DETAILED ACTION
Applicant’s response, filed 22 Sept. 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
It is noted Applicant’s claim amendments fail to comply with 37 CFR 1.121(c)(4)(i), which states No claim text shall be presented for any claim in the claim listing with the status of "canceled" or "not entered.". Claims 70 and 84 are indicated as cancelled, but present text in the claim listing. However, in the interest of compact prosecution, the claims are being examined herein.
Claims 1-67, 69, 70, 74-75, 78-84, and 85 are cancelled.
Claims 68, 71-73, 76-77, and 86 are pending.
Claims 68, 71-73, 76-77, and 86 are rejected.
Claim 68 is objected to.
Priority
Applicant’s claim for the benefit of a prior-filed application, U.S. Non-Provisional App. No. 17/842,893 filed 17 March 2021, U.S. Non-Provisional App. No. 16/730,938 filed 30 Dec. 2019, U.S. Provisional App. No. 62/795,900 filed 23 Jan. 2019, and U.S. Provisional App. No. 62/673,516 filed 18 May 2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 18 May 2018.
Claim Objections
The previous objection to claim 68 in the Office action mailed 22 June 2026 has been withdrawn in view of claim amendments received 22 Sept. 2026.
Claim 68 is objected to because of the following informalities. This objection is newly recited and necessitated by claim amendment.
Claim 68 recites “…h) comparing…; determining that…; and i) administering…”. MPEP 608.01(m) states where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). Accordingly, the determining step within the comparing step should be placed on a separate line indentation. Furthermore, the determining step should use the label “i)” and the administering step should used “j)”.
Claim 68 recites “i) administering…adoptive T cell therapy or chemotherapeutic agent”, which is a grammatical error and should include a comma after “therapy” and an article “a” before chemotherapeutic, such that claim 68 recites “adoptive T cell therapy, or a chemotherapeutic agent”.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 22 June 2026 regarding the claim objections have been fully considered but they do not pertain to the newly recited objection set forth above.
Claim Interpretation
Claim 84 recites “The method of claim 70 wherein the reference profile is obtained from the subject prior to a cancer treatment”. This limitation only serves to define the process in which the reference profile was previously determined. However, the claims do not require a step of obtaining the reference profile. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). See MPEP 2113 I.
Claim Rejections - 35 USC § 112(b)
The previous rejection of claims 68, 70-73, 76-77, 84, and 86 under 35 U.S.C. 112(b) in the Office action mailed 22 June 2026 has been withdrawn in view of claim amendments and cancellations received 22 Sept. 2026.
Claim Rejections - 35 USC § 101
The rejection of claims 68, 70-73, 76-77, 84, and 86 under 35 U.S.C. 112(b) in the Office action mailed 22 June 2026 has been withdrawn in view of claim amendments and cancellations received 22 Sept. 2026.
Independent claim 68 recites “comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile to determine the cancer status of the subject…determining that the cfDNA fragmentation profile is different from the reference cfDNA fragmentation profile and thereby identifying the subject as having cancer; and administering to the subject identified as having cancer a cancer treatment, wherein the cancer treatment comprises an immune checkpoint inhibitor, adoptive T cell therapy, or chemotherapeutic agent”. Therefore, the claims integrate the recited judicial exception into a practical application of effecting a particular treatment for cancer.
Claim Rejections - 35 USC § 103
The rejection of claims 70 and 84 under 35 U.S.C. 103 in the Office action mailed 22 June 2026 has been withdrawn in view of the cancellation of these claims received 22 Sept. 2026.
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 68, 71-73, 76-77, 84, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (2017) in view of Ma (2017) and Chiu (2013), as evidenced by Heitzer (2015). Any newly recited portion is necessitated by claim amendment.
Cited reference:
Lo et al., US 2019/0130065 A1; effectively filed 02 Nov. 2017 based on priority to Provisional App. No. 62/580,906 (previously cited);
Ma et al., Cell-Free DNA Provides a Good Representation of the Tumor Genome Despite Its Biased Fragmentation Patterns, 2017, PLOS ONE, pg. 1-18 and suppl. (previously cited; suppl information is newly recited);
Lo et al. (referred to as Chiu) US 2013/0237431 A1 (previously cited); and
Heitzer et al., Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123 (previously cited).
Regarding claim 68 Lo discloses a method for detecting cancer in a subject (Abstract; [0007]; [0028]), comprising the following steps:
Lo discloses a) processing a blood sample to obtain plasma ([0028]; [0050]; [0185]).
Lo discloses b) extracting and purifying cfDNA fragments from the plasma ([0185]-[0186]).
Lo discloses c) performing sequencing library preparation on the cfDNA fragments to obtain sequence libraries ([0147], e.g. fragments from entire genome; [0186]; [0190]).
Lo discloses d) subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments ([0032]; [0191], e.g. random sequencing is performed on all nucleic acid fragments in sample).
Lo discloses e) after sequencing, mapping the sequence reads to a reference genome to provide a length of the fragment and to determine the location of each read (i.e. positional and size-based data) ([0029]; [0192]).
Lo discloses f) producing a fragment size distribution of the sequence reads in the sample ([0031]; [0062]; FIG. 1), a ratio of a first amount of cell-free DNA molecules in a first size range to a second amount of cell-free DNA molecules in a second size range, ([0101]-[0102]; [0160]; FIG. 12; claims 1 and 11), sequence coverages for each size ratio of cfDNA fragments in chromosome arms (FIG. 10, #1040, e.g. Genomic Representation for sample for chromosome arms 1-N; [0147], e.g. genomic representation of a sequence coverage on a particular region), and cfDNA fragment size ratios of cfDNA fragments in each of multiple regions (i.e. positional fragmentation metrics across subgenomic intervals) (FIG. 6 #602, 604 and 610; [0097]-[0100]), thus producing the cfDNA fragmentation profile as claimed.
