DETAILED ACTION
Applicant’s response, filed 23 July 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 1-67, 69-72, 77, 80-81, 84, 86-87, and 98-100 are cancelled.
Claims 68, 73-76, 78-79, 82-83, 85, and 88-97 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Claims 89-97 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention.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, and 88 are rejected.
Claim 68 is objected to.
Claim Objections
The previous objection to claims 68 and 100 in the Office action mailed 23 Feb. 2026 has been withdrawn in view of claim amendments and cancellations received 23 July 2026.
Claim 68 is objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claim 68 recites “…predicting, by a machine learning model…a tissue of origin of the cancer based on…”, which should be amended to recite “a tissue of origin of the cancer of the subject” to increase clarity.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 23 July 2026 regarding the claim objections have been fully considered but they are not persuasive because they do not pertain to the newly recited objection set forth above.
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 Rejections - 35 USC § 112(b)
The rejection of claims 79 and 82 under 35 U.S.C. 112(b) in the Office action mailed 23 Feb. 2026 has been withdrawn in view of claim amendments received 23 July 2026.
Claim Rejections - 35 USC § 101
The rejection of claim 100 under 35 U.S.C. 101 in the Office action mailed 23 Feb. 2026 has been withdrawn in view of the cancellation of this claim received 23 July 2026.
The rejection of claims 68, 73-76, 78-79, 82-83, 85, and 88 under 35 U.S.C. 101 in the Office action mailed 23 Feb. 2026 has been withdrawn in view of claim amendments received 23 July 2026.
Claim 68 recites “administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer based on the predicted tissue of origin wherein the therapeutic 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”. Therefore, claim 68 recites an additional element that integrates the judicial exception of identifying the subject as having cancer, including a tissue of origin, into the practical application of effecting a particular treatment. See MPEP 2106.04(d)(2).
Claim Rejections - 35 USC § 103
The rejection of claim 100 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) in the Office action mailed 23 Feb. 2026 has been withdrawn in view of the cancellation of these claims received 23 July 2026.
The rejection of claims 68, 73-74, 76, 78-79, 82-83, 85, and 88 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) in the Office action mailed 23 Feb. 2026 has been withdrawn in view of claim amendments received 23 July 2026.
The rejection of claim 75 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) in the Office action mailed 23 Feb. 2026 has been withdrawn in view of claim amendments received 23 July 2026.
However, after further consideration of the claims, a new grounds of rejection is set forth below further in view of Abdueva.
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, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Chiu (2013) in view of Sims (2014), Maggi (2018), and Abdueva (2018), as evidenced by Lo (2014). This rejection is newly recited and 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);
Abdueva, US 2019/0352695 A1, effectively filed 2018 Jan. 10 based on priority to Provisional App. No. 62/615,885 (previously cited); and
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 %).
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 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, the ratio of small to large cfDNA fragments of Chiu represents a size variability of fragments, and patients with cancer have a flatter (more variable) fragment size distribution.
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 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 recognized 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.
Further regarding claim 68, Chiu does not disclose 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 the cancer based on the cfDNA fragmentation profile. Chiu further does not disclose administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer based on the predicted tissue of origin wherein the therapeutic 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.
However, Abdueva discloses a method for predicting a tissue of origin in a subject based on a fragmentome profile (i.e. a fragmentation profile) from cell-free DNA (Abstract), which comprises determining a ratio of a number of fragments with dinucleosomal protection and a number of fragments with mononucleosomal protection ([0224]). Abdueva further discloses cfDNA fragments with dinucleosomal protection have a typical size distribution centered around 334 bp, while cfDNA fragments with mononucleosomal protection result in shorter fragments with a fragment size of less than 240 base pairs ([0140]), such that the ratio is a ratio of larger fragments to smaller fragments analogous to the ratio in Chiu. Abdueva further discloses using a trained classifier to predict a tissue of origin of a cancer in the subject based on the fragmentome profile ([0038]-[0039], e.g. class of clinical significance of classifier indicates tissue of origin; [0080]; [0279]; [0285]-[0286]). Abdueva further discloses administering a therapeutic intervention to treat the cancer of the subject ([0041]; [0079]; [0088]), wherein the information about the presence or absence of a particular disease can be used to select an appropriate treatment for the subject (i.e. a suitable treatment selected based on a tissue of origin)([0194]). Abdueva further discloses a treatment for a cancer patient includes a surgical resection of the cancer ([0348]; FIG. 26B).
