector…”, and “determining the disease or physiological condition in the subject as…”.
Independent claims 1 and 3 recite mathematical concepts of “determining at least one first training sample for the first fragment endpoints…”, “determining at least one second training sample for the second fragment endpoints…”, “assigning to each of the sample fragment endpoints a sample vector…” and “calculating at least one first probability score for the sample vector and the first vector and at least one second probability score…”.
Independent claims 1 and 3 recite a law of nature of determining the type of cancer in a subject using cfDNA which is a naturally occurring correlation and determining the disease or physiological condition in a subject using cfDNA which is a naturally occurring correlation.
Dependent claim 2 recites a mental process of “applying a label to match the determined cancer type”. Dependent claim 7 recites a mental process of “applying a label to match the determined disease or physiological condition”. Dependent claim 13 recites a mental process of “providing a report listing a plurality of probability scores calculated…”. Dependent claim 14 recites a mental process of “recommending treatment for the identified disease or condition in the subject”.
The claims recite steps of analyzing data/evaluating data and making observations as “determining genomic locations of the first fragment endpoints within a reference genome…”, “determining at least one first training sample for the first fragment endpoints…”, “determining genomic locations of the second fragment endpoints within the reference genome…”, “determining at least one second training sample for the second fragment endpoints…”, “determining genomic locations of the sample fragment endpoints within the reference genome…”, “assigning to each of the sample fragment endpoints a sample vector…”, “determining type of cancer in the subject as…”, and “determining the disease or physiological condition in the subject as…”. The claims further recite steps of making a judgement about data as “applying a label to match the determined cancer type”, “applying a label to match the determined disease or physiological condition”, “providing a report listing a plurality of probability scores calculated…”, and “recommending treatment for the identified disease or condition in the subject”. The human mind is capable of analyzing data/evaluating data, making observations, and making judgments. The claims recite mathematical concepts of mathematical calculations as “determining at least one first training sample for the first fragment endpoints…”, “determining at least one second training sample for the second fragment endpoints…”, “assigning to each of the sample fragment endpoints a sample vector…” and “calculating at least one first probability score for the sample vector and the first vector and at least one second probability score…” which show calculating a number of observed fragments at genomic coordinates and calculating probabilities. The claims further recite a law of nature of correlating cfDNA fragment endpoints with the pathological or physiological state of a subject.
(Step 2A Prong 2)
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). Integration into a practical application is evaluated by identifying whether there are any additional elements recited in the claim and evaluating those additional elements to determine whether they integrate the exception into a practical application.
The additional element in claims 1 and 3 of isolating cell-free DNA from a biological sample, constructing sequencing libraries, and sequencing cell-free DNA fragments, the additional elements of 4-6 which further limit the subject in which the samples where derived, the additional element in claim 8 of wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound, the additional element in claim 9 of further limiting the upper bound and the lower bound, the additional element in claim 10 of wherein a subset of isolated cfDNA fragments from the subject are targeted to a genomic location, the additional elements in claims 11-12 which limits the genomic location, and the additional element in claim 16 of wherein the biological sample comprises or consists of whole blood, peripheral blood plasma, urine, or cerebral spinal fluid does not integrate the judicial exception into a practical application because this is adding insignificant extra solution activity of data gathering. These additional elements amount to insignificant extra solution activity of data gathering because these additional elements interact with the recited judicial exceptions in a manner that is solely to provide data to be processed by the judicial exceptions.
The additional element in claims 1 and 3 of using a generic computer to perform judicial exceptions does not integrate the judicial exception into a practical application because this is simply applying the judicial exception to a generic computer without and improvement to computer technology see MPEP 2106.04(d)(1).
Thus, the additional elements do not integrate the judicial exceptions into a practical application.
(Step 2B)
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
The additional element in claims 1 and 3 of using a generic computer to perform judicial exceptions is conventional see MPEP 2106.05(b) and 2106.05(d)(II).