Lo discloses (g) determining the presence of a DNA copy number (CN) change of a chromosomal arm in the sequenced fragments ([0071]; [0097], e.g. cell-free DNA sample; [0098], e.g. copy number determined for chromosomal arm; [0099]; [0109], e.g. the machine learning outputs probability of a copy number aberration based on comparison to a reference size pattern; Fig. 6).
Lo discloses h) comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile (FIG. 12 #1202-1208, e.g. size ratio pattern of sample and reference are compared; [0158]-[0161] and [0164]), and classifying (i.e. determining) the subject as having cancer based on differences between the fragment size ranges (i.e. fragmentation profile) of the subject and the reference size ranges exceeding a threshold, wherein the size ranges are determined for a specific genomic region (i.e. i.e. based on position dependent differences in fragmentation patterns indicative of cancer, thereby determining the cancer status) (FIG. 10, e.g. ratios for different chromosomal arms; [0102]; [0164]-[0165], e.g. subject classified as having cancer based on a similarity of the measurement sizes to the reference sizes exceeding a cutoff; FIG. 12).
Lo discloses classifying the subject as having cancer based on differences between the fragment size ranges (i.e. fragmentation profile) of the subject and the reference size ranges exceeding a threshold (i.e. the cfDNA fragmentation profile of the subject is determined different than the reference profile, indicating the subject has cancer) ([0164]-[0165], e.g. subject classified as having cancer based on a similarity of the measurement sizes to the reference sizes exceeding a cutoff; FIG. 12).
Lo discloses i) treating the disease in the patient after determining the level of the disease or the condition of the patient, wherein the treatment may include any suitable therapy described herein ([0184]; [0110]).
Regarding claims 68 and dependent claim 77, Lo does not disclose the following:
Regarding claim 68, Lo does not explicitly disclose the cfDNA fragments are nucleosome protected cfDNA fragments. However, this limitation is inherent in Lo, as evidenced by Heizer.
Specifically, Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that the limitation of extracting and purifying nucleosome protected fragments is inherent in extraction and purification of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Therefore, given Lo discloses extracting and purifying cfDNA fragments, as discussed above, this inherently discloses that nucleosome-protected cfDNA fragments are extracted and purified.
Further regarding claim 68 and dependent claims 77 and 86, Lo does not disclose the following limitations:
Regarding claims 68 and 77, Lo further does not disclose the whole genome sequencing is performed at a coverage of 9x to 0.1x, as recited in claim 68, or at a coverage of 2x, 1x, 0.5x, 0.2x or 0.1x, as recited in claim 77.
However, Ma analyzes methods for performing sequencing on cfDNA (Abstract), and discloses that next-generation sequencing techniques have been deployed at low coverage depths from 0.1X-10X to successfully identify copy number variation in cfDNA (pg. 2, para. 2; pg. 7, para. 3), and specifically discloses performing whole-genome sequencing a depth of coverage of 1X (Fig. 1B; pg. 5, para. 2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Lo to have performed whole-genome sequencing at depth of 1X on the cfDNA fragments, as shown by Ma (pg. 2, para 2; pg. 5, para. 2; pg. 7, para. 3; Fig. 1B). One of ordinary skill in the art would have been motivated to combine the methods of Lo and Ma to utilize coverage that allows for successful identification of copy number variation, as shown by Ma (pg. 2, para. 2; pg. 7, para. 3), given Lo involves detecting copy numbers from sequencing cell-free DNA, as discussed above. This modification would have had a reasonable expectation of success because both Lo and Ma discloses performing whole-genome sequencing on cell-free DNA, such that the low-coverage sequencing method of Ma is applicable to the method of Lo.
Further regarding claim 68, Lo does not disclose the size ratio is a ratio of small cfDNA fragments of 100 to 150 base pairs in length to large cfDNA fragments 151 to 220 base pairs in length.
However, Chiu similarly discloses a method for determining a cell-free DNA fragmentation profile for a subject (Abstract), which comprises determining a size profile including size parameters ([0051]; [0099]), wherein the size parameters include a ratio of the amount of cfDNA fragment of 100 to 150 base pairs in length to the amount of cfDNA fragments 163-169 base pairs in length (i.e. a ratio of smaller 100-150 base pair fragments to larger 151-220 base pair fragments) ([0019]; [0099]; FIG. 5; FIG. 20), and furthermore a size ratio is determined for each genomic region of multiple genomic regions ([0176]-[0177]). Regarding the claimed range of large fragments of 151 bp to 220 bp in length, the range of 163-169 bp in length is within the claimed range of 151-220 and therefore anticipates the range. See MPEP 2131.03. Chiu further discloses the ratio of small to large fragments is compared to a reference ratio for each region to classify a likelihood cancer exists in the subject ([0174]; [0178]-[0179] FIG. 16A, e.g. higher size ratio corresponds to higher tumor %). Chiu discloses this ratio of small to large fragments is positively correlated with tumor percentage in the subject (FIG. 15A-B; FIG. 16A-B; FIG. 17).
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 size ratio of Lo to have utilized a size ratio of 100 to 150 bp to 163-169 bp in the classification of cancer, as shown by Chiu, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Lo and Chiu given Chiu discloses that the size ratio of 100 to 150 bp to 163-169 bp is positively correlated with a tumor percentage in the subject (FIG. 15-17), thus providing a predictive biomarker for cancer classification as performed in Lo. This modification would have had a reasonable expectation of success given both Lo and Chiu use a size ratio of cfDNA fragments in genomic regions to predict cancer in a subject, such that the ratio of Chiu is applicable to the method of Lo.
