DETAILED ACTION
Applicant’s response, filed 29 Dec. 2025 and entered 26 Jan. 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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 Jan. 2026 has been entered.
Status of Claims
It is noted that the claim amendments fail to comply with 37 CFR 1.121(c)(4), which states no claim text shall be presented for any claim in the claim listing with the status of "canceled" or "not entered.". Claims 80-81 are indicated as cancelled but include claim text. In future responses, the cancelled claims should not include any text, as in currently cancelled claims 86-87.
Claims 1-67, 69, 70-72, 77, 80-81, 84, 86-87, and 98-99 are cancelled.
Claims 68, 73-76, 78-79, 82-83, 85, 88-97, and 100 are pending.
Claims 89-97 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention. Applicant timely traversed the restriction (election) requirement in the reply filed on 19 July 2021.
Claims 68, 73-76, 78-79, 82-83, 85, 88, and 100 are rejected.
Claims 68 and 100 are objected to.
Priority
The effective filing date is 18 May 2018.
Claim Objections
The previous objection to claims 68 and 85 in the Office action mailed 24 Sept. 2025 has been withdrawn in view of claim amendments received 26 Jan. 2026.
Claims 68 and 100 are objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claim 68 recites “…determining a cfDNA fragmentation profile…wherein the cfDNA fragmentation profile comprises cfDNA fragment length distribution…”, which is grammatically incorrect and should recite “…a cfDNA fragment length distribution”.
Claim 68 recites “…determining a cfDNA fragmentation profile…wherein the cfDNA fragmentation profile comprises [a] cfDNA fragment length distribution, position dependent fragmentation metrics…, and a ratio…, and a sequence coverage…”, which is grammatically incorrect and should only include an “and” after the penultimate member of the list. The “and” before “a ratio” should be removed.
Claim 100 recites “the cancer treatment”, which should be amended to recite “the therapeutic treatment” to use consistent language with claim 68 and increase clarity.
Appropriate correction is required.
Claim Interpretation
Claim 68 recites “…wherein genome coverage is from about 0.1x to 9x”. One of ordinary skill in the art would be able to ascertain the scope of the claim based on variation in genome coverage due to experimental variation (e.g. 8.6X to 9.4X coverage is considered 9X coverage).
Claim 68 recites “…analyzing the genomic intervals of mapped sequences in multiple windows, each of the multiple windows covering a portion of the human genome and wherein each window is a genomic interval of the genomic intervals of mapped cfDNA sequence fragments…”. Therefore a window of the multiple window is required to be a genomic interval of the genomic intervals.
Claim 68 recites “predicting, by a machine learning model using position-dependent cfDNA fragmentation profiles from a plurality of subjects with cancer and healthy subjects, a tissue of origin…based on the cfDNA fragmentation profile in the subject”. In light of Applicant’s specification, the limitation of “a machine learning model using position-dependent cfDNA fragmentation profiles from a plurality of subjects…” is interpreted to refer to a machine learning that has been trained on (i.e. uses) these fragmentation profiles from the plurality of subjects with cancer and healthy subjects.
Claim 68 recites “…if the subject has cancer, predicting, by a machine learning model, a tissue of origin of a cancer based on the cfDNA fragmentation profile in the subject.”. The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. See MPEP 2111.04 II. In the instant case, claim 68 recites “the subject has or is at risk of having cancer”, but does not require the subject has cancer (as opposed to simply being at risk of having cancer). Therefore, under the broadest reasonable interpretation of the claim, the predicting, by a machine learning model step and the step of administering to the subject identified as having a cancer a therapeutic treatment are not required by the claims, given the subject was not required to be identified as having cancer.
Claim 100 further limits the cancer treatment being administered and thus is similarly not required by the claims for the same reasons discussed above for claim 68 regarding the administering step.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 68, 70, 73-76, 78-83, 85, 88, and 100 under 35 U.S.C. 112(b) in the Office action mailed 24 Sept. 2025 has been withdrawn in view of claim amendments and cancellations received 26 Jan. 2026.
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 79 and 82 are rejected under 35 U.S.C. 112(b) second paragraph, 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.
Claims 79 and 82 are indefinite for recitation of “the cfDNA fragmentation profile”. Claim 68, from which claims 79 and 82 depend, recites “a cfDNA fragmentation profile for the subject” in addition to a “reference cfDNA fragmentation profile” and “position-dependent cfDNA fragmentation profiles for a plurality of subjects…”. As a result, it is unclear what cfDNA fragmentation profile claim 79 is referring to. For purpose of examination, claims 79 and 82 are interpreted to refer to “the cfDNA fragmentation profile for the subject”.
Response to Arguments
Applicant's arguments filed 29 Dec. 2025 regarding 35 U.S.C. 112(b) have been fully considered but they do not pertain to the new grounds of rejection set forth above.
Claim Rejections - 35 USC § 101
The rejection of claims 70 and 80-81 under 35 U.S.C. 101 in the Office action mailed 24 Sept. 2025 has been withdrawn in view of the cancellation of these claims received 26 Jan. 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 68, 73-76, 78-79, 82-83, 85, 88, and 100 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more. Any newly recited portion 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 (claim 68 being representative) is directed to a method for determining a cfDNA fragmentation profile. Therefore, the instantly claimed invention falls into one of the four statutory categories. [Step 1: YES]
Step 2A: First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A, Prong 1: Under the MPEP § 2106.04, the Step 2A (Prong 1) analysis requires determining whether a claim recites an abstract idea, law of nature, or natural phenomenon.
Claim 68 recites the following steps which fall under the mathematical concepts and/or mental processes groupings of abstract ideas:
analyzing the cfDNA sequenced fragments to obtain a cfDNA fragmentation profile…, wherein analyzing the cfDNA sequenced fragments to obtain a cfDNA fragmentation profile comprises:
mapping cfDNA sequenced fragments to a human genome to obtain genomic intervals of mapped cfDNA sequences, wherein the genomic intervals each comprise thousands to millions of base pairs,
analyzing the genomic intervals of mapped cfDNA sequenced fragments in multiple windows, each of the multiple windows covering a portion of the human genome and wherein each window is a genomic interval of the genomic intervals of mapped cfDNA sequence fragments;
determining cfDNA fragment lengths for the mapped cfDNA sequence fragments within each of the multiple windows;
determining a cfDNA fragmentation profile for the subject based on the determined cfDNA fragment lengths, wherein the cfDNA fragmentation profile comprises a cfDNA fragment length distribution, position dependent fragmentation metrics across the whole genome or subgenomic intervals, a ratio of small cfDNA fragments of 100 base pairs to 150 base pairs to large cfDNA fragments of 151 base pairs to 220 base pairs in length, and a sequence coverage of at least one of the small cfDNA fragments and the large cfDNA fragments across the genome;
comparing the cfDNA fragmentation profile in the subject to a reference cfDNA fragmentation profile from a subject that does not have cancer;
determining, based on the comparison, that the determined cfDNA fragment length distribution in the subject is more variable than a reference cfDNA fragment length distribution from a subject that does not have cancer which indicates the subject has or is at risk of having cancer; and
if the subject has cancer, predicting, by a machine learning model using position-dependent cfDNA fragmentation profiles from a plurality of subjects with cancer and healthy subjects, a tissue of origin of a cancer based on the cfDNA fragmentation profile in the subject.
