DETAILED ACTION
Applicant’s response, filed 16 March 2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 5, 7-8, 12-13, 15, and 21-68 are cancelled.
Claims 1-4, 6, 9-11, 14, and 16-20 are pending.
Claims 1-4, 6, 9-11, 14, and 16-20 are rejected.
Priority
The effective filing date of the claimed invention is 18 May 2018.
Claim Objections
The objection to claim 14 in the Office action mailed 16 Dec. 2025 has been withdrawn in view of claim amendments filed 16 March 2026.
Claim Interpretation
Claim 20 recites “…in the mammal is lower than a correlation of fragment ratios to reference DNA ratios of the reference cfDNA fragment ratios in a healthy mammal”. Applicant’s specification at pg. 16, lines 6-14 discloses a healthy mammal has a correlation of fragment ratios (e.g. a correlation of DNA fragment ratios to reference DNA ratios such as DNA fragment ratios from one or more healthy mammals) of about 1, and a mammal having cancer has a correlation of about 0.19 to 0.3, suggesting the fragment ratios of the mammal (i.e. of the fragmentation profile) are compared to reference fragment ratios from a healthy mammal (i.e. a reference sample). Therefore, in light of Applicant’s specification, claim 20 is interpreted to mean that the correlation of fragment ratios in the cfDNA fragmentation profile to the reference profile is lower than a correlation of fragment ratios of a reference to itself (i.e. reference DNA ratios). In other words, the correlation is lower than a correlation of 1.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 16 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 16 is indefinite for recitation of “The method of claim 15, wherein the reference….”. There is insufficient antecedent basis for the method of claim 15 because claim 15 is cancelled. For purpose of examination, claim 16 will be interpreted to depend from claim 14.
Claim Rejections - 35 USC § 101
The rejection of claims 1-4, 6, 8-11, and 14-20 under 35 U.S.C. 101 in the Office action mailed 16 Dec. 2025 has been withdrawn in view of claim amendments and cancellations received 16 March 2026.
Independent claims 1 and 14 recite an abstract idea that results in the identification of a mammal as having cancer, and further recite the additional element of “administering to the mammal identified as having cancer a cancer treatment, wherein the cancer treatment comprises an immune checkpoint inhibitor, an adaptive Tcell therapy, a chemotherapeutic agent, or a combination thereof, thereby treating the mammal”. Therefore, the claims integrate the recited judicial exception into the practical application of effecting a particular treatment for cancer. See MPEP 2106.04(d)(2).
Claim Rejections - 35 USC § 103
The rejection of claims 1-4, 6, and 9-11 under 35 U.S.C. 103 as being unpatentable over Lo (2016) in view of Sims (2014), as evidenced by Insilicase (2017) in the Office action mailed 16 Dec. 2025 has been withdrawn in view of claim amendments and cancellations received 16 March 2026.
The rejection of claims 14-20 under 35 U.S.C. 103 as being unpatentable over Lo (2016) in view of Sims (2014) and Chiu (2013) in the Office action mailed 16 Dec. 2025 has been withdrawn in view of claim amendments and cancellations received 16 March 2026.
However, after further consideration, new grounds of rejection are set forth below.
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.
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 1-4, 6, 9-11, 14, and 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chiu (2013) in view of Sims (2014), Lo (2016), and Heitzer (2015), as evidenced by Insilicase (2017). This rejection is newly recited and necessitated by claim amendment.
Cited references:
Lo et al. (hereinafter Chiu) US 2013/0237431 A1 (cited in IDS filed 29 April 2024; previously cited); and
Sims et al., Sequencing depth and coverage: key considerations in genomic analysis, 2014, Nat Rev Genet, 15, pg. 121-132 (cited in IDS filed 29 April 2024; previously cited);
Lo et al., US 2016/0201142 A1 (previously cited);
Heitzer et al., Circulating Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123 (newly cited); and
Insilicase, Chromosome lengths, 2017, pg. 1-2 (previously cited).
Regarding independent claims 1 and 14, 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 (Abstract; [0047]; [0140]), extracting and purifying cfDNA fragments from the plasma sample ([0145]), and 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 aligning (i.e. mapping) the sequence reads to the human reference genome ([0067]; [0140]). Chiu discloses aligning the reads to the genome provides a length of each fragment (i.e. sized-based data) ([0048]), and further discloses dividing the genome into bins (i.e. windows) ([0176]), thus obtaining positional and size-based data in windows of mapped sequences.
Chiu discloses analyzing the bins of mapped reads to determine a size profile of DNA fragments within one or more predetermined regions of a genome (i.e. subgenomic intervals) ([0051];[0140]; [0176]-[0177], e.g. size analysis for multiple bins). Chiu discloses the size profile comprises size parameters ([0051]; [0099], wherein the size parameters include a histogram providing a distribution of DNA fragments at various sizes (i.e. a cfDNA fragment size distribution) and a number of DNA fragments of a particular size in a region (i.e. a coverage metric) for each subgenomic interval (i.e. position dependent fragmentation metrics across subgenomic intervals) ([0019]; [0071]; [0099]; [0101]-[0106], e.g. ratios, frequency counters of histogram; [0166]; [0176]-[0177]). Chiu further 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. the ratio of small to large cfDNA fragments in said windows) ([0019]; [0099]; FIG. 5; FIG. 210).