Further regarding claim 68, Lo does not explicitly disclose the cancer treatment comprises an immune checkpoint inhibitor, adoptive T cell therapy, or chemotherapeutic agent.
However, Ma further discloses chemotherapy is a treatment for patients with cancer (S1 Table, e.g. Gemcitabine, Docetaxel, etc.; pg. 9, para. 2-3, e.g. treatment histories in S1 Table).
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 administering a treatment step of Lo to have used a chemotherapy treatment as shown by Ma (S1 Table). One of ordinary skill in the art would have been motivated to further combine the methods of Lo and Ma based on the simple substitution of the cancer therapy shown by Lo with the prior art element of a chemotherapy cancer treatment shown by Ma. One of ordinary skill in the art would have recognized that the results of the substitution would have been predictable given Lo discloses the treatment may include any suitable therapy ([0184]; [0110]), and Ma provides a suitable chemotherapy therapy for cancer (Table S1).
Regarding the dependent claims:
Regarding claim 71, Lo further discloses the reference cfDNA fragmentation profile is determined from subjects without cancer ([0161]), and the subjects can be human (i.e. a mammal without cancer) ([0191]), such that the reference cfDNA fragmentation profile is of at least one mammal without cancer.
Regarding claim 72, Lo further discloses the reference cfDNA fragmentation profile is generated from reference samples from subjects without cancer ([0135]; [0161]), and the subjects can be human (i.e. a mammal without cancer) ([0191]).
Regarding claim 73, Lo discloses the cancer can be lung cancer, colon cancer, or ovarian cancer ([0165]).
Regarding claim 76, Lo discloses the cfDNA fragmentation profile of the subject comprises sequence coverages for each size ratio of cfDNA fragments in chromosome arms (FIG. 10, #1040, e.g. Genomic Representation for sample for chromosome arms 1-N; [0147], e.g. genomic representation if a sequence coverage on a particular region).
Regarding claim 84, the claims recites a product by process limitation as explained in the claim interpretation section. As discussed above, Lo discloses the reference cfDNA fragmentation profile is determined from subjects without cancer ([0161]), and the subjects can be human (i.e. a mammal without cancer) ([0191]), such that the reference cfDNA fragmentation profile is of at least one mammal without cancer. A reference profile generated from a human without cancer, as disclosed in Lo, is the same product as a reference profile generated from the subject prior to cancer treatment, since the latter encompasses a reference profile taken while the subject is healthy (i.e. a reference profile from a human without cancer, as described in Lo). Therefore, Lo discloses the limitations of claim 84 See MPEP 2113. I.
Regarding claim 86, Lo discloses the cfDNA fragment size ratios of cfDNA fragments are determined in each of multiple nonoverlapping chromosome arms ([0097]-[0100]; FIG. 10, e.g. genome split into chromosome arms and GR determined for each chromosome arm 1 through N)
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 22 Sept. 2026 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks that the Examiner concedes that Lo does not disclose the size ratio recited in amended step f), and therefore the rejection of the limitation rests on Chiu and the reason to substitute Chiu’s ratio into Lo (Applicant’s remarks at pg. 12, para. 1-2). Applicant remarks that Lo’s size analysis is not conducted over the two defined populations of small fragments of 100 to 150 base pairs and large fragments of 151 to 220 base pairs, and instead Lo discloses the size ranges may be determined by a machine learning model that can vary which ranges are used to optimize sensitivity and specificity for detecting a clinical condition, thus leaving the choice of center points for the size ranges to be selected empirically by a machine learning model which points to no particular pair of populations of size ranges (Applicant’s remarks at pg. 12, para. 3).
This argument is not persuasive because Lo is not relied upon to teach the specific size ranges. Instead Chiu is relied upon for this limitation.
Applicant remarks that Chiu does not remedy the deficiencies of Lo because Chiu’s ratio of fragments is 100 to 150 bp in length to fragments 163-169 bp in length, which lies within the claimed range of 151 to 220 pb, however, the citation to MPEP 2131.03 that ranges that lie within a claimed range anticipate the range does not apply here because claim 68 does not recite a range within which a single prior art value may fall, but define which fragments must be counted in forming the ratio (Applicant’s remarks at pg. 13, para 1). Applicant further remarks Chiu’s general disclosure does not supply what its worked examples omit, and therefore nothing in Chiu or Lo would have led to the selection of 151 to 220 pb fragments other than Applicant’s own claims (Applicant’s remarks at pg. 13, para. 2).
This argument is not persuasive. Contrary to Applicant’s assertion, the recited ranges do not define which fragments must be counted in forming the ratio. Rather, claim 68 recites “a ratio of small cfDNA fragments to large cfDNA fragments, wherein a small cfDNA fragment is 100 base pairs (bp) to 150 bp in length and a large cfDNA fragment is 151 to 220 bp in length”. In other words, claim 68 requires a ratio of small to large cfDNA fragments, and then merely defines the range of lengths that a cfDNA fragment may be to qualify as a “small” or “large” fragment. Therefore, for example, a ratio of fragments of exactly 110 bp in length to fragments of exactly 200 bp in length would read on the claimed ratio of small to large cfDNA fragments, given fragments of 110 bp are “small” fragments and fragments of 200 bp are “large fragments”. For the same reasons, the fragments that are 163-169 bp in length of Chiu are also considered large cfDNA fragments based on the definition of large fragments (i.e. fragments 151 to 220 bp in length) in the claim. Therefore, the ratio of 100 to 150 bp fragments to 163-169 bp fragments of Chiu reads on the recited ratio of small to large fragments in the claim, consistent with MPEP 2131.03 I, which states a specific example in the prior art which is within a claimed range anticipates the claimed range. Therefore, the ratio of fragments 100 to 150 bp to fragments of 163 to 169 bp in length of Chiu is a ratio of small cfDNA fragments to large cfDNA fragments as claimed.