The identified claim limitations fall into the groups of abstract ideas of mental processes for the following reasons. First, mapping sequence fragments to a human genome to obtain genomic intervals involves performing data comparisons between sequence reads and a reference and dividing a genome into (e.g. 2) intervals, which amounts to a mere analysis of data that can be practically performed in the mind. Specifically, mapping the fragments to a human reference genome encompasses comparing each fragment, one-by-one, to the reference genome to determine an alignment, which can be done in the human mind or using a computer as a tool, without any specialized computer elements required. Next, the step of analyzing the intervals of mapped reads in multiple (e.g. two) windows covering a portion of the human genome and determining cfDNA fragment lengths within each of the multiple (e.g. two) windows involves analyzing the lengths of the reads mapped to each of the windows, which can be practically performed in the mind. The step of determining a cfDNA fragmentation profile involves analyzing the fragment lengths of the sample to determine a profile of said fragments lengths (i.e. a fragmentation profile), including creating a distribution of fragment lengths, counting frequencies of certain lengths of fragments in a subgenomic interval, calculating a ratio of small cfDNA fragments of 100 to 150 base pairs to large cfDNA fragments of 151 to 220 base pairs, and determining a sequence coverage (i.e. counting the number of reads mapped to a location) for the small or large cfDNA fragments, each which can be practically performed in the mind. Comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile can be performed mentally to determine if a standard deviation of a distribution of the cfDNA fragmentation profile is greater (i.e. more variable) than the reference. Last, using a trained machine learning model to predict a tissue of origin of the cancer using the cfDNA fragmentation profile can be performed mentally aided with pen and paper by inputting values from the cfDNA fragmentation profile into a trained linear regression model to calculate a probability of the subject having a cancer with a particular origin. Therefore, these limitations recite a mental process. That is, other than reciting the limitations are carried out by a processor, nothing in the claims precludes the steps from being practically performed in the mind. See MPEP 2106.04(a)(2) III.
Furthermore, the step of determining a cfDNA fragmentation profile comprising a fragment size distribution and a ratio of small 100 to 150 base pair cfDNA fragments to large 151 to 220 base pair cfDNA fragments and predicting, by a machine learning model using position-dependent cfDNA fragmentation profiles, a tissue or origin of a cancer based on the fragmentation profile further recite a mathematical concept. First, determining a fragment size distribution represents a mathematical relationship of fragment sizes. Furthermore, a ratio of small to large cfDNA fragments represents a mathematical equation of the number of small cfDNA fragments to a number of large cfDNA fragments. For example, MPEP 2106.04(a)(2) I. B. states the phrase "determining a ratio of A to B" is merely using a textual replacement for the particular equation (ratio = A/B). Furthermore, using the broadest reasonable interpretation of using a machine learning model to predict a tissue of origin of the cancer encompasses inputting numerical values of the fragmentation profile into a linear regression classifier to calculate a probability of the cancer being of a particular tissue origin, which amounts to a textual equivalent of performing mathematical calculations (e.g. multiplication and addition). Therefore, these limitations further recite a mathematical concept. See MPEP 2106.04(a)(2) I.
Dependent claims 73-76, 78-79, 82, and 85 further recite an abstract idea and/or are part of the abstract idea of claim 28. Claim 73 further limits the abstract idea of claim 58 to perform the comparison using a reference nucleosome cfDNA fragmentation profile. Dependent claim 74 further recites the mental process of distinguishing circulating tumor DNA (ctDNA) from non-cancer associated white blood cell DNA in a blood sample collected from the subjected based on the cfDNA fragmentation profile. Claims 75 and 98 further recite the mental process of analysis of diving the genome into between ten thousand and one hundred thousand genomic intervals. Claim 76 further recites the mental process of dividing the genome into non-overlapping genomic intervals. Claim 78 further recites the mental process of determining a cfDNA fragmentation profile for each of the genomic intervals. Claims 79 further recites the mental process and mathematical concept of analyzing the fragmentation profile to comprise a determining a median fragment size. Claim 82 further recites the mental process the cfDNA fragmentation profile to include 20,000 reads per genomic interval. Claim 85 further limits the mental process and mathematical concept of claim 68 to use the machine learning model to predict a particular cancer type.
Furthermore, the claims further recite the law of nature of a natural correlation between cell-free DNA fragment lengths in plasma of a subject and the presence of cancer in the subject, analogous to a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). See MPEP 2106.04(b).
Therefore, claims 68, 73-76, 78-79, 82-83, 85, 88, and 100 recite an abstract idea and law of nature. [Step 2A, Prong 1: YES]
Step 2A: Prong 2: Under the MPEP § 2106.04, the Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. This judicial exception is not integrated into a practical application for the following reasons.
Claims 69, 72-76, 78-79, 82, 85, and 98 do not recite any elements in addition to the recited judicial exception, and thus are part of the judicial exception.
The additional elements of claim 68 include:
a memory;
a processor;
obtaining a sample from the subject;
processing the same to obtain a plasma fraction;
extracting and enriching cfDNA fragments from the plasma fraction;
processing cfDNA fragments into sequencing libraries;
subjecting the sequencing libraries to whole genome sequencing to obtain cfDNA sequenced fragments, wherein genome coverage is from about 0.1x to 9x;
administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer.
The additional elements of claims 83 and 88 include:
wherein the genome coverage is 0.1x, 0.2x, 0.5x, 1x, or 2x (claim 83);
wherein the sample is a blood or plasma (claim 88).
The additional element of claim 100 includes:
wherein the cancer treatment is selected from the group consisting of surgery, adjuvant chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy, targeted therapy, and any combination thereof.
First, the additional element of claims 68 of a processor and memory are generic computer components and/or functions. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See MPEP 2106.05(f).
The limitations of obtaining a blood sample, processing the sample, extracting cfDNA fragments, generating sequencing libraries, and sequencing the sequencing libraries at a low coverage (e.g. 1X) only serves to collect data for use by the abstract idea (e.g. sequencing data to generate the cfDNA fragmentation profile), which amounts to insignificant extra-solution activity that does not integrate the recited judicial exception into a practical application. See MPEP 2106.05(g).
Last, the step of administering to the subject a cancer treatment from the recited group does not integrate the recited judicial exception into the practical application of a particular treatment because (1) the treatment is not required by the claims, (2) the treatment is not particular and furthermore, (3) the treatment has a nominal or insignificant relationship to the exception. See MPEP 2106.04(d)(2). First, as explained in claim interpretation regarding (1), under the broadest reasonable interpretation of the claims, the administering step is not required because the subject is not required to be identified as having cancer, as opposed to only being at risk for cancer. Furthermore, regarding (2), the claim encompasses administering a “surgery” to treat the cancer, which is not particular, and further encompasses any surgery, including those without a significant relationship to cancer (e.g. an appendectomy). In addition, regarding (3) the administering step does not apply the prediction of a tissue of origin of the subject, and instead amounts to mere instructions to apply the exception to administer an “appropriate” cancer treatment, regardless of the tissue of origin of the cancer. Therefore, the limitation amounts to mere instructions to apply an exception, which does not provide integration. See MPEP 2106.05(f).