Chiu discloses analyzing a size parameter (i.e. the cfDNA fragmentation profile) of the subject against a reference size parameter (i.e. a reference cfDNA fragmentation profile) determined from a healthy human (i.e. mammal) subject ([0047]; [0172], e.g. size parameter compared to reference value). Chiu further discloses identifying the subject as having cancer is performed using a linear regression algorithm trained on training size values, that takes the subject’s size parameters as input ([0076]-[0078; [0148]; [0153]), such that the analyzing is performed via machine learning as recited in claim 14.
Chiu discloses determining the subject has cancer when the size parameter of the subject is statistically different from the reference parameter ([0173]; [0178]).
Regarding independent claims 1 and 14, Chiu does not disclose the following:
First, regarding claims 1 and 14, Chiu does not disclose the whole genome sequencing is low-coverage sequencing.
However, 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 to 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).
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 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, as discussed above, 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). This modification would have had a reasonable expectation of success because Sims discloses high depth of coverage is required to accurately call SNVs, which is not required by Chiu, and thus the sequencing method of Sims is applicable to the method of Chiu.
Further regarding claims 1 and 14, while Chiu discloses identifying the mammal as having cancer based on detecting a difference between the size parameter and reference size parameter, Chiu does not explicitly disclosed the identification of cancer is based on detecting that the cfDNA fragmentation profile of the mammal is more variable than the reference cfDNA fragmentation profile.
However, Chiu makes obvious this limitation for the following reasons:
Regarding claims 1 and 14, as discussed above, Chiu does disclose comparing a ratio of small to large fragments parameter (i.e. of the cfDNA fragmentation profile) of the subject to a reference ratio (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, indicating a higher likelihood cancer exists ([0174]; FIG. 16A).
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/tumor 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; FIG. 15, e.g. see increased proportion of short fragments in higher %tumor samples).
It is noted that while the actual depicted examples of fragment size distributions in Chiu correspond to fetal DNA, Lo also discloses the shift from large to small cfDNA fragments with increasing tumor fractions, discussed above by Chiu, results in more variable distributions (Lo: [0186]; FIG. 18).
Therefore, the detection of an increased in the ratio of short to large fragments associated with cancer is considered to read on, or make obvious, detecting that the cfDNA fragmentation profile is more variable than the reference profile (i.e. detecting the shift in the distribution toward lower fragments).
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 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 and Lo demonstrate the shift from large to small fragments indicative of cancer, as measured in the size ratio, results in a flattened, more variable distribution, as discussed above. One of ordinary skill in the art would recognize that the detected increased ratio could be substituted for the detection of increased variation with predictable results given, Chiu demonstrates the shift from large to small fragments (reflected in the ratio) serves as a measure of a more variable distribution, and Lo clearly demonstrates that increased variability in size distributions with higher tumor fractions (FIG. 18).
Last regarding claims 1 and 14, While, Chiu generally discloses using the above method to monitor a patient before and after treatment and determine treatment success ([0162]), Chiu does not disclose administering to the mammal identified as having cancer, a cancer treatment comprising an immune checkpoint inhibitor, an adaptive T cell therapy, a chemotherapeutic agent, or a combination thereof.
However, Heitzer overviews the use of circulating tumor DNA as a liquid biopsy for cancer detection (Abstract), as performed in Chiu, and discloses that liquid biopsies can be used to indicate if a specific treatment is applicable or will reduce the risk of recurrence or progression (pg. 117, col. 1, para. 2). Chiu discloses liquid biopsies are applied to detect cancer specific alleles in plasma at baseline and before each cycle of chemotherapy (pg. 120, col. 2, para. 2), demonstrating the administration of chemotherapy in response to detection of cancer.
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 in view of Sims to have further administered chemotherapy in response to detecting the cancer in the subject, as shown by Heitzer above. One of ordinary skill in the art would have been motivated to combine the methods of Chiu in view of Sims and Heitzer in order to administer an applicable treatment that will reduce the risk of cancer progression, as shown by Heitzer (pg. 117, col. 1, para. 2). This modification would have had a reasonable expectation of success given Chiu discloses a method for performing a liquid biopsy to detect cancer, and Heitzer discusses applications of such liquid biopsies include informing treatment decisions.
Regarding claim 2, 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 1 Mbs bins of the genome ([0176]), such that the mapped sequences comprise tens to thousands of windows, as evidenced by Insilicase, which shows the lengths of human chromosomes (pg. 1, see column of lengths (bp) for chromosomes 1-22 ).
Regarding claim 3, Chiu further discloses the analysis may be performed for specific chromosomes (i.e. non-overlapping windows) ([0176]).
Regarding claim 4, Chiu further discloses the analysis may be performed for specific chromosomes (i.e. non-overlapping windows) ([0176]), which each inherently comprise 5 million base pairs, as evidenced by Insilicase (pg. 1, see column of lengths (bp) for chromosomes 1-22 ).