Applicant remarks the proposed combination also lacks a rational underpinning because Chiu merely discloses a ratio of fragments 100-150 bp in length to 163-169 bp in length is positively correlated with a tumor percentage in the subject, which is just an aggregate, genome-wide quantity compared against a threshold to determine the level of cancer, while claim 68 requires the ratio form part of a cfDNA fragmentation profile further comprising “positional fragmentation metrics across the whole genome or subgenomic intervals”, and that cancer status can be determined using “positional dependent differences…”, and thus a correlation between an aggregate size ratio and tumor burden furnishes no reason to expect that ratio to resolve position-dependent differences in fragmentation, and the Examiner offers no evidence or reasoning bridging that gap (Applicant’s remarks at pg. 13, para. 3 to pg. 14, para. 1).
This argument is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Lo is relied upon to teach determining a ratio of small to large fragments in subgenomic intervals (FIG. 6 #602, 604 and 610; FIG. 10; [0097]-[0100]), and then using position dependent differences in fragmentation patterns (e.g. a size ratio for each chromosomal arm) to distinguish cancer from reference cfDNA (FIG. 10, e.g. ratios for different chromosomal arms; [0102]; [0164]-[0165], e.g. subject classified as having cancer based on a similarity of the measurement sizes to the reference sizes exceeding a cutoff; FIG. 12). Accordingly, the combination of Lo in view of Chiu would result in the size ratio of Chiu being determined across different chromosome arms for the cancer determination of the subject.
Furthermore, as noted by Applicant, Lo discloses the specific size range used can be determined by a machine learning model, which optimizes sensitivity and specificity for detecting a clinical condition in the subject (i.e. a size range that can detect a clinical condition is determined ([0099]). Given Chiu discloses the size ratio of 100-150 to 163-169 bp fragments is positively correlated with tumor percentage and is used to classify cancer, the size ratio of Chiu would serve the same function as a size ration determined by the machine learning of Lo, such that the combination would have a reasonable expectation of success.
Regardless, it is further noted that Chiu does disclose the size parameters of a size profile include the ratio of small to large fragments ([0019]; [0099]; FIG. 5; FIG. 20), determining a size ratio for each of multiple genomic regions ([0176]-[0177]), and then comparing each size ratio to a respective reference value for cancer classification ([0178]-[0179]). Therefore, this clearly demonstrates a reasonable expectation of success in the ratio of Chiu representing position dependent differences in fragmentation patterns used for cancer classification in combination with Lo.
Applicant remarks Ma cannot supply the size-ratio limitation that Lo and Chiu lack (Applicant’s remarks at pg. 14, para. 2). Applicant further remarks, regarding the treatment limitation, that pg. 120 does not exist in Ma and instead corresponds to Heitzer, which is an evidentiary reference, and requests the Examiner identify where the treatment is taught (Applicant’s remarks at pg. 14, para. 2).
This argument is not persuasive because Ma is not relied upon to teach the size ratio limitation. Furthermore, Ma discloses the treatment comprises chemotherapy as set forth in the above rejection.
Applicant remarks that Lo states the treatment may include any suitable therapy described herein, but names no agent and a “simple substitution” rational cannot rescue a combination that does not arrive at the claimed cfDNA fragmentation profile in the first instances (Applicant’s remarks at pg. 14, para. 3).
This argument is not persuasive for the reasons discussed above. That is, the claimed reference do disclose the claimed cfDNA fragmentation profile, and the simple substitution corresponding to the treatment is not relied upon to teach the cfDNA fragmentation profile.
Applicant remarks Heitzer is only relied upon as evidence, but does not identify a disclosure in Heitzer for the ration, and therefore, Lo in view of Ma and Chiu as evidenced by Heitzer does not disclose the present claims (Applicant’s at pg. 14, para. 4 to pg. 15, para. 1).
This argument is not persuasive for the reasons discussed above.
Double Patenting
The various nonstatutory double patenting rejections of claims 70 and 84 in the Office action mailed 22 June 2026 have been withdrawn in view of the cancellation of these claims received 22 Sept. 2026.
The rejection of claims 68, 71-73, and 76-77 on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. US 10,982,279 B2 in view of Lo (2017), as evidenced by Heitzer (2015) in the Office action mailed 22 June 2026 have been withdrawn in view of the claim amendments received 22 Sept. 2026. However, a new grounds of rejection is set forth below, further in view of Chiu (2013).
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 68, 71-73, 76-77, and 86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. US 10,982,279 B2 in view of Lo (2017) and Chiu (2013), as evidenced by Heitzer (2015). Any newly recited portion is necessitated by claim amendment.
Cited reference:
Lo et al., US 2019/0130065 A1; effectively filed 02 Nov. 2017 based on priority to Provisional App. No. 62/580,906 (previously cited);
Lo et al. (referred to as Chiu) US 2013/0237431 A1 (previously cited); and
Heitzer et al. (Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123 previously cited)
Regarding instant claim 68¸ reference claim 1 discloses a method comprising processing cfDNA fragments obtained from a sample into sequencing libraries, which would involve obtaining a sample and extracting and purifying cfDNA from the sample.
Reference claim 1 discloses subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments, wherein genome coverage is about 9× to 0.1x.
Reference claim 1 discloses analyzing, from the cell free DNA (cfDNA) sample of a mammal, genomic intervals of mapped sequences to determine cfDNA fragment lengths and determining the cfDNA fragmentation profile using the lengths (i.e. a cfDNA fragmentation profile in a sample obtained from the subject).