Therefore, the additionally recited elements merely invoke computers as a tool to perform an existing process, amount to insignificant extra-solution activity, and/or amount to mere instructions to apply the exception , and as such, the claims as a whole do no integrate the abstract idea into practical application. Thus, claims 68-69, 73-76, 78-79, 82-83, 85, 88, and 100 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.
Claims 69, 72-76, 78-79, 82, 85, and 98 do not recite any elements in addition to the recited judicial exception, and thus are part of the judicial exception.
The additional elements of claim 68 include:
a memory;
a processor;
obtaining a sample from the subject;
processing the same to obtain a plasma fraction;
extracting and enriching cfDNA fragments from the plasma fraction;
processing cfDNA fragments into sequencing libraries;
subjecting the sequencing libraries to whole genome sequencing to obtain cfDNA sequenced fragments, wherein genome coverage is from about 0.1x to 9x;
administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer.
The additional elements of claims 83 and 88 include:
wherein the genome coverage is 0.1x, 0.2x, 0.5x, 1x, or 2x (claim 83);
wherein the sample is a blood or plasma (claim 88).
The additional element of claim 100 includes:
herein the cancer treatment is selected from the group consisting of surgery, adjuvant chemotherapy, neoadjuvant chemotherapy, radiation therapy, hormone therapy, cytotoxic therapy, immunotherapy, adoptive T cell therapy, targeted therapy, and any combination thereof.
The additional elements of a memory and processor are conventional computer components. The courts have found the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit).
The additional elements of obtaining a sample from the subject, obtaining a plasma fraction from the sample, extracting and purifying cfDNA fragments from the plasma fraction, processing the cfDNA fragments into sequencing libraries, and sequencing the sequencing libraries at a sequencing coverage of 0.1X, 0.2X, 0.5X, 1X, or 2X is well-understood, routine, and conventional. This position is supported by Heitzer et al. (Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123; previously cited), Stewart et al. (Circulating cell-free DNA for non-invasive cancer management, 2018, Cancer Genet, , pg. 1-20; Published 11 March 2018; previously recited), and Applicant’s specification.
Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that that methods based on low-coverage sequencing of cell-free DNA have been shown to provide clinically relevant information in a cost-effective manner (pg. 120, col. 1, para. 3). Last, Heitzer discloses that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that this limitation is inherent in the analysis of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Stewart similarly reviews circulating cell-free DNA for non-invasive cancer management (Abstract), and discloses that one of the two main methods of analyzing cell-free DNA include whole-genome sequencing at a low-coverage of ~0.1X (pg. 4, para. 2). Last, Applicant’s specification at pg. 27 lines 5-268, discloses using various commercially available kits known in the art for purifying and preparing cfDNA fragments for sequencing, such that the written description describes the additional elements as known in the art. See MPEP 2106.05(d) I. Accordingly, the combination of additional elements of obtaining a blood/plasma sample of the subject, processing the sample to obtain a plasma fraction, extract/purify nucleosome protected cfDNA, generating sequencing libraries, and then performing whole-genome sequencing on the sequencing libraries at a coverage of 0.1X is well-understood, routine, and conventional.
Last, administering to the subject a cancer treatment is not required by the claims, and thus cannot provide significantly more, and furthermore, is well-understood, routine, and conventional, as supported by Applicant’s specification. Applicant’s specification at para. [0056] discloses anti-cancer therapies are known in the art, citing various chemotherapeutic agents, and further points to treatment guidelines from cancer organizations. Applicant’s specification at para. [0054]-[0055] further cites numerous publications disclosing immune checkpoint inhibitor therapies and adoptive T-cell therapies.
Therefore, taken alone, the additional elements do not amount to significantly more than the above-identified judicial exception. 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 law of nature 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 29 Dec. 2025 regarding 35 U.S.C. 101 have been fully considered but they are not persuasive.
Applicant remarks claim 68 has been amended to include “administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer” and the claims require utilizing the cfDNA fragmentation profile to determine whether the subject has or is at risk of having cancer and then administering a suitable treatment, which involves a specific application of an inventive concept (Applicant’s remarks at pg. 9, para. 2 to pg. 10, para. 2).
This argument is not persuasive. MPEP 2106.04(d)(2) states examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. As explained above in claim interpretation and in the above rejection, the step of administering the treatment is not required by the claims, and thus cannot provide integration or an inventive concept.
Claim Rejections - 35 USC § 103
The rejections of claims 70 and 80-81 under 35 U.S.C. 103 in the Office action mailed 24 Sept. 2025 have been withdrawn in view of the cancellation of these claims received 26 Jan. 2026.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 is incorrect, any correction of the statutory basis 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 68, 73-74, 76, 78-79, 82-83, 85, 88, and 100 are rejected under 35 U.S.C. 103 as being unpatentable over Chiu (2013) in view of Sims (2014), and Maggi (2018), as evidenced by Lo (2014). Any newly recited portion is necessitated by claim amendment.
Lo et al. (referred to as Chiu) (US 2013/0237431 A1 (previously cited);
Sims et al., Sequencing depth and coverage: key considerations in genomic analyses, 2014, Nat Rev Genet, 15, p. 121-132 (previously cited);
Maggi et al., Development of a method to Implement Whole-Genome Bisulfite Sequencing of cfDNA from Cancer Patients and a Mouse Tumor Model, 2018, Frontiers in Genetics, 9(6), pg. 1-12; Pub. Date: Jan. 2018, (previously cited);
Lo et al., US 2014/0080715 A1 (previously cited);
Regarding claim 68, Chiu discloses a method for determining a cell-free DNA fragmentation profile for a subject (Abstract) comprising the following steps:
Chiu discloses obtaining a plasma sample from the subject, which involves obtaining the plasma fraction from blood (Abstract; [0047]; [0140]).
Chiu discloses extracting and purifying (enriching) cfDNA fragments from plasma samples ([0145]).
Chiu discloses performing sequencing library preparation on the cfDNA fragments to generate sequencing libraries ([0097]).
Chiu discloses performing whole-genome sequencing on the sequencing libraries ([0057]; [0067], e.g. the sequencing can be for the entire genome; [0098]; [0140]).
Chiu discloses analyzing, using a system comprising a memory and processor ([0181-[0182]); FIG. 23) to determine a cell-free DNA fragmentation profile for a subject (Abstract) by performing the following steps:
Chiu discloses that the sequence reads were aligned (i.e. mapped) to the human reference genome ([0067]; [0140]), and further shows dividing the genome into bins ([0176], thus obtaining genomic intervals of mapped sequences. Chiu further shows the genomic intervals can be a 1 Mb region (i.e. a million base pairs), which is between thousands of bases pairs and millions of base pairs ([0176]).
Chiu shows analyzing each bin (i.e. the genomic intervals in multiple windows each covering a portion of a genome and being a genomic interval of the genomic intervals) ([0176]) and determining the sizes (i.e. lengths) of the DNA fragments within the bins (i.e. determining cfDNA fragment lengths within each of the mapped windows) ([0140]; [0177]).