Regarding claim 6, Chiu further discloses the cfDNA fragmentation profile can comprise a cfDNA fragment length histogram (i.e. distribution) ([0066]; FIG. 1-2), which necessarily includes a median fragment size ([0066]; [0010], e.g. the histogram includes information on statistical measures of the size profile).
Regarding claims 9-11, while Chiu discloses the profile includes amounts of small/large fragments (i.e. a metric of coverage), Chiu does not explicitly disclose the cfDNA fragmentation profile comprises the sequence coverage of the small and/or large DNA fragments.
However, further regarding claims 9-11, 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 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 Chiu 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 given 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 cf DNA fragments across the genome with the amount of small and/or large cell-free DNA fragments across the genome of Chiu, given both represent an amount of small and/or large cf DNA 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.
Regarding claim 16, Chiu discloses the reference cfDNA fragmentation profile was generated from a cfDNA fragmentation profile of a sample of a healthy human ([0172], e.g. reference values from samples of healthy organism).
Regarding claim 17 Chiu does not explicitly 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 (Abstract)), and further discloses the sizes of circulating DNA resembles the size of mononucleosomal DNA (i.e. nucleosome cfDNA) ([0057]; [0155]-[0156]), such that the reference size distribution reflects nucleosomal cfDNA (i.e. a reference nucleosomal cfDNA fragmentation profile). 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 claims 18-19, Chiu does not explicitly disclose the median fragment size of the cfDNA fragmentation profile is shorter than a median fragment size of the reference cfDNA fragmentation profile, or that the median fragment size of the cfDNA fragmentation profile differs by at least 10 nucleotides as compared to a median of a fragment size distribution of the reference profile.
However, Lo does disclose the above limitations.
Regarding claim 18, Lo similarly discloses a method for detecting cancer using a cell-free DNA fragmentation profile of a human subject (i.e. mammal)(Abstract; [0043]), which comprises comparing a cfDNA fragment size profile comprising statistical values of a subject to a reference statistical value to detect cancer (claim 5; [0043]; [0049]; [0056]; [0063]; [0128], e.g. reference value is statistical value of size distribution; FIG. 1, #140). Lo discloses the statistical value of the size profile of the subject and the reference statistical value comprises a median fragment size ([0127], e.g. statistical value can be median of size distribution; [0128], e.g. reference value may be statistical value of distribution). Lo further discloses determining a difference between the statistical value of the subject and the reference statistical value (i.e. whether the statistical value of the subject is shorter or longer than the reference) ([0129]-[0130), and that the statistical value of the subject can be shorter than the reference ([0149]; claim 34).
Regarding claim 19, Lo further discloses the size profile of the subject comprises a size distribution, including a median ([0137]; [0146]; FIG. 14). While Lo does not explicitly disclose the medians differ by at least 10 nucleotides, Lo discloses the median decreases with increased tumor fraction (FIG. 25; FIG. 26-27; [0211], e.g. size distribution of cancer is shorter than controls). Thus one of ordinary skill in the art would recognize that the median may differ by more than 10 when the subject has a high tumor percentage compared to a healthy reference.
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 a size parameter of a median fragment size shorter by at least 10 nucleotides than the median fragment size of the reference profile, as shown by Lo above. One of ordinary skill in the art would have been motivated to combine the median fragment size parameter of Lo with the method of Chiu, given Lo discloses the median fragment size decreases with increased tumor fraction (FIG. 25; FIG. 26-27; [0211], e.g. size distribution of cancer is shorter than controls), thus providing a reliable statistic for detecting a tumor in a sample as performed in Chiu ([0008]). This modification would have had a reasonable expectation of success given Chiu discloses creating a fragment size profile including a size histogram, which comprises a median, and thus comparing a median fragment size of the subject with a median of a reference profile to detect a 10 nucleotide difference as performed in Lo is applicable to the fragmentation profile of Chiu.
Regarding claim 20, Chiu discloses the cfDNA fragment ratios of the subject identified with cancer are different than the reference (and thus a healthy subject without cancer does not have a statistical difference with the reference values) ([0178]), and therefore, the fragment ratios of a reference profile would necessarily be more correlated with itself (i.e. reference ratios) than the cfDNA fragment ratios of the subject to the reference fragment ratios.
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 16 March 2026 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks Lo does not disclose or suggest administering a cancer treatment to a mammal, does not disclose calculating a ratio of fragments in the 100-150 bp range to fragments in the 151-220 bp range, and does not disclose detecting increased variability of a fragmentation profile comprising the specific ratio (Applicant’s remarks at pg. 11, para. 3 to pg. 12, para. 3 and pg. 13, para. 5-6). Applicant further remarks the above deficiencies of Lo cannot be cured by Sims or Insilicase which does not disclose cfDNA fragmentation profiles (Applicant’s remarks at pg. 12, para. 4 to pg. 13, para. 2).
This argument is not persuasive because Lo is not relied upon for the administering a treatment or calculating a ratio in the new grounds of rejections set forth above. While Lo is partially relied upon for the detection of increased variability, this argument is addressed in more detail below with respect to Chiu.