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 made obvious by Chiu in view of Sims and Maggi, as applied to claim 68 above, to have further determined, using a machine learning model, a tissue of origin of a cancer based on a fragmentation profile of a subject and administered a treatment including surgical resection based on the classification, as shown by Abdueva above. One of ordinary skill in the art would have been motivated to combine the methods of Chiu in view of Sims and Maggi with Abdueva to provide information that can be used to apply a treatment designed to treat the cancer of the subject, as shown by Abdueva ([0082]), thereby improving the health of the subject. This modification would have had a reasonable expectation of success because the fragmentation profiles in both Chiu and Abdueva comprise a ratio of small to large cfDNA fragments of similar size ranges, such that the trained classifier of Abdueva is applicable to the fragmentation profile of Chiu.
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, Maggi, and Abdueva 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, Chiu in view of Sims, Maggi, and Abdueva make obvious the machine learning model predicting a tissue of origin of the cancer, as applied to claim 68 above. Abdueva discloses the tissue origin can include colorectal cancer ([0233]).
Regarding claim 88, Chiu discloses the sample is a blood or plasma sample (0267]).
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Chiu in view of Sims, Maggi, and Abdueva, as applied to claim 68 above, and further in view of Lo (2014). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Lo et al., US 2014/0080715 A1 (previously cited);
Regarding claim 75¸ Chiu in view of Sims, Maggi, and Abdueva, make obvious the method of claim 68 as applied above.
Regarding claim 75, Chiu in view of Sims, Maggi, and Abdueva, 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 23 July 2026 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that the Examiner’s rejection of the predicting and administering steps rely on these steps not being required under the broadest reasonable interpretation of the claims, and the claims have been amended to require these steps in the claims (Applicant’s remarks at pg. 13, para. 2). Applicant remarks that neither Chiu, Sims, Maggi, nor Lo disclose the now mandatory steps of (1) predicting, by a machine learning model, at issue of origin, and (2) administering to the subject, a therapeutic treatment suitable for treatment based on the predicted tissue of origin (Applicant’s remarks at pg. 13, para. 3 to pg. 14, para. 2).
This argument is not persuasive because Chiu, Sims, Maggi, and Lo are not relied upon to teach the now required predicting and administering steps. Instead, Abdueva in the new grounds of rejection set forth above is relied upon to teach these limitations.
Applicant remarks that Chiu does not disclose position-dependent genome-wide fragmentation analysis as claimed because Chiu discloses bins in the context of copy number changes, but not position-dependent fragmentation metrics, and further remarks the present invention achieves improved sensitivity for cancer detection (Applicant’s remarks at pg. 14, 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 Sims and Maggi do not remedy the deficiencies of Chiu, and therefore, Chiu when taken alone or in view of Sims and Maggi as evidenced by Lo does not teach or suggest the present claims alone or in combination (Applicant’s remarks at pg. 14, para. 4 to pg. 15, para. 1).
This argument is not persuasive because Sims, Maggi, and Lo are not relied upon for the above limitations. Instead, Abdueva and Chiu are relied upon for the reasons discussed above.
Applicant remarks the discussion of Chiu, Sims, and Maggi above applies equally to the rejection of claim 75, and the combination does not teach the mandatory steps of predicting a tissue of origin and administering (Applicant’s remarks at pg. 15, para. 2 to pg. 16, para. 1).
This argument is not persuasive for the same reasons discussed above for claim 68.