Chiu shows determining a size profile including size parameters ([0051]; [0099]), wherein the size parameter include a histogram providing a distribution of DNA fragments ate various sizes (i.e. cfDNA fragment length distribution). Chiu further discloses determining cfDNA fragmentation size parameter for each of different sets of regions in the genome ([0019]; [0099]; [0166]; [0176]-[0177], e.g. “a different size value can be determined for each genomic region”), such that any single size parameter is determined for a subgenomic intervals (i.e. position dependent fragmentation metrics across subgenomic intervals). Chiu discloses the size parameters include a ratio of the amount of DNA fragments of 100 to 150 base pairs in length to the amount of DNA fragments of 163 to 169 base pairs in length (i.e. a ratio of smaller to larger cfDNA fragments) ([0019]; [0099]; FIG. 5; FIG. 20). Regarding the claimed range of large fragments of 151 bp to 200 bp in length, the range of 163 to 169 bp in length is within the claimed range of 151 bp to 200 bp and therefore anticipates the range. See MPEP 2131.03.
Chiu discloses comparing a size parameter (i.e. the cfDNA fragmentation profile) of the subject to a reference size parameter (i.e. a reference cfDNA fragmentation profile), and determining that the ratio of small to large cfDNA in the subject exceeds the reference indicates a higher likelihood the cancer exists (i.e. the subject is at risk for cancer) ([0174]); FIG. 16A, e.g. higher size ratio corresponds to higher tumor %).
Regarding the limitations of predicting, by a machine learning model, a tissue of origin of a cancer based on the cfDNA fragmentation profile of the subject and administering a therapeutic treatment to the subject identified as having cancer, as discussed above under claim interpretation, claim 68 does not require that the subject was determined to have cancer. The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met. See MPEP 2111.04 II. Therefore, under the broadest reasonable interpretation of the claim, the claim is not required to determine a tissue of origin of the cancer or administer the therapeutic treatment.
Further regarding claim 68 and additionally dependent claim 83, Chiu does not disclose the following limitations:
Regarding claim 68, Chiu does not explicitly disclose the cfDNA fragmentation profile comprises a sequence coverage of at least one of the small cfDNA fragments and the large cfDNA fragments across the genome. However, Chiu discloses that the size parameter (i.e. the fragmentation profile) comprises an amount of small DNA fragments and the amount of large cfDNA fragments, and that this can be determined for all of the DNA fragments (i.e. across the genome, given the genome is whole-genome sequencing) ([0019]; [0058]; [0066]; [0099], e.g. a parameter can be defined using the sizes of all the DNA fragments). Determining the coverage of small and/or large fragments from the amounts of small and/or large fragments in Chiu would simply involve multiplying the count of the fragments by their length and then dividing by the length of the genome (see Sims pg. 122, Box 1), each which are constants based on the definitions of “small” and “large” and the type of genome used.
Therefore, the amount of small cfDNA fragments and/or the large cfDNA fragments across the genome in the fragmentation profile of Chiu is equivalent to a sequence coverage of at least one of the small cfDNA fragments and large cfDNA fragments across the genome in the instant claims, given one of ordinary skill in the art would recognize the interchangeability of the amount of small and/or large fragments across the genome in Chiu and the sequence coverage of the small and/or large fragments across the genome in the instant claims. See MPEP 2183. That is, determining the coverage of small/large fragments from the amounts of small/large fragments in Chui simply involves multiplying the amounts of fragments by a constant value (i.e. fragment length/genome length). Therefore, the amounts of small and large cfDNA fragments across the genome, as shown by Chiu, are equivalent in representing a coverage of an amount of small and/or large cfDNA fragments across a genome. Furthermore, it would have been prima facie obvious, to one of ordinary in the art, before the effective filing date of the claimed invention to have substituted the coverage of the small and/or large cfDNA fragments across the genome with the amount of small and/or large cell-free DNA fragments across the genome, given both represent an amount of small and/or large cfDNA fragments in a fixed size reference genome, and the results of the substitution would have predictably resulted in a fragmentation profile including a parameter reflecting an amount of small and/or large cfDNA fragments across the genome.
Further regarding claim 68, and also claim 83, Chiu does not show the genome coverage of the whole genome sequencing is 0.1x to 9x, as recited in claim 68, or that the or that the genome coverage is 0.1x, 0.2x, 0.5x, lx or 2x, as recited in claim 83. However, this limitation was obvious, before the effective filing date of the claimed invention, as shown by Sims and Maggi
Regarding claims 68 and 83, Sims reviews several considerations regarding sequencing depth and coverage in genomic analysis (Abstract), including that whole-genome sequencing can range from 1X through 30X coverage (pg. 122, Box 1). Sims further discloses that while high depth of coverage is required to accurately call SNVs, ultra-low-coverage sequencing at a depth of 0.1X-0.5X (i.e. 0.1X or 0.5X, which is from 0.1X to 9X) is sufficient to capture common variation (pg. 124, col. 2, para. 2). Sims further discloses that higher coverage of sequencing inevitably results in higher costs of sequencing (pg. 121, col. 1, para. 1). Furthermore, while Sims does not disclose the above sequencing methods and coverages are performed on cell-free DNA, Maggi discloses a method for analyzing whole-genome sequencing data from cfDNA (Abstract), which includes generating ultra-low, 0.05X coverage sequencing data from cfDNA (pg. 8, col. 2, para. 2).
It would have been prima facie obvious to one of ordinary skill, before the effective filing date of the claimed invention, to have modified the sequencing of the cfDNA fragments shown by Chiu, to have performed low, 0.5X or 1X coverage sequencing, as shown by Sims (pg. 2122 box 2; pg. 124, col. 2, para. 2). One of ordinary skill in the art would have been motivated to combine the methods of Chiu and Sims in order to reduce the cost of sequencing by utilizing lower coverage sequencing, as shown by Sims (pg. 121, col. 1, para. 1), given Chiu involves analyzing the sizes of the sequenced fragments (claim 39), which does not involve identifying single nucleotide variants and thus does not require a high depth of sequencing, as shown by Sims (pg.124, col. 2, para. 2). This modification would have had a reasonable expectation of success because Maggi shows that low-coverage sequencing can be applied to cell-free DNA (pg. 4, col. 2, para. 2; pg. 7, col. 1, para. 1), such that the sequencing method of Sims is applicable to the DNA of Chiu.
Regarding claim 68¸ Chiu does not explicitly disclose determining that a determined cfDNA fragment length distribution in the subject is more variable than a reference fragment length distribution, to determine the subject has or is at risk of having cancer. However, as discussed above, Chiu does disclose comparing a size parameter (i.e. the cfDNA fragmentation profile) of the subject to a reference size parameter (i.e. a reference cfDNA fragmentation profile), and determining that the ratio of small (100 to 150 base pairs) to large (163 to 169 base pairs) cfDNA fragments exceeds the reference ratio indicates a higher likelihood the cancer exists (i.e. the subject is at risk for cancer) ([0174]); FIG. 16A, e.g. higher size ratio corresponds to higher tumor %).
Further Chiu makes obvious this limitation for the following reasons:
Regarding claim 68, Chiu further discloses that tumor-derived DNA is shorter than non-cancer derived DNA in a cancer patient’s genome, and similarly fetal cell-free DNA molecules are generally shorter than the maternally derived ones ([0056]). Chiu discloses the larger number of shorter fragments causes a shift in the size profile of plasma DNA to the shorter spectrum ([0056]), and further provides an examples of size distributions of total cell-free DNA compared to fetal cell-free DNA in a maternal plasma sample (FIG. 1; [0058]) in addition to size distributions of cell-free DNA in maternal plasma with different percentages of fetal cell-free DNA over the same cfDNA size ranges use to indicate cancer (FIG. 2A-B). These size distributions of Chiu clearly demonstrate the shift in fragments of larger size (163-169 base pairs) to a smaller size as fetal cell-free DNA concentrations increases results in a flattening of the distribution (i.e. an increased variability) as fragments around the peak of the left-skewed distribution shift to lower sizes (FIG. 1 and 2A-B).