Applicant remarks that Chiu is directed to determining fractional concentrations of clinically relevant DNA in a mixture of DNA based on amounts of DNA fragments at various sizes, and in contrast the amended claims detect cancer by identifying increased variability in a cfDNA fragmentation profile compared to a reference and not estimating a fractional concentration (Applicant’s remarks at pg. 13, para. 6 to pg. 14, para. 1). Applicant remarks that Chiu does not disclose detecting a cfDNA fragmentation profile is “more variable” than a reference profile as required by the amended claims (Applicant’s remarks at pg. 14, para. 2). Applicant further remarks that Chiu’s linear regression model is not the machine learning model recited in the amended claims because Chiu’s model does not detect increased variability in a fragmentation profile to identify cancer (Applicant’s remarks at pg. 14, para. 3 to pg. 15, para. 1).
This argument is not persuasive. While Chiu does not explicitly mention detecting the fragment size profile is more variable than a reference profile, Chiu makes obvious that the size parameter pertaining to the ratio of small to large fragments is effectively a measure of variability of the size distributions. As explained in the above rejection, Chiu 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). Lo also discloses the shift from large to small cfDNA fragments with increasing tumor fractions, discussed above by Chiu, results in more variable distributions (Lo: [0186]; FIG. 18).
Chiu then detects the cancer by comparing a ratio of small (100 to 150 base pairs) to large fragments (163 to 169 base pairs), and determining that the ratio of small (100 to 150 base pairs) to large (163 to 169 base pairs) cfDNA fragments exceed the reference ratio indicates a higher likelihood cancer exists ([0174]). The ratio of small to large fragments being higher than the reference is due to an increased number of small fragments (from large fragments) in the numerator of the ratio, which demonstrates that the increased variability (distribution flattening) is detected via the ratio.
It is further noted that the claims do not recite any particular metrics of variability that are being used that would distinguish from Chiu. Instead, the claims encompass using a ratio of small to large fragments to detect cancer, and detecting the increased variability via this ratio, as performed in Chiu.
With respect to the machine learning model of Chiu, the machine learning model predicts a fractional concentration of DNA based on the size ratio of small to large fragments (i.e. indicative of variation), as explained in the above rejection. Chiu discloses an increase in cell-free DNA concentration results in the flattening of the distribution (i.e. the increased variability), and thus the machine learning model of Chiu similarly detects increased variability in the size profile via the ratio of small to large fragments as input into the machine learning model.
If Applicant detects variation in the distributions using some size metric different than the metric used in Chiu, it is suggested Applicant amend the claims to specify how the cfDNA fragmentation profile of the subject is determined to be more variable than the reference.
Applicant remarks that Lo in view of Sims and Chiu do not disclose the present claims alone or in combination, and therefore the rejection should be withdrawn (Applicant’s remarks at pg. 15, para. 2).
This argument is not persuasive for the same reasons discussed above.
Double Patenting
The various provisional rejections and/or rejections of claims 8 and 15 on the basis of nonprovisional double patenting in the Office action mailed 16 Dec. 2025 have been withdrawn in view of the cancellation of these claims received 16 March 2026.
The rejection of claims 1-4, 6, and 9-11 on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. US10982279 B2, as evidenced by Lo (2016) in the Office action mailed 16 Dec. 2025 have been withdrawn in view of claim amendments received 16 March 2026. However, a new grounds of rejection over this U.S. Patent is set forth below in view of the amendment.
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 1-4, 6, 9-11, 14, and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70, 73-76, 78-83, 85, 88-97, and 100 of copending Application No. 17/204,892 (reference application). Any newly recited portion is necessitated by claim amendment.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 1, reference claim 68 discloses the limitations of instant clam 1, including processing the cfDNA fragments into libraries, subjecting the sequencing libraries to low genome sequencing, mapping the fragments to a genome to obtained windows of mapped sequences, and analyzing the windows to determine a fragmentation profile in each window. Reference claim 68 discloses the profile includes ratios of small to large fragments in each of multiple windows across the genome, and in reference claims 79-80 that the profile includes median fragment size and a fragment size distribution (i.e. fragment size distribution, coverage, and positional fragmentation metrics). It is noted reference claim 68 is narrower in scope than instant claim 1.
Regarding instant claim 2, reference claim 75 discloses the mapped sequences include ten thousand intervals (i.e. thousands of windows).
Regarding instant claim 3, reference claim 76 discloses the limitation of instant claim 3.
Regarding instant claim 4, reference claim 68 discloses the windows include millions of base pairs (i.e. about 5 million).
Regarding instant claim 6, reference claim 79 disclose the limitation of instant claim 6.
Regarding instant claims 8-11, reference claim 68 discloses the cfDNA fragmentation profile comprises the claimed ratio and sequence coverages of instant claims 8-11.
Regarding instant claim 14¸ reference claims 68, 90-92, and 95 disclose the method of instant claim 14. Specifically, reference claim 68 discloses the steps of determining the fragmentation profile as applied to instant claim 1 above, and claims 90-92 disclose the steps for identifying the subject as having cancer by determining the fragmentation profile based on a comparison of the cfDNA fragmentation profile to a reference profile. Reference claims 68 and 70 discloses the use of a machine learning in determining a type of cancer using the sizes. Reference claim 100 discloses administering the subject a cancer treatment.