Double Patenting
The terminal Disclaimer filed 06 March 2023 over U.S. Patent Numbers 10,982,279 and 10,975,431 was approved 06 March 2023.
The provisional rejections of claim 100 on the ground of nonstatutory double patenting in the previous Office action has been withdrawn in view of the cancellation of this claim received 23 July 2026.
The provisional rejection of claims 68, 73-76, 78-79, 82-83, 85, and 88 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) in the previous Office action has been withdrawn in view of claim amendments received 23 July 2026.
The provisional rejection of claims 68, 73-74, 76, 78-79, 82-83, 85, 88, and 100 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) in the previous Office action has been withdrawn in view of claim amendments received 23 July 2026.
The provisional rejection of claim 75 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) and Abdueva (2018), as applied to claim 68 above, and further in view of Lo (2014) in the previous Office action has been withdrawn in view of claim amendments received 23 July 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.
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Claims 68, 73-76, 78-79, 82-83, 85, and 88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 9-11, 14, and 16-20 of copending Application No. 17/056,726 in view of Abdueva (2018). This rejection is newly recited and necessitated by claim amendment.
Cited reference: Abdueva, US 2019/0352695 A1, effectively filed 2018 Jan. 10 based on priority to Provisional App. No. 62/615,885 (previously cited);
Regarding claim 68, reference claims 1, 4, 9-11, and 14 disclose the limitations of instant claim 68 except for the limitations discussed below:
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.
The reference claims do not disclose the following limitations:
Regarding instant claims 68 and 85, the reference claims do not disclose 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 including colorectal cancer of the cancer based on the cfDNA fragmentation profile. Chiu further does not disclose administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer based on the predicted tissue of origin wherein the therapeutic 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.
However, Abdueva discloses a method for predicting a tissue of origin in a subject based on a fragmentome profile (i.e. a fragmentation profile) from cell-free DNA (Abstract), which comprises determining a ratio of a number of fragments with dinucleosomal protection and a number of fragments with mononucleosomal protection ([0224]). Abdueva further discloses cfDNA fragments with dinucleosomal protection have a typical size distribution centered around 334 bp, while cfDNA fragments with mononucleosomal protection result in shorter fragments with a fragment size of less than 240 base pairs ([0140]), such that the ratio is a ratio of larger fragments to smaller fragments analogous to the ratio in Chiu. Abdueva further discloses using a trained classifier to predict a tissue of origin of a cancer in the subject based on the fragmentome profile ([0038]-[0039], e.g. class of clinical significance of classifier indicates tissue of origin; [0080]; [0279]; [0285]-[0286]). Abdueva discloses the tissue origin can include colorectal cancer ([0233]). bdueva further discloses administering a therapeutic intervention to treat the cancer of the subject ([0041]; [0079]; [0088]), wherein the information about the presence or absence of a particular disease can be used to select an appropriate treatment for the subject (i.e. a suitable treatment selected based on a tissue of origin)([0194]). Abdueva further discloses a treatment for a cancer patient includes a surgical resection of the cancer ([0348]; FIG. 26B).
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 made obvious by the reference claims, as applied to claim 68 above, to have further determined, using a machine learning model, a tissue of origin of a cancer based on a fragmentation profile of a subject and administered a treatment including surgical resection based on the classification, as shown by Abdueva above. One of ordinary skill in the art would have been motivated to combine the method of the reference claims with Abdueva to provide information that can be used to apply a treatment designed to treat the cancer of the subject, as shown by Abdueva ([0082]), thereby improving the health of the subject. This modification would have had a reasonable expectation of success because the fragmentation profiles in both the reference claims and Abdueva comprise a ratio of small to large cfDNA fragments of similar size ranges, such that the trained classifier of Abdueva is applicable to the fragmentation profile of the reference claims.
This is a provisional nonstatutory double patenting rejection.