Therefore, it is prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the detected increase in a ratio of short to large fragments in the subject relative to the reference of Chiu, to have detected or determined the cfDNA fragment length distribution in the subject is more variable than the reference distribution, based on the comparison, given Chiu demonstrates the shift from large to small fragments, as measured in the size ratio, results in a flattened, more variable distribution, as discussed above. This modification would have had a reasonable expectation of success given one of ordinary skill in the art would have recognize the increased ratio of small to large fragments is indicative of a flatter, more variable distribution compared to the reference, as demonstrated by Chiu in FIG. 1-2, such that both reflect cancer in the subject.
Regarding the dependent claims:
Regarding claim 73 Chiu does not disclose the reference cfDNA fragmentation profile is a reference nucleosome cfDNA fragmentation profile. However, these limitations are inherent in Chiu, as evidenced by Lo. Specifically, Lo discloses a system for determining a cell-free DNA fragmentation profile for a subject ([0008]; [0241]-[[0243]), and discloses that the majority of cfDNA fragments correspond to cfDNA fragments associated with mononucleosomes (i.e. nucleosome-protected cfDNA fragments) ([0228]). Therefore, given, Chiu discloses using cfDNA fragments and a reference cfDNA profile, the cfDNA fragments and reference cfDNA profile are necessarily nucleosome protected fragments and a nucleosome reference cfDNA profile, respectively.
Regarding claim 74, Chiu shows the cfDNA fragments were obtained from a plasma (i.e. blood) sample from a patient with a tumor ([0140]), and using the size parameter (i.e. the cfDNA fragmentation profile) to predict a tumor DNA percentage in the sample (i.e. distinguish ctDNA from non-cancer associated DNA, which includes white blood cell DNA) ([0063]; [0140]; [0153]-[0155]).
Regarding claim 76, Chiu further discloses the bins can be specific chromosomes (i.e. non-overlapping regions) ([0176]).
Regarding claim 78, Chiu further discloses that the analysis, which includes determining a cfDNA fragmentation size parameter (i.e. cfDNA fragmentation profile) ([0019]; [0099]; FIG. 5) can be performed for each bin of the 1 Mbs bins of the genome ([0176]), such that the size parameter (cfDNA fragmentation profile) is determined for each bin (i.e. each genomic interval).
Regarding claim 79, Chiu further discloses the cfDNA fragmentation profile can comprise a cfDNA fragment length histogram (i.e. distribution) ([0066]; FIG. 1-2), as recited in claim 80, which includes information regarding a median fragment size, as recited in claim 79 ([0066]; [0010], e.g. the histogram includes information on statistical measures of the size profile).
Regarding claim 82, Chiu in view of Sims and Maggi disclose the limitations of claim 68, as applied above. Chiu does not disclose the genomic intervals include over 20,000 reads per interval. However, as discussed above, Chiu shows the genomic intervals are each 1Mb in length ([0176]). Furthermore, this limitation was obvious, before the effective filing date of the claimed invention, as shown by Sims.
Further regarding claim 82, Sims reviews several considerations regarding sequencing depth and coverage in genomic analysis (Abstract), including that the number of reads per genomic interval (e.g. per 1Mb in of Chui) is a function of the depth of coverage of the bin and the length of the bin, given Sims shows the depth of coverage is the average aligned read depth, which is based on the number and length of the reads. (pg. 121, col. 1, para. 1). Sims further shows the read length of the Illumina HiSeq 2000 platform, used by Chiu ([0140]), is 100 base pairs (pg. 122, Box 1). Sims further shows the sequencing coverage can range from 1x to 30x (pg. 122, Box 1), which includes various coverages that would result in at least 20,000 reads per 1Mb genomic interval (e.g. 2x, 3x, coverage; 2x coverage results in ~2*1,000,000/100 = 20,000 reads per 1Mb interval), as recited in claim 82. Sims further shows higher depths of sequencing can rescue inadequacies in sequencing methods and provide stronger evidence for particular sequencing calls during analysis (pg. 1, col. 2, para. 1), but inevitably results in higher costs of sequencing (pg. 121, col. 1, para. 1).
It would have been further prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the sequencing shown by Chui to have used over 20,000 reads per genomic interval, as recited in claim 82, through routine experimentation of the sequencing coverage within the prior art conditions of reducing sequencing costs by using lower coverage and rescuing inadequacies in sequencing by increasing coverage, as shown by Sims (pg. 1, col. 1, para. 1 and col. 2, para. 1). See MPEP 2144.05 II. A.
Regarding claim 85, As discussed above with respect to claim 68, the claims do not require that the subject has cancer, and therefore, the limitation regarding predicting a tissue of origin of a cancer for the subject is not required under the broadest reasonable interpretation of the claim. See MPEP 2111.04 II.
Regarding claim 88, Chiu discloses the sample is a blood or plasma sample (0267]).
Regarding claim 100, the step of administering a cancer treatment is not required by the claims as discussed above in claim interpretation. Therefore claim 100 is rejected for the same reasons discussed above for claim 68.
Regardless in the interest of compact prosecution:
Chiu does not explicitly disclose administering the surgery treatment to the subject, as claimed. However, Chiu discloses surgically resecting tumors from the subject (i.e. administering surgery) ([0140]), which suggests performing surgery on the subject. Chiu further discloses the size analysis can be performed after surgical resection of a tumor and compared to the size analysis before surgery to see changes in fractional tumor DNA concentration and determine how successful the treatment was ([0140]-[0141]; [0155]; [0162], e.g. change pre- and post- treatment used to determine how successful the treatment was), such that surgery was performed after analyzing a fractional tumor DNA concentration (i.e. based on the comparison, given the fragmentation profile represents a % tumor fraction as discussed above).
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 modified the method of Chiu to have administered a surgery to the subject based on the comparison, as suggested by Chiu ([0140]). One of ordinary skill in the art would have been motivated to modify Chiu with the suggestion of Chiu in order to administer the surgery to the subject, allowing for the determination of changes in fractional tumor DNA concentration after surgery and how successful a treatment was, as shown by Chiu ([0140]-[0141]; [0155]). This modification would have had a reasonable expectation of success given Chiu suggest monitoring surgical treatment.
Therefore, the invention is prima facie obvious.
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Chiu in view of Sims and Maggi, as applied to claim 68 above, and further in view of Lo (2014). The basis for this rejection is the same as previously presented.
Cited reference: Lo et al., US 2014/0080715 A1 (previously cited);
Regarding claim 75¸ Chiu in view of Sims and Maggi, make obvious the method of claim 68 as applied above.
Regarding claim 75, Chiu in view of Sims and Maggi, does not disclose the mapped sequences comprise between ten thousand and one hundred thousand genomic intervals.