Reference claims 6-11 discloses the various elements of the fragmentation profile as claimed.
Reference claim 1 further discloses determining the subject has cancer by detecting the cfDNA fragmentation profile is more variable than a reference profile (i.e. based on positional fragmentation characteristic differences). Reference claim 1 further discloses detecting that the cfDNA fragmentation profile that is more variable than a reference cfDNA fragmentation profile from a healthy subject (i.e. comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile). Reference claim 1 further discloses the increased variability of the fragmentation profile obtained from the mammal compared to the reference profile (i.e. the cfDNA fragmentation profile is different from the reference fragmentation profile) is indicative of the mammal as having cancer and that the mammal was identified as having cancer.
Reference claim 1 discloses the administering step.
Further regarding instant claim 68, the reference claims do not disclose determining the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject or that the sample is a plasma sample.
However, Lo discloses a method for detecting cancer in a subject (Abstract; [0007]; [0028]), comprising determining the presence of a DNA copy number (CN) change of a chromosomal arm in a plasma sample comprising cell-free DNA (cfDNA) from a subject relative to a reference ([0071]; [0097], e.g. cell-free DNA sample; [0098], e.g. copy number determined for chromosomal arm; [0099]; [0109], e.g. the machine learning outputs probability of a copy number aberration based on comparison to a reference size pattern; Fig. 6). Lo further discloses that the determined copy number change of the chromosomal arm relative to the reference indicates cancer and using the determined copy number change to determine a level of cancer in the subject (i.e. classifying the subject as having cancer when there is a change in the copy number relative to the reference) ([0110]; [0120]). Lo discloses determining the change in chromosomal arm copy number from a profile of cfDNA fragment size ratios (i.e. a cfDNA fragmentation profile) determined from a sample of the subject (FIG. 6 #602, 604 and 610; [0097]-[0100]). Lo further discloses the detected change in copy number can be used to indicate cancer in the subject ([0110]; [0120]).
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 a cfDNA fragmentation profile of the subject, to determine the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject, as shown by Lo ([0071] ;[0097]; [0099]; [0109]-[0110]; [0112]; FIG. 6). One of ordinary skill in the art would have been motivated to combine the method of the reference claims and Lo to indicate cancer in the subject, as shown by Lo ([0110]; [0120]), given the reference claims also pertain to identifying cancer in a subject.
Further regarding instant claim 68, the reference claims do not explicitly disclose purifying nucleosome protected cfDNA fragments from the plasma fraction. However, this limitation is inherent in the reference claims, as evidenced by Heizer.
Specifically, Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that the limitation of extracting and purifying nucleosome protected fragments is inherent in extraction and purification of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Therefore, given the reference claims disclose extracting and purifying cfDNA fragments, as discussed above, this inherently discloses that nucleosome-protected cfDNA fragments are extracted and purified.
Regarding instant claim 68, the reference claims in view of Lo do not disclose a small fragment is 100-150 base pairs and a large fragment is 151 to 220 base pairs in length.
However, Chiu similarly discloses a method for determining a cell-free DNA fragmentation profile for a subject (Abstract), which comprises determining a size profile including size parameters ([0051]; [0099]), wherein the size parameters include a ratio of the amount of cfDNA fragment of 100 to 150 base pairs in length to the amount of cfDNA fragments 163-169 base pairs in length (i.e. a ratio of smaller 100-150 base pair fragments to larger 151-220 base pair fragments) ([0019]; [0099]; FIG. 5; FIG. 20). Regarding the claimed range of large fragments of 151 bp to 220 bp in length, the range of 163-169 bp in length is within the claimed range of 151-220 and therefore anticipates the range. See MPEP 2131.03. Chiu further discloses the ratio of small to large fragments is compared to a reference ratio to classify a likelihood cancer exists in the subject ([0174]; FIG. 16A, e.g. higher size ratio corresponds to higher tumor %). Chiu discloses this ratio of small to large fragments is positively correlated with tumor percentage in the subject (FIG. 15A-B; FIG. 16A-B; FIG. 17).
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 size ratio of the reference claims to have utilized a size ratio of 100 to 150 bp to 163-169 bp in the classification of cancer, as shown by Chiu, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of the reference claims and Chiu given Chiu discloses that the size ratio of 100 to 150 bp to 163-169 bp is positively correlated with a tumor percentage in the subject (FIG. 15-17), thus providing a predictive biomarker for cancer classification as performed in the reference claims This modification would have had a reasonable expectation of success given both the reference claims and Chiu use a size ratio of cfDNA fragments to predict cancer in a subject, such that the ratio of Chiu is applicable to the method of the reference claims.
Regarding instant claim 71 ¸ reference claim 1 discloses the reference cfDNA fragmentation profile is from a healthy mammal (i.e. a mammal without cancer).
Regarding instant claim 72, reference claim 1 discloses the reference cfDNA fragmentation profile was generated from cfDNA of a healthy mammal (i.e. a mammal without cancer).
Regarding instant claim 73, instant claim 73 fails to further limit instant claim 68 and thus is rejected for the same reasons as instant claim 68 discussed above.
Regarding instant claim 76, reference claim 9 discloses the cfDNA fragmentation profile comprises the sequence coverage of small cfDNA fragments in genomic intervals across the genome, such that the cfDNA fragmentation profile necessarily comprises the sequence coverage of chromosome arms within the genome.
Regarding instant claim 77, reference claim 15 discloses the genome coverage is from about 2x, 1x, 0.5x, 0.2x or 0.1x.