The additional elements in claims 1 and 3 of isolating cell-free DNA from a biological sample, constructing sequencing libraries, and sequencing cell-free DNA fragments, the additional elements of 4-6 which further limit the subject in which the samples where derived, and the additional element in claim 16 of wherein the biological sample comprises or consists of whole blood, peripheral blood plasma, urine, or cerebral spinal fluid are conventional as shown in the online methods of Ulz et al. (Nat Genet 48, 1273–1278 (2016); previously cited) which shows isolation, library construction, sequencing, and samples from cancer and healthy patients, as shown on page 79 of Xia et al. (Lung Cancer. 2015 Oct;90(1):78-84; previously cited) which shows isolation, library construction, sequencing, and samples from cancer and healthy patients, and shown by the instant disclosure which provides that a commercially available kit (QIAGEN QIAamp Circulating Nucleic Acid kit) is commonly used to isolate cfDNA (instant disclosure [0044]) and provides any method known to one skilled in the art may be used to generate a dataset consisting of at least one “read” along with commercially available sequencers for sequencing (instant disclosure [0053]-[0057].
The additional elements in claim 8 of wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound, the additional element in claim 9 of further limiting the upper bound and the lower bound, the additional element in claim 10 of wherein a subset of isolated cfDNA fragments from the subject are targeted to a genomic location, and the additional elements in claims 11-12 which limits the genomic location are conventional as shown by Wan et al. (Nat Rev Cancer 17, 223–238 (2017); newly cited) which reviews liquid biopsies, shows experimental size selection, and targeted sequencing with hybrid capture that captures specific loci or gene panels for analysis (Wan et al. page 228), also shown by Mouliere et al. (BioRxiv (2017): 134437; newly cited) which shows selecting DNA fragments between 90-150 bp utilizing a size selection process of automated electrophoresis agarose gel selection (Mouliere et al. page 2 para. 3), and also shown by Underhill et al. (PLoS genetics 12.7 (2016): e1006162; newly cited) which shows size selection and mutant allele DNAbeing common around 132-145 bp (Underhill page 1 abstract).
Thus, the additional elements do not amount to significantly more than the judicial exception because they are conventional.
Response to Arguments
Applicant's arguments filed 23 December 2025 have been fully considered but they are not persuasive.
Applicant argues that the claims as a whole recite methods that are an improvement over other cfDNA-based liquid biopsy assays used in the field of diagnostics (Reply p. 7).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(a) “It is important to note, the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements… In addition, the improvement can be provided by the additional element(s) in combination with the recited judicial exception”. The determination of an improvement to technology has two steps, the identification of additional elements (which define the technology) and the evaluation of the additional elements to determine if the improvement is realized in the additional elements either by the additional elements themselves or the additional element in combination with the judicial exception (i.e. the interaction between the judicial exceptions and the additional elements). The additional elements of isolating cell-free DNA from a biological sample, constructing sequencing libraries, and sequencing cell-free DNA fragments, wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound, further limiting the upper bound and the lower bound, and wherein the biological sample comprises or consists of whole blood, peripheral blood plasma, urine, or cerebral spinal fluid only interact with the judicial exceptions in a manner which constitutes as insignificant extra solution activity of data gathering because they only provide data to the judicial exceptions to process. Further, the additional element of using a generic computer to perform judicial exceptions only interacts with the judicial exceptions by utilizing a computer as a tool to perform judicial exceptions. These additional elements do not interact with the judicial exceptions in a manner in which an improvement is realized in the additional elements. The argued improvement is being provided by the analysis of the fragment endpoints to provide a better probability score, which amounts to an improved judicial exception, but does not provide how the isolating/sequencing steps provide an improved assay.
Applicant argues that the method are non-routine and unconventional (Reply p. 7).
This argument has been fully considered but found to be not persuasive. The MPEP states at 2106.05(d)(II) that “Another consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional activities previously known to the industry” which shows that the analysis for conventionality is reserved for additional elements. As described above, the additional elements of isolating cell-free DNA from a biological sample, constructing sequencing libraries, and sequencing cell-free DNA fragments, wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound, further limiting the upper bound and the lower bound, wherein the biological sample comprises or consists of whole blood, peripheral blood plasma, urine, or cerebral spinal fluid, and using a generic computer to perform judicial exceptions are conventional.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-7, 10-14, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Lo et al. (US 20170024513 A1; previously cited) in view of Listgarten et al. (Clin Cancer Res. 2004 Apr 15;10(8):2725-37; previously cited).