However, regarding claim 75, Lo further discloses determining the cell-free DNA fragmentation profile includes mapping sequence reads to the human reference genome ([0066]), dividing the genome into bins of particular sizes, including dividing the genome into bins of 500 kb or 100 kb bins ([0181]), which would obtain mapped sequences comprising 27,340 genomic intervals (i.e. between 10,000 and 100,000 genomic intervals (FIG. 26C; [0037], e.g. 1 Mb bins across the genome correspond to 2734 bins, such that 100 kb bins would correspond to 27340 bins). Lo et al. further discloses dividing the genome into 10 Mb, 5 Mb, 2 Mb, 1 Mb, 500 kb, 100 kb bins allows the analysis to be adjusted to the desired level of resolution ([0181]).
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 Chiu to have used between ten thousand and one hundred thousand genomic intervals, as shown by Lo (FIG. 26C; [0037]; [0181]), thus obtaining mapped sequences comprising between ten thousand and one hundred thousand genomic intervals. One of ordinary skill in the art would have been motivated to combine the methods of Chiu and Lo in order to increase the resolution of the cell-free DNA fragmentation profile analysis, as shown by Lo ([0181]), and because Chiu also discloses the size analyses can be performed for bins of the same length ([0176]). This modification would have had a reasonable expectation of success because Chiu. already shows the analyses can be performed for multiple bins in the genome ([0176]).
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 29 Dec. 2025 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that the cited references do not teach or suggest a cfDNA fragmentation profile comprising a cfDNA fragment length distribution, position dependent fragmentation metrics across the whole genome or subgenomic intervals, a ratio of small cfDNA fragments to large cfDNA fragments (as claimed), and a sequence coverage of at least one of the small and the large cfDNA fragments across the genome (Applicant’s remarks at pg. 12, para. 2).
This argument is not persuasive. Applicant has not considered the newly cited portions of Chiu discussed above necessitated by the claim amendments. Chiu shows determining a size profile including size parameters ([0051]; [0099]), wherein the size parameter include a histogram providing a distribution of DNA fragments ate various sizes (i.e. cfDNA fragment length distribution). Chiu further discloses determining cfDNA fragmentation size parameter for each of different sets of regions in the genome ([0019]; [0099]; [0166]; [0176]-[0177], e.g. “a different size value can be determined for each genomic region”), such that a size parameter is determined for a subgenomic intervals (i.e. position dependent fragmentation metrics across subgenomic intervals). Chiu discloses the size parameters include a ratio of the amount of DNA fragments of 100 to 150 base pairs in length to the amount of DNA fragments of 163 to 169 base pairs in length (i.e. a ratio of smaller to larger cfDNA fragments) ([0019]; [0099]; FIG. 5; FIG. 20). Last, Chiu makes obvious the sequence coverage of small and/or large cfDNA fragments as applied in the above rejection and as discussed in the previous rejection.
Applicant remarks the references do not teach using position-dependent cfDNA fragmentation profiles from a plurality of subjects with cancer and healthy subjects (Applicant’s remarks at pg. 12, para. 2).
This argument is not persuasive because the step of predicting, by a machine learning model using position-dependent cfDNA fragmentation profiles from a plurality of subjects with cancer and healthy subjects is not required under the broadest reasonable interpretation of the claims, as explained above in claim interpretation and in the above rejection.
Applicant remarks that Chiu does not disclose position-dependent genome-wide analysis, and Chiu’s “bins” are not position-dependent fragmentation analysis because Chiu discloses bins n the context of analyzing copy number changes and not position-dependent fragmentation metrics for cancer detection, and the current application shows analyzing position-dependent fragmentation metrics is critical to improved sensitivity (Applicant’s remarks at pg. 12, para. 3).
This argument is not persuasive. Claim 68 requires the fragmentation profile of the subject includes “position dependent fragmentation metrics across the whole genome or subgenomic intervals”, and thus a genome-wide analysis is not required in claim 68. As explained in the above rejection, Chiu explicitly discloses that the size parameters may be determined for each genomic region in a set of genomic regions ([0176]-[0177]). Given the size parameters are determined for different regions, this clearly discloses “position dependent fragmentation metrics” in subgenomic intervals.
In response to applicant's argument that the instant fragment profile increases diagnostic sensitivity, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Therefore, because the fragmentation profile of Chiu in view of Sims, Maggi, and Lo, is the same as the fragmentation profile in the instant claims, the advantage recognized by Applicant would flow naturally following the fragmentation profile of the prior art.
Applicant remarks that Chiu uses a ratio of small to large fragments as a single numerical value while the claimed invention determines the fragment length distribution is “more variable”, which the specification demonstrates is measured by correlation analysis (Applicant’s remarks at pg. 12, para. 4).
This argument is not persuasive. It is improper to import claim limitations from the specification. See MPEP 2111.01 II. The claims do not require that the variability is determined by a correlation analysis. Applicant previously argued that Chiu does not disclose there is higher variability in fragment length distributions indicates the subject has cancer, which was responded to in detail in the previous Office action mailed 24 Sept. 2025 (see para. [121]-[123] of the previous Office action mailed 24 Sept. 2025). Applicant does not address this response and instead merely repeats the assertion that Chiu does not disclose the determination of “more variable” fragment lengths.
Applicant remarks Sims, Maggi, and Lo do not remedy the deficiencies of Chiu discussed above (Applicant’s remarks at pg. 12, para. 5 to pg. 13, para. 3).
This argument is not persuasive for the reasons discussed above with respect to Chiu, and because Sims an Maggi are not relied upon for these limitations.
Applicant remarks the current application demonstrates unexpected results by disclosing 80% sensitivity at 95%, and discloses detection of 79% of patients with resectable cancer, provides superior performance compared to prior art methods because position-dependent analysis is critical, and that the results would not have been expected from combining Chiu’s fetal DNA detection with low-coverage sequencing (Applicant’s remarks at pg. 13, para. 4 to pg. 14, para. 2).
This argument is not persuasive. As discussed above, Chiu does disclose using position-dependent analysis of size metrics, and furthermore, the claims do not require any particular accuracy or sensitivity.
Furthermore, in response to applicant's argument that the instant fragment profile increases diagnostic accuracy and/or sensitivity, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Therefore, because the fragmentation profile of Chiu in view of Sims, Maggi, and Lo, is the same as the fragmentation profile in the instant claims, the advantage recognized by Applicant would flow naturally following the fragmentation profile of the prior art.
Applicant remarks, regarding claim 75, that Lo 2014 does not remedy the deficiencies of Chiu, Sims, Maggi, and Lo and thus the rejection should be withdrawn (Applicant’s remarks at pg. 15, para. 2-4).
This argument is not persuasive for the reasons discussed above with respect to claim 68.
Double Patenting
The terminal Disclaimer filed 06 March 2023 over Patent Numbers 10,982,279 and 10,975,431 was approved 06 March 2023.
The provisional rejections of claims 70 and 80-81 on the ground of nonstatutory double patenting in the previous Office action has been withdrawn in view of the cancellation of these claims received 26 Jan. 2026.
The 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 68, 73-76, 78-79, 82-83, 85, 88, and 100 and provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-11, and 14-20 of copending Application No. 17/056,726 in view of Chiu (2013). Newly recited portions are necessitated by claim amendment.