Regarding instant claim 86, reference claim 8 discloses determining the ratio of small to large cfDNA fragments in windows of mapped sequences, and reference claim 3 discloses the intervals are nonoverlapping.
Claims 68, 71-73, 76-77, and 86 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. US 10,975,431 B2 in view of Lo (2017), as evidenced by Heitzer (2015). Any newly recited portion herein is necessitated by claim amendment.
Cited reference:
Lo et al., US 2019/0130065 A1; effectively filed 02 Nov. 2017 based on priority to Provisional App. No. 62/580,906 (previously cited); and
Heitzer et al. (Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123’ previously cited)
Regarding instant claim 68¸ reference claim 1 discloses a cfDNA fragmentation profile of sequenced fragments obtained through whole genome sequencing of a sample obtained from the subject, and reference claim 13 discloses the genome coverage is 1X genome coverage. Reference claim 16 discloses the sample is a plasma sample.
Reference claim 1 discloses analyzing, from a cell free DNA (cfDNA) sample of a mammal, genomic intervals of mapped sequences to determine a cfDNA fragmentation profile(i.e. a cfDNA fragmentation profile in a sample obtained from the subject).
Reference claims 1 and 7-11 discloses the fragmentation profile comprises small to large fragments, a fragment size distribution, fragment coverage metrics, and positional metrics across the genome.
Reference claim 1 further discloses determining the subject has cancer by detecting the cfDNA fragmentation profile is more variable than a reference profile (i.e. based on fragmentation characteristics). Reference claim 1 further discloses detecting that the cfDNA fragmentation profile that is more variable than a reference cfDNA fragmentation profile (i.e. comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile). Reference claim 1 further discloses the increased variability of the fragmentation profile obtained from the mammal compared to the reference profile (i.e. the cfDNA fragmentation profile is different from the reference fragmentation profile) is indicative of the mammal as having cancer and that the mammal was identified as having cancer.
Reference claim 1 disclose administering an immunotherapeutic treatment to the subject.
Regarding instant claim 68¸ the reference claims do not disclose the following limitations:
Regarding instant claim 68¸ while the reference claims utilize sequenced fragments from whole-genome sequencing data, the claims do not explicitly require a step of processing the cfDNA fragments into sequencing libraries and performing whole genome sequencing on the sequencing library.
However, Lo further discloses processing cfDNA fragments from the subject into sequencing libraries ([0186]; [0190]), and discloses subjecting the sequencing libraries to whole genome sequencing to obtain sequenced fragments ([0032]; [0191], e.g. random sequencing is performed on all nucleic acid fragments in sample).
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 performed the steps of library preparation and whole genome sequencing on the sequencing library, as shown by Lo ([0032]; [0186]; [0190]-[0191]). One of ordinary skill in the art would have been motivated to combine the method of the reference claims with the method of Lo in order to generate the sequenced fragments that are required for the method of the reference claims, thus facilitating the generation of cfDNA fragmentation profiles and the detection of cancer according to the reference claims. This modification would have had a reasonable expectation of success given the reference claims analyze sequenced fragments across a genome, such that the sequencing data of Lo is applicable to the reference claims.
Further regarding instant claim 68, the reference claims do not explicitly disclose purifying nucleosome protected cfDNA fragments from the plasma fraction. However, this limitation is inherent in the reference claims, as evidenced by Heizer.
Specifically, Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that the limitation of extracting and purifying nucleosome protected fragments is inherent in extraction and purification of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Therefore, given the reference claims disclose extracting and purifying cfDNA fragments, as discussed above, this inherently discloses that nucleosome-protected cfDNA fragments are extracted and purified.
Further regarding instant claim 68, the reference claims do not disclose determining the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject.
However, Lo discloses a method for detecting cancer in a subject (Abstract; [0007]; [0028]), comprising determining the presence of a DNA copy number (CN) change of a chromosomal arm in a biological sample comprising cell-free DNA (cfDNA) from a subject relative to a reference ([0071]; [0097], e.g. cell-free DNA sample; [0098], e.g. copy number determined for chromosomal arm; [0099]; [0109], e.g. the machine learning outputs probability of a copy number aberration based on comparison to a reference size pattern; Fig. 6). Lo further discloses that the determined copy number change of the chromosomal arm relative to the reference indicates cancer and using the determined copy number change to determine a level of cancer in the subject (i.e. classifying the subject as having cancer when there is a change in the copy number relative to the reference) ([0110]; [0120]). Lo discloses determining the change in chromosomal arm copy number from a profile of cfDNA fragment size ratios (i.e. a cfDNA fragmentation profile) determined from a sample of the subject (FIG. 6 #602, 604 and 610; [0097]-[0100]). Lo further discloses the detected change in copy number can be used to indicate cancer in the subject ([0110]; [0120]).
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 determined the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject, as shown by Lo ([0071] ;[0097]; [0099]; [0109]-[0110]; [0112]; FIG. 6). One of ordinary skill in the art would have been motivated to combine the method of the reference claims and Lo to indicate cancer in the subject, as shown by Lo ([0110]; [0120]), given the reference claims also pertain to identifying cancer in a subject.
Regarding instant claim 71¸ reference claim 4 discloses the reference cfDNA fragmentation profile is from a healthy subject.
Regarding instant claim 72, reference claim 1 discloses the reference cfDNA fragmentation profile was generated from cfDNA of a healthy subject (i.e. a subject without cancer).
Regarding instant claims 71-72, the reference claims do not disclose that the healthy subject is a mammal.
However, Lo further discloses the reference cfDNA fragmentation profile is determined from subjects without cancer ([0161]), and the subjects can be human (i.e. a mammal without cancer) ([0191]), such that the reference cfDNA fragmentation profile is of at least one mammal without cancer. Lo further discloses the method can be used to administer cancer treatments to the mammal upon identification of cancer ([0033]).