This rejection is newly recited for claim 14
Claim 1 is directed to isolating cell-free DNA (cfDNA) from biological sample(s) from one or more subjects with a first cancer, the isolated cfDNA comprising a first plurality of cfDNA fragments, constructing a first sequencing library from the first plurality of cfDNA fragments, sequencing first fragment endpoints of the first plurality of cfDNA fragments,
Lo et al. shows the isolation of cell-free DNA from a biological sample (Lo et al. [0053]). Lo et al. shows obtaining sequence reads of fragment endpoints through massively parallel sequencing (Lo et al. [0057]). Massively parallel sequencing requires a step of library construction. Lo et al. shows that cell-free DNA profiles of preferred ends can be compared at different time of a pathological (e.g. cancer) process. Lo et al. further shows that different time points can be before and after progression of cancer (Lo et al. [0080]). It is interpreted that the first type of cancer may be before progression of cancer.
determining genomic locations of the first fragment endpoints within a reference genome for at least some of the first plurality of cfDNA fragments as a function of the sequences by use of a computer;
Lo et al. shows the genomic coordinate of the end position is derived though sequence alignment to a reference (Lo et al. [0057]).
determining at least one first training sample for the first fragment endpoints, wherein the at least one first training sample comprises a first vector corresponding to the number of first fragment endpoints observed at each respective genomic location by use of a computer
Lo et al. shows that preferred ending positions can be determining by analyzing a rate at which cell-free DNA molecules end on genomic positions, comparisons such rates to other samples (e.g., not having a relevant condition), and comparisons of sets of genomic positions with high occurrence rates of ends of cell-free DNA molecules for different tissues and/or different samples differing in a condition (Lo et al. [0069]).
isolating cfDNA from biological sample(s) from one or more subjects with a second cancer, the cfDNA comprising a second plurality of cfDNA fragments, constructing a second sequencing library from the second plurality of cfDNA fragments, sequencing second fragment endpoints of the second plurality of cfDNA fragments
Lo et al. shows the isolation of cell-free DNA from a biological sample (Lo et al. [0053]). Lo et al. shows obtaining sequence reads of fragment endpoints through massively parallel sequencing (Lo et al. [0057]). Massively parallel sequencing requires a step of library construction. Lo et al. shows that cell-free DNA profiles of preferred ends can be compared at different time of a pathological (e.g. cancer) process. Lo et al. further shows that different time points can be before and after progression of cancer (Lo et al. [0080]). It is interpreted that the second type of cancer may be after progression of cancer.
determining genomic locations of the second fragment endpoints within the reference genome for at least some of the second plurality of cfDNA fragments as a function of the sequences-by use of a computer,
Lo et al. shows the genomic coordinate of the end position is derived though sequence alignment to a reference (Lo et al. [0057]).
determining at least one second training sample for the second fragment endpoints, wherein the at least one second training sample comprises a second vector corresponding to the number of second fragment endpoints observed at each respective genomic location by use of a computer
Lo et al. shows that preferred ending positions can be determining by analyzing a rate at which cell-free DNA molecules end on genomic positions, comparisons such rates to other samples (e.g., not having a relevant condition), and comparisons of sets of genomic positions with high occurrence rates of ends of cell-free DNA molecules for different tissues and/or different samples differing in a condition (Lo et al. [0069]).
isolating cfDNA from a biological sample from the subject, the isolated cfDNA comprising a sample plurality of cfDNA fragments, constructing a sample sequencing library from the sample plurality of cfDNA fragments, sequencing sample fragment endpoints of the sample plurality of cfDNA fragments
Lo et al. shows after a catalog of cell-free DNA preferred ends is established for any physiological or pathological state, targeted methods could be used to detect their presence in cell-free DNA samples, e.g. plasma, or other individuals to determine a classification of the other tested individuals having a similar health, physiologic or disease state. Lo et al. shows hybridization capture of loci with high density of preferred ends could be performed on the cell-free DNA samples to enrich the sample with cell-free DNA molecules with such preferred ends (Lo et al. [0083]).
determining genomic locations of the sample fragment endpoints within the reference genome for at least some of the sample plurality of cfDNA fragments as a function of the sequences by use of a computer
Lo et al. shows the genomic coordinate of the end position is derived though sequence alignment to a reference (Lo et al. [0057]).
assigning to each of the sample fragment endpoints a sample vector corresponding to the number of samples cfDNA fragment endpoints observed at the genomic location
Lo et al. shows that preferred ending positions can be determined by analyzing a rate at which cell-free DNA molecules end on genomic positions (Lo et al. [0069]).
Lo et al. does not explicitly show calculating at least one first probability score for the sample vector and the first vector and at least one second probability score for the sample vector and the second vector, each calculated according to a multinomial probability formula and determining type of cancer in the subject as the first cancer if the at least one first probability score is higher than that at least one second probability score; or ii. the second cancer if the at least one second probability score is higher than the that at least one first probability score.