Cited reference: Lo et al. (referred to as Chiu) (US 2013/0237431 A1 (previously cited).
Reference claims 1, 4, 9-11, 14-15 disclose the limitations of instant claim 68 except for the limitations discussed below:
First, while the reference claims do not disclose predicting by a machine learning mode, a tissue of origin for the cancer if the subject has cancer. However, this limitation is not required under the broadest reasonable interpretation of the claims. Furthermore, given the instant claims require this contingent machine learning step, the scope of the claims are not the same.
Furthermore, regarding instant claim 68¸ the reference claims do not explicitly disclose determining that a determined cfDNA fragment length distribution in the subject is more variable than a reference fragment length distribution, to determine the subject has or is at risk of having cancer. Instead, reference claim 14 discloses determining a cfDNA fragmentation profile, which comprises a length distribution (reference claim 7), is different than a reference cfDNA fragmentation profile, indicting the subject has cancer.
However, Chiu does disclose comparing a size parameter determined from cfDNA fragments (i.e. a cfDNA fragmentation profile) of a subject to a reference size parameter (i.e. a reference cfDNA fragmentation profile), and determining that the ratio of small to large cfDNA in the subject exceeds the reference indicates a higher likelihood the cancer exists (i.e. the subject is at risk for cancer) ([0174]); FIG. 16A, e.g. higher size ratio corresponds to higher tumor %).Chiu further discloses that tumor-derived DNA is shorter than non-cancer derived DNA in a cancer patient’s genome, and similarly fetal cell-free DNA molecules are generally shorter than the maternally derived ones ([0056]). Chiu discloses the larger number of shorter fragments causes a shift in the size profile of plasma DNA to the shorter spectrum ([0056]), and further provides an examples of size distributions of total cell-free DNA compared to fetal cell-free DNA in a maternal plasma sample (FIG. 1; [0058]) in addition to size distributions of cell-free DNA in maternal plasma with different percentages of fetal cell-free DNA (FIG. 2A-B). These size distributions of Chiu clearly demonstrate the shift in fragments of larger size to a smaller size as fetal cell-free DNA concentrations increases results in a flattening of the distribution (i.e. an increased variability) as fragments around the peak of the left-skewed distribution shift to lower sizes (FIG. 1 and 2A-B).
Therefore, it is prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have modified the detected difference in a fragment size distibution in the subject relative to the reference of the reference claims, to have detected or determined the cfDNA fragment length distribution in the subject is more variable than the reference distribution, based on the comparison, as suggested by Chiu, given Chiu demonstrates the shift from large to small fragments, as measured in the size ratio, results in a flattened, more variable distribution, as discussed above,. This modification would have had a reasonable expectation of success given one of ordinary skill in the art would have recognize the increased ratio of small to large fragments is indicative of a flatter, more variable distribution compared to the reference, as demonstrated by Chiu in FIG. 1-2, such that both reflect cancer in the subject.
Regarding instant claim 73, reference claim 17 discloses the limitation.
Regarding instant claims 74 and 88, reference claim 1 discloses the sample Is plasma, which is necessarily from blood.
Regarding instant claims 75-76, reference claims 2-3 disclose these limitations.
Regarding instant claims 78, reference claims 10 and 14 discloses these limitations.
Regarding instant claims 79, reference claims 6 and 12 disclose this limitations.
Regarding instant claim 82, reference claim 4 discloses this limitation given the coverage is low (e.g. 1x).
Regarding instant claim 83, reference claim 1 discloses the coverage is low, which makes obvious this limitation given there are finite options.
Regarding instant claim 85, the limitation is not required under the broadest reasonable interpretation of the claims.
Regarding instant claim 100¸ the reference claims do not disclose administering a treatment as claimed. However, this limitation is not required by the claims, and therefore, this claim is rejected for the same reasons as instant claim 68.
Regardless, it is noted that Chiu discloses surgically resecting tumors from the subject (i.e. administering surgery) ([0140]), which suggests that an instruction to perform surgery on the subject was provided, and further discloses that any of the method steps can be performed partially with a computer system ([0187]), Chiu further discloses the size analysis can be performed after surgical resection of a tumor and compared to the size analysis before surgery to see changes in fractional tumor DNA concentration and determine how successful the treatment was ([0140]-[0141]; [0155]; [0162], e.g. change pre- and post- treatment used to determine how successful the treatment was), such that an instruction to administer surgery was provided after analyzing a fractional tumor DNA concentration (i.e. based on the comparison, given the fragmentation profile represents a % tumor fraction as discussed above).
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 modified the method of the reference claims to have administered a surgery to the subject based on the comparison, as suggested by Chiu ([0140]). One of ordinary skill in the art would have been motivated to modify the method of the reference claims with the suggestion of Chiu in order to administer the surgery to the subject, allowing for the determination of changes in fractional tumor DNA concentration after surgery and how successful a treatment was, as shown by Chiu ([0140]-[0141]; [0155]). This modification would have had a reasonable expectation of success given Chiu suggest monitoring surgical treatment.
This is a provisional nonstatutory double patenting rejection.
Claims 68, 73-74, 76, 78-79, 82-83, 85, 88, and 100 and provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70-73, and 76-78 of copending Application No. 17/842,893 in view of Chiu (2013). Newly recited portions are necessitated by claim amendment.
Cited reference: Lo et al. (referred to as Chiu) (US 2013/0237431 A1 (previously cited); and
Regarding instant claim 68¸ reference claim 68 discloses the limitations of instant claim 68 except for the specifically recited small to large fragment ratios, determining the subject’s fragment distribution is more variable than the reference distribution indicates cancer, or the specific genomic intervals in the instant claims.
Regarding instant claim 85, the limitations are not required under the broadest reasonable interpretation of the claims.
Regarding instant claims 73-74 and 88, the reference claim 1 discloses the analyzed fragments are nucleosome protected fragments and the sample is a plasma sample from blood.
The reference claims do not disclose the following:
Regarding instant claim 68, the reference claims do not disclose the specifically recited small to large fragment ratios, the specific genomic intervals in the instant claims, or the enrichment of nucleosome protected cfDNA in plasma.
Regarding instant claim 78, reference claim 78 discloses the profile can be over a subgenomic interval or the whole genome, which makes obvious determining the profile for an interval over the genome.
Regarding instant claim 82, reference claim 78 discloses the profile is determined over the entire genome and reference claim 77 discloses the coverage can be 2x, which shows the profile includes more than 20,000 reads.
Regarding instant claim 83, reference claim 77 shows this limitation.
The reference claims further do not disclose the limitations of instant claims 76 and 79.
However, regarding instant claim 68, Chiu discloses a method for determining a cell-free DNA fragmentation profile for a subject (Abstract) comprising the following steps: Chiu discloses that the sequence reads were aligned (i.e. mapped) to the human reference genome ([0067]; [0140]), and further shows dividing the genome into bins ([0176], thus obtaining genomic intervals of mapped sequences. Chiu further shows the genomic intervals can be a 1 Mb region (i.e. a million base pairs), which is between thousands of bases pairs and millions of base pairs ([0176]).
Chiu shows analyzing each bin (i.e. the genomic intervals in multiple windows each covering a portion of a genome and being a genomic interval of the genomic intervals) ([0176]) and determining the sizes (i.e. lengths) of the DNA fragments within the bins (i.e. determining cfDNA fragment lengths within each of the mapped windows) ([0140]; [0177]).