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 obtained the reference cfDNA fragmentation profile from a mammal without cancer, as shown by Lo ([0161]; [0191]). One of ordinary skill in the art would have been motivated to combine the method of the reference claims with the method of Lo to identify cancer in a mammal, specifically, facilitating the administration of cancer therapy to a mammal, as shown by Lo ([0033]). This modification would have had a reasonable expectation of success because the method of the reference claims analyze cfDNA from a subject, which could also be applied to a mammal subject.
Regarding instant claim 73, instant claim 73 fails to further limit instant claim 68 and thus is rejected for the same reasons as instant claim 68 discussed above.
Regarding instant claim 76, reference claims 8-10 disclose the cfDNA fragmentation profile comprises an amount of small and large cfDNA fragments in genomic intervals across the genome, such that the cfDNA fragmentation profile necessarily comprises the sequence coverage of chromosome arms within the genome.
Regarding instant claim 77, reference claim 13 discloses the genome coverage is from about 2x, 1x, 0.5x, 0.2x or 0.1x.
Regarding instant claim 86, reference claim 11 discloses the fragmentation profile comprises small and large cfDNA fragments in windows across the genome.
Claims 68, 71-73, 76-77, and 86 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 68, 70, 73-76, 78-83, 85, and 88-97 of copending Application No. 17/204,892 in view of Lo (2017) as evidenced by Heitzer (2015). Any newly recited portion is necessitated by claim amendment.
Cited reference:
Lo et al., US 2019/0130065 A1; effectively filed 02 Nov. 2017 based on priority to Provisional App. No. 62/580,906 (previously recited); and
Heitzer et al. (Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123’ previously cited)
Regarding instant claim 68, reference claim 68 discloses the limitations of instant claim 68, except for determining the existence of a change in chromosomal arm DNA copy number from the sequenced fragments.
Further regarding instant claim 68, the reference claims do not explicitly disclose extracting nucleosome protected cfDNA fragments from the plasma fraction. However, this limitation is inherent in the reference claims, as evidenced by Heizer.
Specifically, Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that the limitation of extracting and purifying nucleosome protected fragments is inherent in extraction and purification of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Therefore, given the reference claims disclose extracting and purifying cfDNA fragments, as discussed above, this inherently discloses that nucleosome-protected cfDNA fragments are extracted and purified.
Further regarding instant claim 68, the reference claims do not disclose determining the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject.
However, Lo discloses a method for detecting cancer in a subject (Abstract; [0007]; [0028]), comprising using a machine learning model to determine the presence of a DNA copy number (CN) change of a chromosomal arm in a biological sample comprising cell-free DNA (cfDNA) from a subject relative to a reference ([0071]; [0097], e.g. cell-free DNA sample; [0098], e.g. copy number determined for chromosomal arm; [0099]; [0109], e.g. the machine learning outputs probability of a copy number aberration based on comparison to a reference size pattern; Fig. 6). Lo further discloses that the determined copy number change of the chromosomal arm relative to the reference indicates cancer and using the determined copy number change to determine a level of cancer in the subject (i.e. classifying the subject as having cancer when there is a change in the copy number relative to the reference) ([0110]; [0120]). Lo discloses determining the change in chromosomal arm copy number from a profile of cfDNA fragment size ratios (i.e. a cfDNA fragmentation profile) determined from a sample of the subject (FIG. 6 #602, 604 and 610; [0097]-[0100]). Lo further discloses the detected change in copy number can be used to indicate cancer in the subject ([0110]; [0120]).
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 a cfDNA fragmentation profile of the subject and determined the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject as shown by Lo ([0071] ;[0097]; [0099]; [0109]-[0110]; [0112]; FIG. 6). One of ordinary skill in the art would have been motivated to combine the method of the reference claims and Lo to indicate cancer in the subject, as shown by Lo ([0110]; [0120]), given the reference claims also pertain to identifying cancer in a subject.
Regarding instant claim 69¸reference claim 89 discloses the limitation of instant claim 69.
Regarding instant claims 71-72, the reference claims do not disclose that the reference cfDNA fragmentation profile was determined from at least one mammal without cancer.
However, Lo further discloses the reference cfDNA fragmentation profile is determined from subjects without cancer ([0161]), and the subjects can be human (i.e. a mammal without cancer) ([0191]), such that the reference cfDNA fragmentation profile is of at least one mammal without cancer. Lo further discloses the method can be used to administer cancer treatments to the mammal upon identification of cancer ([0033]).
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 obtained the reference cfDNA fragmentation profile from a mammal without cancer, as shown by Lo ([0161]; [0191]). One of ordinary skill in the art would have been motivated to combine the method of the reference claims with the method of Lo to identify cancer in a mammal, specifically, facilitating the administration of cancer therapy to a mammal, as shown by Lo ([0033]). This modification would have had a reasonable expectation of success because the method of the reference claims analyze cfDNA from a subject, which could also be applied to a mammal subject.
Regarding instant claim 73, instant claim 73 fails to further limit the subject matter of instant claim 68, and thus is rejected for the same reasons as instant claim 68 discussed above.
Regarding instant claim 76, reference claim 68 discloses the cfDNA fragmentation profile comprises a sequence coverage across the human genome.
Regarding instant claim 77, reference claim 83 discloses the genomic coverage is 0.1x, 0.2x, 0.5x, 1x, or 2x.
Regarding instant claim 86, reference claim 68 discloses the profile includes position dependent fragmentation metrics across the whole genome, and reference claim 76 discloses the genomic intervals are nonoverlapping.
This is a provisional nonstatutory double patenting rejection.