Regarding instant claims 15-16, reference claims 95-96 disclose the reference cfDNA fragmentation profile was determined from a healthy subject.
Regarding instant claim 17, reference claim 73 discloses the limitation of instant claim 17.
Regarding instant claim 18, reference claim 79 discloses the median fragment size, which can be less variable to a reference profile as recited in reference claim 68.
Regarding instant claim 19¸ reference claims 68 and 80 discloses the fragment size distribution with size ratios, and the ratio of 100-150 to 151-200 fragments (i.e. an 11 nucleotide difference) can be compared to a reference to determine if the cfDNA profile is more variable than the reference.
Regarding instant claim 20, reference claim 68 discloses the limitations of instant claim 20.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 6, and 9-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 68-73, 76-77, 84, and 86 of copending Application No. 17/842,893 (reference application) in view of Lo (2016), evidenced by Sims. Any newly recited portion is necessitated by claim amendment. Although the claims at issue are not identical, they are not patentably distinct from each other because
Cited reference:
Lo et al., US 2016/0201142 A1 (previously cited); and
Sims et al., Sequencing depth and coverage: key considerations in genomic analysis, 2014, Nat Rev Genet, 15, pg. 121-132 (cited in IDS filed 29 April 2024; previously cited);
Regarding instant claim 1, reference claim 68 discloses processing cfDNA fragments from the sample into sequencing libraries and performing low coverage sequencing on the sequencing libraries, and further discloses the cfDNA fragmentation profile as claimed. Reference claim 86 discloses the ratio of small to large fragments.
The limitations of instant claim 1 not taught by the reference claims are discussed below.
Further regarding instant claim 1 the reference claims do not disclose mapping the sequenced fragments to a genome to obtain windows of mapped sequences or detecting an increased variation in the cfDNA fragmentation profile compared to the reference.
Further regarding instant claims 2-4, the reference claims do not disclose the mapped sequences comprise tends to thousands of windows, the windows or nonoverlapping, the windows comprise 5 million base pairs, and that a cfDNA fragmentation profile is determined in each window. However, these limitations are taught by Lo.
Regarding instant claims 6 and 9-11, the reference claims do not disclose the fragmentation profile includes a ratio of small to large cfDNA fragments, and a median fragment size, and the sequence coverage of small cfDNA fragments and/or of large cfDNA fragments.
Regarding instant claims 1-4, 6, and 9-11 Lo discloses a method for detecting cancer using a cell-free DNA fragmentation profile of a human subject (i.e. mammal)(Abstract; [0043]), which comprising subjecting sequencing libraries to whole genome sequencing to obtain sequenced fragments ([0216], Hi-Seq sequencing; [0056], e.g. genome-wide size profile created), aligning the sequence reads to a reference genome ([0062]), to obtain chromosomal regions of aligned sequences (claim 1; [0074];, e.g. each of a plurality of chromosomal regions analyzed), as recited in instant claim 1. Lo further discloses the size profiles of samples with tumor DNA shifts to the left due to the presence of shorter fragments from longer fragments, demonstrating the detection of increased variation in sizes in cancer ([0186]; FIG. 18)
Lo further discloses analyzing chromosomal regions (i.e. windows) to determine cfDNA sizes (i.e. fragment lengths) (claim 1, e.g. calculate statistical value of size distribution of reads of a particular region; FIG. 1 and 6, e.g. repeat for all regions). Regarding instant claim 2, Lo further discloses the reads are mapped to all 22 chromosomal regions (i.e. tens of windows) (Fig. 2; FIG. 7; [0012]). Regarding instant claim 3¸ Lo further discloses the chromosomal regions are nonoverlapping ([0094]; FIG. 2 and 7). Regarding instant claim 4, as discussed above, Lo further discloses the regions are 22 human chromosomal regions (Fig. 2; Fig. 7; [0012]), which each inherently comprise 5 million base pairs, as evidenced by Insilicase (pg. 1, see column of lengths (bp) for chromosomes 1-22 ). Regarding instant claim 6, Lo further discloses the fragmentation profile includes a median size of the size distribution ([0098]; [0127]). Regarding instant claim 7, Lo further discloses the cfDNA fragmentation profile comprises a size distribution ([0049]; [0098]; [0120]-[0121]). Regarding instant claims 9-11, Lo discloses the cfDNA fragmentation profiles comprises amounts of cfDNA fragments at a variety of sizes genome-wide ([0049]; [0056] and [0073], e.g. regions can be the whole genome; [0154]), including small and large DNA fragments ([0127]). However, Lo does not explicitly disclose the cfDNA fragmentation profile comprises the sequence coverage of small and/or large DNA fragments.
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 mapped the sequenced fragments to a genome to obtain windows and then used the various window types, lengths, and fragmentation profiles of Lo, thus arriving at the invention of instant claims 1-4, 6-11, and 14. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Lo to increase resolution of the analysis, as shown by Lo ([0056]; [0079]). This modification would have had a reasonable expectation of success given both Lo and the reference claims analyze cfDNA fragmentation profiles.