Chiu shows determining a size parameter (i.e. cfDNA fragmentation profile) comprising a ratio of the amount of DNA fragments of 100 to 150 base pairs in length to the amount of DNA fragments of 163 to 169 base pairs in length (i.e. a ratio of smaller to larger cfDNA fragments) ([0019]; [0099]; FIG. 5; FIG. 20). Regarding the claimed range of large fragments of 151 bp to 200 bp in length, the range of 163 to 169 bp in length is within the claimed range of 151 bp to 200 bp and therefore anticipates the range. See MPEP 2131.03.
Chiu discloses comparing the size parameter (i.e. the cfDNA fragmentation profile) of the subject to a reference size parameter (i.e. a reference cfDNA fragmentation profile), and determining that the ratio of small to large cfDNA in the subject exceeds the reference indicates a higher likelihood the cancer exists (i.e. the subject is at risk for cancer) ([0174]); FIG. 16A, e.g. higher size ratio corresponds to higher tumor %) and a higher size ratio corresponds to a higher variability in fragment sizes (i.e. both small and large fragments present) (i.e. higher variability indicates higher cancer risk). Chiu further discloses that tumor-derived DNA is shorter than non-cancer derived DNA in a cancer patient’s genome, and similarly fetal cell-free DNA molecules are generally shorter than the maternally derived ones ([0056]). Chiu discloses the larger number of shorter fragments causes a shift in the size profile of plasma DNA to the shorter spectrum ([0056]), and further provides an examples of size distributions of total cell-free DNA compared to fetal cell-free DNA in a maternal plasma sample (FIG. 1; [0058]) in addition to size distributions of cell-free DNA in maternal plasma with different percentages of fetal cell-free DNA (FIG. 2A-B). These size distributions of Chiu clearly demonstrate the shift in fragments of larger size to a smaller size as fetal cell-free DNA concentrations increases results in a flattening of the distribution (i.e. an increased variability) as fragments around the peak of the left-skewed distribution shift to lower sizes (FIG. 1 and 2A-B).
Regarding instant claim 76, Chiu further discloses the bins can be specific chromosomes (i.e. non-overlapping regions) ([0176]).
Regarding instant claims 79, Chiu further discloses the cfDNA fragmentation profile can comprise a cfDNA fragment length histogram (i.e. distribution) ([0066]; FIG. 1-2), as recited in claim 80, which includes information regarding a median fragment size, as recited in claim 79 ([0066]; [0010], e.g. the histogram includes information on statistical measures of the size profile).
It would have bene 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 used the cfDNA fragmentation profile of Chiu to detect a fragment distribution is more variable than the reference distribution to determine cancer, given Chiu discloses the fragmentation profile can be used to detect cancer, including a tumor fraction (FIG. 18-20; [0063]; [0169]), and the claimed size ratio is representative of variation of a size distribution (FIG. 1-2). One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Chiu to provide a tumor fraction of the subject, as shown by Chiu ([0169]). This modification would have had a reasonable expectation of success given both the reference claims and Chiu analyze cfDNA fragment sizes.
Regarding instant claim 100, the reference claims do not disclose administering a treatment as claimed. However, this step is not required under the broadest reasonable interpretation of the claims, and thus is rejected for the same reasons as instant claim 68.
Regardless, Chiu discloses surgically resecting tumors from the subject (i.e. administering surgery) ([0140]), which suggests that an instruction to perform surgery on the subject was provided, and further discloses that any of the method steps can be performed partially with a computer system ([0187]), Chiu further discloses the size analysis can be performed after surgical resection of a tumor and compared to the size analysis before surgery to see changes in fractional tumor DNA concentration and determine how successful the treatment was ([0140]-[0141]; [0155]; [0162], e.g. change pre- and post- treatment used to determine how successful the treatment was), such that an instruction to administer surgery was provided after analyzing a fractional tumor DNA concentration (i.e. based on the comparison, given the fragmentation profile represents a % tumor fraction as discussed above).
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 modified the method of the reference claims to have administered a surgery to the subject based on the comparison, as suggested by Chiu ([0140]). One of ordinary skill in the art would have been motivated to modify the method of the reference claims with the suggestion of Chiu in order to administer the surgery to the subject, allowing for the determination of changes in fractional tumor DNA concentration after surgery and how successful a treatment was, as shown by Chiu ([0140]-[0141]; [0155]). This modification would have had a reasonable expectation of success given Chiu suggest monitoring surgical treatment.
Claim 75 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70-73, 76-78, and 85-85 of copending Application No. 17/842,893 in view Chiu (2013), as applied to claim 68 above, and further in view of Lo (2014). Any newly recited portion is necessitated by claim amendment.
Cited reference: Lo et al., US 2014/0080715 A1 (previously cited);
Regarding claim 75, The reference claims in view of Chiu does not disclose the mapped sequences comprise between ten thousand and one hundred thousand genomic intervals.
However, regarding claim 75, Lo further discloses determining the cell-free DNA fragmentation profile includes mapping sequence reads to the human reference genome ([0066]), dividing the genome into bins of particular sizes, including dividing the genome into bins of 500 kb or 100 kb bins ([0181]), which would obtain mapped sequences comprising 27,340 genomic intervals (i.e. between 10,000 and 100,000 genomic intervals (FIG. 26C; [0037], e.g. 1 Mb bins across the genome correspond to 2734 bins, such that 100 kb bins would correspond to 27340 bins). Lo et al. further discloses dividing the genome into 10 Mb, 5 Mb, 2 Mb, 1 Mb, 500 kb, 100 kb bins allows the analysis to be adjusted to the desired level of resolution ([0181]).
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 in view of Chiu to have used between ten thousand and one hundred thousand genomic intervals, as shown by Lo (FIG. 26C; [0037]; [0181]), thus obtaining mapped sequences comprising between ten thousand and one hundred thousand genomic intervals. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims in view of Chiu and Lo in order to increase the resolution of the cell-free DNA fragmentation profile analysis, as shown by Lo ([0181]), and because Chiu also discloses the size analyses can be performed for bins of the same length ([0176]). This modification would have had a reasonable expectation of success because Chiu. already shows the analyses can be performed for multiple bins in the genome ([0176]).
Response to Arguments
Applicant's arguments filed 29 Dec. 2025 regarding double patenting have been fully considered but they are not persuasive.
Applicant remarks that the cited applications and the present claims are distinct, and for example independent claim 68 recites “…determining, that the cfDNA fragment…is more variable than a reference cfDNA fragment length distribution…; if the subject has cancer, predicting…”, which are not recited in the cited application claims and thus the provisional rejection should be withdrawn (Applicant’s remarks at pg. 15, para. 5 to pg. 17, para. 2).
This argument is not persuasive. While the specific comparison determining the fragment length distribution is more variable than a reference cfDNA fragment length distribution is not recited in the reference claims, this limitation is disclosed by Chiu as applied in the above rejection. Furthermore, the predicting limitation is contingent on the subject having cancer, which is not required by the instant claims. Therefore, the instant claims are not patentably distinct from the reference claims, and instead the instant claims are an obvious variant of the reference claims.
Conclusion
No claims are allowed.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685