Like Lo et al., Listgarten et al. shows the analysis of sequencing data. Listgarten et al. shows the use of a multinomial probability formula as a Naïve Bayes model which uses the frequencies of different values of each feature, within known classes, to predict the class of the new sample with specified features but no label (Listgarten et al. page 2733 left column). Listgarten et al. shows the probability of a class for a set of features is equal to the product of the probabilities of a class for each feature which is interpreted as a multinomial probability formula (Listgarten et al. page 2733 left col.). Under the BRI of the claim the step of “determining the type of cancer in the subject as…” is not required because it is contingent on at least one first probability score is higher than at least one second probability score (for the first cancer) or at least one second probability score is higher than at least one first probability score (for the second cancer). There exists an embodiment where the first probability score and second probability score are equal (i.e., both of these conditions are not met) and the type of cancer is not determined. Regardless, in the interest of compact prosecution, Listgarten et al. shows the class with the highest probability is the one to which the new example is classified (Listgarten et al. page 2733 left column).
Independent claim 3 is directed to the method of claim 1 for determining the disease or physiological condition in the subject as the first disease or physiological condition or second disease or physiological condition.
Lo et al. shows a relevant physiological state may include when a person is healthy or has cancer (Lo et al. [0058]).
Claim 2 is directed to applying a label to match the determined cancer type. Claim 7 is directed to applying a label to match the determined disease or physiological condition.
Under the BRI of this claim step is dependent on the cancer type being determined (which is contingent on conditions being met and is not required by the claim). As discussed above, there exists an embodiment where the first probability score and second probability score are equal (i.e., both of these conditions are not met) and the type of cancer is not determined. Since the cancer type is not required to be determined, then applying a label to match the determined cancer type is not required because there exists an embodiment where the cancer type is not determined. Regardless, in the interest of compact prosecution, Listgarten et al. shows the use of training data which is labeled data that pertains to the class it is used to predict (Listgarten et al. page 2733 left col).
Claim 4 is directed to wherein at least one of the first physiological states is a healthy condition. Claim 5 is directed to wherein the at least second physiological state is selected from the group of cancer. Dependent claim 6 is directed to wherein the at least one second physiological state is cancer.
Lo et al. shows a relevant physiological state may include when a person is healthy or has cancer (Lo et al. [0058]).
Claim 10 is directed to wherein a subset of isolated cfDNA fragments from the subject are targeted to a genomic location. Claim 11 is directed to wherein the genomic location comprises one or more genomic annotations. Claim 12 is directed to wherein the one or more genomic annotations comprises or consists of transcription start sites (TSSs).
Lo et al. shows hybridization capture of loci with high density of preferred ends could be performed on the cell-free DNA samples to enrich the sample with cell-free DNA molecules with such preferred ends (Lo et al. [0083]). Lo et al. shows that it was known that DNA fragment ends are not random close to transcriptional start sites (Lo et al. [0113]). It is implicit that this non-randomness makes these areas obvious targets for extracting data about preferred ends.
Claim 13 is directed to providing a report listing a plurality of probability scores calculated for the sample using either or both of the at least one first training sample and/or the at least one second training sample.
Lo et al. shows after a catalog of cell-free DNA preferred ends is established for any physiological or pathological state, targeted methods could be used to detect their presence in cell-free DNA samples, e.g. plasma, or other individuals to determine a classification of the other tested individuals having a similar health, physiologic or disease state (Lo et al. [0083]). Lo et al. further shows outputting data to a user (Lo et al. [0354]).
Claim 14 is directed to recommending treatment for the type of cancer identified in the subject.
Under the BRI of this claim step is dependent on the cancer type being determined (which is contingent on conditions being met and is not required by the claim). As discussed above, there exists an embodiment where the first probability score and second probability score are equal (i.e., both of these conditions are not met) and the type of cancer is not. Since the cancer type is not required to be determined, then recommending treatment for the type of cancer identified in the subject is not required because there exists an embodiment where the cancer type is not determined.
Claim 16 is directed to wherein the biological sample comprises urine.
Lo et al. shows the biological sample being urine (Lo et al. [0053]).