Further regarding instant claims 9-11, determining the coverage of small and/or large fragments from the amounts of small and/or large fragments in the reference claims in view of Lo would simply involve multiplying the count of the fragments by their length and then dividing by the length of the genome (evidenced by 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 Lo is equivalent to 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 Lo 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 Lo 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 Lo 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 cf DNA 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 cf DNA 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14 and 16-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over 68, 70-73, 76-77, 84, and 86 of copending Application No. 17/842,893 (reference application) in view of Lo (2016) and Chiu (2013). Any newly recited portion herein is necessitated by claim amendment.
Cited reference:
Lo et al., US 2016/0201142 A1 (previously cited); and
Lo et al. (hereinafter Chiu) US 2013/0237431 A1 (cited in IDS filed 29 April 2024; previously cited).
Regarding instant claim 14, reference claim 68 discloses processing cfDNA fragments from the sample into sequencing libraries and performing low coverage sequencing on the sequencing libraries. Reference claims 68 and 70 disclose determining a cfDNA fragmentation profile in the sample of the subject as claimed, comparing the cfDNA fragmentation profile to a reference profile, and identifying the subject as having cancer when the cfDNA fragmentation profile of the subject is different than the reference. Reference claim 86 discloses the claimed ratio.
The limitations of instant claim 14 not taught by the reference claims are discussed below.
Regarding instant claim 16, reference claims 71-72 disclose the limitations of instant claim 16.
Regarding instant claim 17¸ reference claim 68 discloses the cell-free DNA is nucleosome protected cell-free DNA.
Regarding instant claims 18-20, reference claim 70 disclose the limitations of instant claims 18-20.
The reference claims do not disclose the following limitations:
Further regarding instant claim 14, the reference claims do not disclose mapping the sequenced fragments to a genome to obtain windows of mapped sequences. The reference claims do not disclose the detection of increased variability.
Regarding instant claims 14 Lo discloses a method for detecting cancer using a cell-free DNA fragmentation profile of a human subject (i.e. mammal)(Abstract; [0043]), which comprising subjecting sequencing libraries to whole genome sequencing to obtain sequenced fragments ([0216], Hi-Seq sequencing; [0056], e.g. genome-wide size profile created), aligning the sequence reads to a reference genome ([0062]), to obtain chromosomal regions of aligned sequences (claim 1; [0074];, e.g. each of a plurality of chromosomal regions analyzed), as recited in instant claim 14. Lo further discloses using the above methods to track the progress of a patient after cancer treatment ([0090]), demonstrating that the method involves iteratively analyzing fragmentation profiles and treating the subject. Lo further discloses the size profiles of samples with tumor DNA shifts to the left due to the presence of shorter fragments from longer fragments, demonstrating the detection of increased variation in sizes in cancer ([0186]; FIG. 18)
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 mapped the sequenced fragments to a genome to obtain windows and then used the various window types, lengths, and fragmentation profiles of Lo, in addition to treating the subject with a cancer treatment, as shown by LO, thus arriving at the invention of instant claims 1-4, 6-11, and 14. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Lo to increase resolution of the analysis and to track the progress of a patient after treatment, as shown by Lo ([0056]; [0079]; [0090]). This modification would have had a reasonable expectation of success given both Lo and the reference claims analyze cfDNA fragmentation profiles.
Further regarding instant claim 14, the reference claims do not disclose the detection of cancer is performed using machine learning.
However, Chiu discloses a method for size-based cfDNA analysis for determining cancer in a subject (Abstract), which comprises training a linear regression model to establish a relationship between the sizes of the cell-free DNA fragments and fractional DNA concentrations ranging from 0 to 1.0 in training samples, including a training sample with little to no fractional DNA concentration (i.e. a reference cfDNA fragmentation profile) ([0147]-[0150]; claim 7), wherein the fractional DNA concentration is a concentration of tumor DNA ([0153]). Chiu then uses the trained machine learning model to estimate the tumor fractional concentration of a sample not in the training set (i.e. the subject) by comparing the subject’s size ratio to the model and training values ([0076]-[0078; [0148]; [0153]), thereby detecting cancer in the subject. Furthermore detecting a tumor fraction concentration in the subject identifies that the subject has a fractional DNA fragmentation profile different than the reference with little to no fractional DNA concentration (FIG. 14A-B, e.g. see samples with lower size rations and <5% concentration compared to high size ratios and higher concentrations).
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 Lo to have used machine learning to perform the comparison and detect cancer, as shown by Chiu ([0076]-[0078; [0148]; [0153]). One of ordinary skill in the art would have been motivated to combine the methods the reference claims in view of Lo and Chiu to have allowed for providing a range of estimated tumor fractions as an output ([0079]), thus providing additional information regarding the cancer and facilitating the detection of cancer as performed in the reference claims. This modification would have had a reasonable expectation of success given the reference claims and Chiu both analyze fragment lengths to detect cancer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4, 6, 9-11, 14, and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. US10982279 B2 in view of Chiu (2013). Any newly recited portion is necessitated by claim amendment. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Cited reference: Lo et al. (hereinafter Chiu) US 2013/0237431 A1 (cited in IDS filed 29 April 2024; previously cited).