Claims 68, 71-73, 76-77, and 86 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 Lo (2017), as evidenced by Heitzer (2015). Any newly recited portion herein is necessitated by claim amendment.
Cited reference:
Lo et al., US 2019/0130065 A1; effectively filed 02 Nov. 2017 based on priority to Provisional App. No. 62/580,906 (newly cited); and
Heitzer et al. (Circulation Tumor DNA as a Liquid Biopsy for Cancer, 2015, Clinical Chemistry, 61:1, pg. 112-123; previously cited)
Regarding instant claim 68¸ reference claim 1 discloses processing cfDNA fragments of a sample into sequencing libraries.
Reference claim 1 discloses subjecting the sequencing libraries to low-coverage whole genome sequencing to obtain sequencing fragments. Regarding the ow-coverage whole genome sequencing (i.e. 0.1x-10x). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See MPEP 2144.05.
Reference claim 1 discloses mapping the sequenced fragments to a genome to obtained mapped sequences (i.e. location data) used to generate size information.
Reference claim 1 discloses determining cfDNA fragment lengths according to the mapped windows (i.e. the cfDNA fragmentation profile). Reference claims 1 and 6-11 disclose the elements of the fragmentation profile as claimed.
Reference claim 14 discloses determining a cell free DNA (cfDNA) fragmentation profile in a sample from a mammal, comparing the cfDNA fragmentation profile to a reference cfDNA fragmentation profile, and identifying the mammal as having cancer when the cfDNA fragmentation profile obtained from the mammal is different from the reference cfDNA fragmentation profile.
Reference claim 1 discloses the administering step.
Further regarding instant claim 68, the reference claims do not explicitly disclose purifying nucleosome protected cfDNA fragments from the plasma fraction. However, this limitation is inherent in the reference claims, as evidenced by Heizer.
Specifically, Heitzer reviews the use of circulating tumor DNA as a liquid biopsy for cancer, and discloses that since 1994, numerous studies have analyzed DNA in plasma (i.e. cfDNA), including by performing library preparation and whole-genome sequencing (pg. 118, col. 3, para. 4 to pg. 119, col. 1, para. 1). Heitzer discloses such liquid biopsies include blood collection, processing, and DNA extraction from plasma fractions (pg. 120, col. 2, para. 3), and that it is known that cell-free DNA fragments being analyzed in plasma correspond to nucleosome-protected fragments, such that the limitation of extracting and purifying nucleosome protected fragments is inherent in extraction and purification of cell-free DNA from plasma (Fig. 4; pg. 114, col. 2, para. 1). Therefore, given the reference claims disclose extracting and purifying cfDNA fragments, as discussed above, this inherently discloses that nucleosome-protected cfDNA fragments are extracted and purified.
Further regarding instant claims 68, the reference claims do not disclose determining the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject, as recited in claim 68.
However, Lo discloses a method for detecting cancer in a subject (Abstract; [0007]; [0028]), comprising using a machine learning model to determine the presence of a DNA copy number (CN) change of a chromosomal arm in a biological sample comprising cell-free DNA (cfDNA) from a subject relative to a reference ([0071]; [0097], e.g. cell-free DNA sample; [0098], e.g. copy number determined for chromosomal arm; [0099]; [0109], e.g. the machine learning outputs probability of a copy number aberration based on comparison to a reference size pattern; Fig. 6). Lo further discloses that the determined copy number change of the chromosomal arm relative to the reference indicates cancer and using the determined copy number change to determine a level of cancer in the subject (i.e. classifying the subject as having cancer when there is a change in the copy number relative to the reference) ([0110]; [0120]). Lo discloses determining the change in chromosomal arm copy number from a profile of cfDNA fragment size ratios (i.e. a cfDNA fragmentation profile) determined from a sample of the subject (FIG. 6 #602, 604 and 610; [0097]-[0100]). Lo further discloses the detected change in copy number can be used to indicate cancer in the subject ([0110]; [0120]).
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 a cfDNA fragmentation profile of the subject, to determine the existence of a change in chromosomal arm DNA copy number from a sample of cfDNA from the subject, as shown by Lo ([0071] ;[0097]; [0099]; [0109]-[0110]; [0112]; FIG. 6). One of ordinary skill in the art would have been motivated to combine the method of the reference claims and Lo to indicate cancer in the subject, as shown by Lo ([0110]; [0120]), given the reference claims also pertain to identifying cancer in a subject.
Regarding instant claims 71-72,, reference claims 15-16 disclose the reference cfDNA fragmentation profile was generated from a cfDNA fragmentation profile in a sample obtained from a healthy mammal (i.e. a mammal without cancer).
Regarding instant claim 73, instant claim 73 fails to further limit the subject matter of instant claim 68, and thus is rejected for the same reasons as instant claim 68 discussed above.
Regarding instant claim 76, reference claims 9-11 disclose the cfDNA fragmentation profile comprises sequence coverage across the genome.
Regarding instant claim 77, reference claim 1 discloses subjecting the sequencing libraries to low-coverage whole genome sequencing (i.e. 0.1x-10x), which encompasses the range of 2x to 0.1x. "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See MPEP 2144.05.
Regarding instant claim 86, reference claim 1 discloses determining the ratio across windows of mapped sequences, and reference claim 3 discloses the windows are nonoverlapping windows.
Response to Arguments
Applicant's arguments filed 22 Sept. 2026 regarding double patenting have been fully considered but they are not persuasive.
Applicant remarks the double patenting rejections are traversed, and requests the rejections be held in abeyance till the claims are otherwise found allowable (Applicant’s remarks at pg. 16, para. 2-7).
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 applications and patents. Furthermore, as filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. See MPEP 804.
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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