Claims 68, 73-74, 76, 78-79, 82-83, 85, and 88 and provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70-73, 76-77, and 84-86 of copending Application No. 17/842,893 in view of Chiu (2013) and Abdueva (2018). This rejection is newly recited and necessitated by claim amendment.
Cited reference:
Lo et al. (referred to as Chiu) (US 2013/0237431 A1 (previously cited); and
Abdueva, US 2019/0352695 A1, effectively filed 2018 Jan. 10 based on priority to Provisional App. No. 62/615,885 (previously cited);
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, the specific genomic intervals in the instant claims, and predicting a tissue of origin as claimed.
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.
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 68 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 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 claims 68 and 85, the reference claims do not disclose 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 including colorectal cancer of the cancer based on the cfDNA fragmentation profile. Chiu further does not disclose administering to the subject identified as having cancer, a therapeutic treatment suitable for treatment of the cancer based on the predicted tissue of origin wherein the therapeutic 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 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.
Further regarding claims 68 and 85, Abdueva discloses a method for predicting a tissue of origin in a subject based on a fragmentome profile (i.e. a fragmentation profile) from cell-free DNA (Abstract), which comprises determining a ratio of a number of fragments with dinucleosomal protection and a number of fragments with mononucleosomal protection ([0224]). Abdueva further discloses cfDNA fragments with dinucleosomal protection have a typical size distribution centered around 334 bp, while cfDNA fragments with mononucleosomal protection result in shorter fragments with a fragment size of less than 240 base pairs ([0140]), such that the ratio is a ratio of larger fragments to smaller fragments analogous to the ratio in Chiu. Abdueva further discloses using a trained classifier to predict a tissue of origin of a cancer in the subject based on the fragmentome profile ([0038]-[0039], e.g. class of clinical significance of classifier indicates tissue of origin; [0080]; [0279]; [0285]-[0286]). Abdueva discloses the tissue origin can include colorectal cancer ([0233]). bdueva further discloses administering a therapeutic intervention to treat the cancer of the subject ([0041]; [0079]; [0088]), wherein the information about the presence or absence of a particular disease can be used to select an appropriate treatment for the subject (i.e. a suitable treatment selected based on a tissue of origin)([0194]). Abdueva further discloses a treatment for a cancer patient includes a surgical resection of the cancer ([0348]; FIG. 26B).
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 made obvious by the reference claims, as applied to claim 68 above, to have further determined, using a machine learning model, a tissue of origin of a cancer based on a fragmentation profile of a subject and administered a treatment including surgical resection based on the classification, as shown by Abdueva above. One of ordinary skill in the art would have been motivated to combine the method of the reference claims with Abdueva to provide information that can be used to apply a treatment designed to treat the cancer of the subject, as shown by Abdueva ([0082]), thereby improving the health of the subject. This modification would have had a reasonable expectation of success because the fragmentation profiles in both the reference claims and Abdueva comprise a ratio of small to large cfDNA fragments of similar size ranges, such that the trained classifier of Abdueva is applicable to the fragmentation profile of the reference claims.
This is a provisional nonstatutory double patenting rejection.
Claim 75 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70-73, 76-77, and 84-86 of copending Application No. 17/842,893 in view Chiu (2013) and Abdueva (2018), as applied to claim 68 above, and further in view of Lo (2014). This rejection is newly recited and 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 and Abdueva 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 and Abdueva 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 23 July 2026 regarding double patenting have been fully considered but they are not persuasive.
Applicant remarks that Applicant traverses the rejection and requests the rejection to be held in abeyance till the claims are allowable (Applicant’s remarks at pg. 16, para. 2 to 7).
This argument is not persuasive because Applicant does not provide any arguments regarding why the rejection is traversed.
Conclusion
No claims are allowed.
Claims 68, 73-76, 78-79, 82-83, 85, and 88 are patent eligible for the reasons set forth above under 35 U.S.C. 101.
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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Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAITLYN L MINCHELLA whose telephone number is (571)272-6485. The examiner can normally be reached 7:00 - 4:00 M-Th.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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