Reference claim 1 discloses the limitations of instant claims 1 and 14, including the “processing..”, “subjecting…”, “mapping…”, and “analyzing…” of the determining a fragmentation profile, the step of determining the fragmentation profile, comparing the cfDNA fragmentation profile to a reference profile, identifying the mammal has cancer if the profiles are different (e.g. more variable), and administering to the mammal identified as having cancer, a cancer treatment. Reference claims 5-9 disclose narrower embodiments of the fragmentation profile of instant claim 14.
Further regarding claim 14, the reference claims do not disclose the identifying the mammal has cancer is performed using machine learning.
However, Chiu discloses a method for size-based cfDNA analysis for determining cancer in a subject (Abstract), which comprises training a linear regression model to establish a relationship between the sizes of the cell-free DNA fragments and fractional DNA concentrations ranging from 0 to 1.0 in training samples, including a training sample with little to no fractional DNA concentration (i.e. a reference cfDNA fragmentation profile) ([0147]-[0150]; claim 7), wherein the fractional DNA concentration is a concentration of tumor DNA ([0153]). Chiu then uses the trained machine learning model to estimate the tumor fractional concentration of a sample not in the training set (i.e. the subject) by comparing the subject’s size ratio to the model and training values ([0076]-[0078; [0148]; [0153]), thereby detecting cancer in the subject. Furthermore detecting a tumor fraction concentration in the subject identifies that the subject has a fractional DNA fragmentation profile different than the reference with little to no fractional DNA concentration (FIG. 14A-B, e.g. see samples with lower size rations and <5% concentration compared to high size ratios and higher concentrations).
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 used machine learning to perform the comparison and detect cancer, as shown by Chiu ([0076]-[0078; [0148]; [0153]). One of ordinary skill in the art would have been motivated to combine the methods the reference claims and Chiu to have allowed for providing a range of estimated tumor fractions as an output ([0079]), thus providing additional information regarding the cancer and facilitating the detection of cancer as performed in the reference claims. This modification would have had a reasonable expectation of success given the reference claims and Chiu both analyze fragment lengths to detect cancer.
Regarding claims 1 and 14, the reference claims do not disclose the ratio is of small fragments 100 to 150 bp in length to large fragments 151 to 220 bp
Chiu discloses a method for size-based cfDNA analysis for determining cancer in a subject (Abstract), which comprises determining a size profile of the subject comprising a ratio of cfDNA fragments of small fragments of 100 bp to 150 bp in length to large fragments of 163 to 169 bp in length (i.e. cfDNA fragments of 151 to 220 bp; see MPEP 2131.03) ([0022]; [0114]; FIG. 17). Lo further discloses the ratio of small to large fragments (i.e. correlation) in the subject is lower than a correlation of small to large fragments in the reference profile (FIG. 18A). Chiu further discloses that there is a reduction in both fractional tumor concentration and the size ratio after tumor resection ([0157]-[0159]; FIG. 16-17).
Reference claims 2-11 explicitly disclose the limitations of instant claims 2-6, and 8-11.
Reference claim 1 discloses the limitations of instant claims 15-16, including the reference profile is of a healthy mammal.
Regarding instant claim 17, the reference claims do not explicitly disclose the reference DNA fragmentation pattern is a reference nucleosomal cfDNA pattern, this limitation is inherent in the reference claims, as evidenced by Lo. Lo discloses the sizes of circulating DNA resembles the size of mononucleosomal DNA (i.e. nucleosome cfDNA) ([0057]), such that the reference size distribution reflects nucleosomal cfDNA (i.e. a reference nucleosomal cfDNA fragmentation profile).
Reference claims 1 and 6 disclose the limitations of instant claim 18, by disclosing the profile includes a median fragment size and determining the profile is more variable than the reference (i.e. shorter or longer).
Reference claims 1 and 7 disclose the limitations of instant claim 19 by disclosing the profile includes a fragment size distribution and determining the distribution is more variable compared to the reference.
Regarding instant claim 20, reference claim 8 discloses the cfDNA fragmentation profile comprises a ratio of small cfDNA fragments to large cfDNA fragments, while instant claim 1 discloses determining increased variability of the profile compared to a reference (i.e. the difference is based on nucleotide sizes).
Further regarding instant claim 20, the reference claims do not disclose the difference is at least 10 nucleotides. However, Chiu further discloses the ratio of small to large fragments (i.e. correlation) in the subject is lower than a correlation of small to large fragments in the reference profile (FIG. 18A). Chiu further discloses that there is a reduction in both fractional tumor concentration and the size ratio after tumor resection ([0157]-[0159]; FIG. 16-17), which makes obvious the difference in the median may be 10 nucleotides.
Claims 1, 4, 6, and 9-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. US10975431 B2. Any newly recited portion is necessitated by claim amendment. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Reference claim 1 discloses the limitations of instant claim 1, including sequenced fragments obtained through whole genome sequencing, mapping the sequenced fragments to obtain windows, and determining fragment lengths. Reference claim 8 discloses the genome coverage is low. Reference claims 6-8 disclose embodiments of the features of the fragmentation profile of instant claim 1.