It would have been obvious to one of ordinary skill in the art before the effective filling date to have applied the known technique of a Naïve Bayes model to predict the class of a new sample with specified features but no label for cancer classification using feature frequency to the known method of Listgarten et al. to the known method of analyzing the frequency of cfDNA fragment ends at genomic positions that are associated with cancer or a condition of Lo et al. because this known technique would have yielded a predictable method that utilizes a mathematical method that is trained on preferred ends that have been shown to correlate with certain states of a subject to produce a diagnosis (or prediction) about a test subject. This known technique would have resulted in an improved method of classifying cancer or a condition utilizing the frequency of cfDNA fragment ends at genomic positions because Listgarten et al. shows Naïve Bayes models have been found to work well in practice (Listgarten et al. page 2733 left col.).
Claim 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Lo et al. in view of Listgarten et al. as applied to claim 1 above, and further in view of Mouliere et al. (BioRxiv (2017): 134437; newly cited).
This rejection is newly recited.
Claim 8 is directed to wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound. Claim 9 is directed to wherein the upper bound is limited to being a number of base pairs as recited in the claim and the lower bound s limited to being a number of base pairs as recited in the claim.
Lo et al. does not explicitly show a wherein any of the cfDNA fragments are subjected to a size selection to retain only cfDNA fragments having a length between an upper bound and a lower bound or wherein the upper bound is limited to being a number of base pairs as recited in the claim such as 150 and the lower bound s limited to being a number of base pairs as recited in the claim such as 90.
Like Lo et al. in view of Listgarten et al., Mouliere et al. shows analyzing cell-free DNA associated with cancer. Mouliere et al. shows selecting DNA fragments between 90-150 bp utilizing a size selection process of automated electrophoresis agarose gel selection (Mouliere et al. page 2 para. 3).
An invention would have been obvious to one or ordinary skill in the art if some motivation in the prior art would have led that person to modify reference teachings to arrive at the claimed invention. It would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the step of isolating of cell free DNA of Lo et al. in view of Listgarten et al. with the size selection process for selecting DNA fragments between 90-150 bp of Mouliere et al. because this would allow for a method which isolates circulating tumor DNA in a sample for the classification between cancer types. One would be motivated to make this modification because Mouliere et al. shows that selecting DNA fragments between 90-150 bp before analysis yielded enrichment of mutated DNA fraction of up to 11-fold and that size selection allows detection of tumor alterations masked by non-tumor DNA in plasma (which is sizes greater than 150 bp) (Mouliere et al. page 1 para. 1 and page 2 para. 3). One would have a reasonable expectation of success because Lo et al. in view of Listgarten et al. shows isolating cell-free DNA from a biological sample for classification of cancer types while Mouliere et al. shows a size selection method which enriches circulating tumor DNA allowing for detection of tumor alterations masked by non-tumor DNA in plasma.
Response to Arguments
Applicant's arguments filed 23 December 2025 have been fully considered but they are not persuasive.
Applicant arguments are directed to that one of ordinary skill in the art would not have combined the teachings of Lo et al. and Listgarten et al. without hindsight knowledge and even if these documents are combined, one of ordinary skill in the art would not arrive at the present claims (Reply p. 8).
These arguments have been fully considered but found to be not persuasive. Lo et al. is relied upon to show the analysis of genomic coordinates of cell-free fragment endpoints and their association with cancer types, a healthy state, and disease states. Lo et al. provides a known method for analyzing cell-free DNA fragment endpoints in the analysis of cancer and disease states. Listgarten et al. is relied upon to show a known technique of a Naïve Bayes model to predict the class of a new sample with specified features but no label for cancer classification using feature frequency. Listgarten et al. is relied upon to show a process of calculating probability scores of features using multinomial probability formula as the probability of a class for a set of features is equal to the product of the probabilities of a class for each feature. Although the features utilized in Listgarten et al. are SNPs rather than fragment endpoints, Listgarten et al. provides a known technique which calculated probability scores of features using a multinomial probability formula for classification of a disease state which can be applied to the features derived from the known method of analyzing cell-free fragment endpoints which are associated with disease states. Which would lead to a method of utilizing a mathematical model which calculates probability scores of cell-free fragment endpoint features using a multinomial probability formula for the classification of disease states or cancer types.
Conclusion
No claims are allowed.
The prior art made of record an not relied upon is considered pertinent to applicant’s disclosure. Sawyers. (Nature 432, 294–297 (2004); previously cited) which provides cancer therapy options for treating cancer that can be recommended to patients.
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/J.E.H./Examiner, Art Unit 1685
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685