Reference claim 14 discloses each window is millions of bases in length, which is about 5 million bases as recited in instant claim 4.
Reference claim 6 explicitly discloses the limitation of instant claim 6.
Reference claims 9-11 explicitly discloses the limitations of instant claims 9-11.
Claims 2-3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. US10975431 B2, as applied to instant claim 1 above, and further in view of Lo (2016). This rejection is previously cited.
Cited reference: Lo et al., US 2016/0201142 A1 (previously cited).
Regarding instant claims 2-3, the reference claims disclose the method of instant claim 1, as applied above.
Further regarding instant claims 2-3, the reference claims do not explicitly disclose the mapped sequences comprise tends to thousands of windows or that the windows are non-overlapping windows, respectively.
However, Lo discloses a method for detecting cancer using a cell-free DNA fragmentation profile of a human subject (i.e. mammal)(Abstract; [0043]), which comprises analyzing the sequence reads in chromosomal regions (i.e. windows) to determine cfDNA sizes (i.e. fragment lengths) (claim 1, e.g. calculate statistical value of size distribution of reads of a particular region; FIG. 1 and 6, e.g. repeat for all regions). Lo further discloses the reads were mapped to all 22 chromosomal regions (i.e. tens of windows) (Fig. 2; FIG. 7; [0012]), as recited in instant claim 2, and that the chromosomal regions are nonoverlapping ([0094]; FIG. 2 and 7), as recited in instant claim 3.
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 used tens of non-overlapping windows of Lo, thus arriving at the invention of instant claims 2-3. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Lo to increase resolution of the size analysis, as shown by Lo ([0056]; [0079]). This modification would have had a reasonable expectation of success given Lo discloses cfDNA fragmentation profiles can be determined for windows ([0218]), such that the fragmentation profile of the reference claims can be applied to various windows.
Claims 14 and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. US10975431 B2 in view of Chiu (2013). Any newly recited portion is necessitated by claim amendment.
Cited reference: Lo et al. (hereinafter Chiu) US 2013/0237431 A1 (cited in IDS filed 29 April 2024; previously cited).
Reference claim 1 discloses the limitations of instant claim 14, including sequenced fragments obtained through whole genome sequencing, mapping the sequenced fragments to obtain windows, and determining fragment lengths. Reference claim 8 discloses the genome coverage is low. It is noted reference claim 1 is narrower in scope than instant claim 14. Reference claim 1 discloses determining a fragmentation profile of the subject, and identifying the subject has having cancer based on comparing the fragmentation profile to a reference profile. Reference claim 8 discloses the genome coverage is low. Reference claims 6-8 disclose embodiments of the features of the fragmentation profile of instant claim 14.
Further regarding claim 14, the reference claims do not disclose the identifying the mammal has cancer is performed using machine learning.
However, Chiu discloses a method for size-based cfDNA analysis for determining cancer in a subject (Abstract), which comprises training a linear regression model to establish a relationship between the sizes of the cell-free DNA fragments and fractional DNA concentrations ranging from 0 to 1.0 in training samples, including a training sample with little to no fractional DNA concentration (i.e. a reference cfDNA fragmentation profile) ([0147]-[0150]; claim 7), wherein the fractional DNA concentration is a concentration of tumor DNA ([0153]). Chiu then uses the trained machine learning model to estimate the tumor fractional concentration of a sample not in the training set (i.e. the subject) by comparing the subject’s size ratio to the model and training values ([0076]-[0078; [0148]; [0153]), thereby detecting cancer in the subject. Furthermore detecting a tumor fraction concentration in the subject identifies that the subject has a fractional DNA fragmentation profile different than the reference with little to no fractional DNA concentration (FIG. 14A-B, e.g. see samples with lower size rations and <5% concentration compared to high size ratios and higher concentrations).
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 used machine learning to perform the comparison and detect cancer, as shown by Chiu ([0076]-[0078; [0148]; [0153]). One of ordinary skill in the art would have been motivated to combine the methods the reference claims and Chiu to have allowed for providing a range of estimated tumor fractions as an output ([0079]), thus providing additional information regarding the cancer and facilitating the detection of cancer as performed in the reference claims. This modification would have had a reasonable expectation of success given the reference claims and Chiu both analyze fragment lengths to detect cancer.
Reference claim 12 discloses the reference cfDNA fragmentation profile was generated from a sample of a healthy mammal, as recited in instant claim 16.
Reference claim 5 explicitly discloses the limitation of instant claim 17.
Reference claims 6-8 explicitly disclose the limitations of instant claims 18-20.
Response to Arguments
Applicant's arguments filed 16 March 2026 regarding double patenting have been fully considered but they are not persuasive.
Applicant remarks the recited claims of the reference applications do not expressly recite Applicant’s claims, and thus the rejections should be withdrawn (Applicant’s remarks at pg. 15, para. 3 to pg. 16, para. 9).
This argument is not persuasive. Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the reference claims. Claims in a reference application are not required to “expressly recite” the exact same language as the instant claims to support a double patenting rejection. While the reference claims do not use the exact same words with the exact same scope, the reference claims disclose an embodiment which reads on the instant claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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