DETAILED ACTION
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 .
Claims Status
Claims 1-6, 8, 9, 11-16, 23-27, 29, 30, 32-37, & 40 filed on 03/16/2026 are pending. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-6, 8, 9, 11-16, 23-27, 29, 30, 32-37, & 40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the recitation of “generating clusters of TF binding sites based on the estimated cfDNA fragment length distributions” in lines 7-8 of the claim is unclear what the relationship is between clusters of TF binding sites and being “based on” estimated cfDNA fragment length distributions.
Regarding claim 23, the recitation of “generating clusters of TF binding sites based on the estimated cfDNA fragment length distributions” in lines 8-9 of the claim is unclear what the relationship is between clusters of TF binding sites and being “based on” estimated cfDNA fragment length distributions.
Regarding claim 40, the recitation of “generating clusters of TF binding sites based on the estimated cfDNA fragment length distributions” in lines 8-9 of the claim is unclear what the relationship is between clusters of TF binding sites and being “based on” estimated cfDNA fragment length distributions.
Claims 2-6, 8, 9, 11-16 are rejected due to their dependence on claim 1 and claims 24-27, 29, 30, 32-37 are rejected due to their dependence on claim 23.
Claim Rejections - 35 USC § 102
Claim(s) 1-6, 11, 12, & 13-16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Snyder (Snyder et al.; Cell, Vol. 164, pages 57-68, January 2015), as cited on the IDS dated 04/05/2023.
Regarding amended claim 1, it is noted that the pg. 14 of the instant specification teaches that cfDNA fragments shorter than about 147 bp are fragments associated with subnucleosomes (pg. 14 of instant specification).
Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (obtaining a map of subnucleosomes at promoters associated with a map of TF binding sites through the sequencing of cfDNA) to infer cell types contributing to pathological states such as cancer and to determine patterns of nucleosome spacing that correlate with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (determining whether the subject has the disease or disorder if the map for the subject matches a signature for an individual having the disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11). In addition, Snyder teaches that cfDNA fragments of nucleosomes peak at a range around 147 bp and that the method of single-stranded sequencing library preparation used in the method results in enrichment of short fragments of cfDNA ranging from 50-120 bp (subnucleosomes has a fragment length distribution of less than about 147 basepairs) (pg. 57 paragraph bridging column 1 & 2 lines 11-13; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-7; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5;Figure 1(D)). In addition, Snyder teaches this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4).
Regarding claim 2, Snyder teaches that a map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (a map of subnucleosomes at promoters associated with a map of TF binding sites) in healthy individuals correlates with particular tissue or cell types of lymphoid and myeloid cell lines (subject is determined to be free of disease or disorder if the map for the subject matches a signature for an individual that is healthy/free of disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61 paragraph bridging column 1 & 2 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11; pg. 62-63 paragraph bridging pg. 62 & pg. 63 lines 15-19).
Regarding claim 3, Snyder teaches that a map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in healthy individuals correlates with particular tissue or cell types of lymphoid and myeloid cell lines (the signature for an individual that is free of disease or disorder comprises sites in lymphoid and myeloid cells) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61 paragraph bridging column 1 & 2 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11; pg. 62-63 paragraph bridging pg. 62 & pg. 63 lines 15-19).
Regarding claim 4, Snyder teaches that a map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in cancer patients correlates with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (the signature for an individual having the disease or disorder comprises sites in cells associated with the disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11).
Regarding claims 5 & 6, Snyder teaches the disease is ductal carcinoma in situ breast cancer (disease or disorder is breast cancer) (pg. 63 column 1 1st full paragraph lines 1-8 & 14-19).
Regarding claims 11 & 12, Snyder teaches the cfDNA is sequenced on a single-stranded cfDNA sequencing library derived from the subject comprising identifying fragment length distribution that is enriched for shorter fragments (identifying unique length profiles), obtaining a map of nucleosome occupancy and footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (obtaining a map of cfDNA fragments identifying transcription start sites (TSS)) in which TSS of shorter cfDNA indicates a map of transcription factor binding sites and gene expression (provides a map of TF binding and a map of gene expression) (pg. 58 column 1 2nd full paragraph lines 5-16; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11; pg. 63 column 1 1st full paragraph lines 1-6; pg. 65 column 2 3rd full paragraph lines 6-7; Figure 1).
Regarding claim 13, Snyder teaches that cfDNA fragments of nucleosomes peak at a range around 147 bp and that the method of single-stranded sequencing library preparation results in enrichment of short fragments of cfDNA ranging from 50-120 bp (cfDNA associated with TF binding has a fragment length distribution of less than about 147 basepairs) (pg. 57 paragraph bridging column 1 & 2 lines 11-13; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-7; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5; Figure 1(D)).
Regarding claim 14, Snyder teaches that this method enables observations in nucleosome footprints to infer cell types contributing to cfDNA in pathological states in which the nucleosome footprint in healthy individuals correlates with particular tissue or cell types of lymphoid and myeloid cell lines compared to the footprint in cancer patients that correlates with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (comparing the map of subnucleosomes at promoters and TF binding sites for the subject to a map for a healthy individual to a map of an individual having disease or disorder) (abstract lines 1-21; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17).
Regarding claims 15 & 16, Snyder teaches the samples comprises human plasma from healthy individuals and breast cancer patients (patient-derived xenograft (PDX) is breast cancer PDX) (pg. 63 column 1 1st full paragraph lines 1-6; pg. 65 column 2 2nd full paragraph lines 1-10).
Response to Arguments
The response traverses the rejection. The response asserts that independent claim 1, as amended herein, more particularly points out that obtaining the map of subnucleosomes at TF binding sites comprises estimating cfDNA fragment length distribution, generating clusters of TF binding sites based on the estimated cfDNA fragment length distributions to identify a subset of TF biding sites having a fragment length distribution characteristic of TF occupancy and while Snyder generally discusses cfDNA based analysis and promoter or TF-related genomic analysis, Snyder fails to teach generating clusters of TF binding sits based of cfDNA fragment length distributions to identify a subset of TF binding sites based on cfDNA fragment length distribution characteristic of TF occupancy at these binding sites. This argument has been thoroughly reviewed but was not found persuasive as, as discussed above, Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in which this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4). Therefore, Snyder teaches every limitation of amended claim 1.
The response also asserts that applicant submits that independent claim 1, as amended herein, and dependent claims 2-6, 11, 12, & 13-16 which depend either directly or indirectly from independent claim 1, are not anticipated by Snyder. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 8 & 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Snyder (Snyder et al.; Cell, Vol. 164, pages 57-68, January 2015), as cited on the IDS dated 04/05/2023, in view of Hurtado (Hurtado et al.; Nature Genetics, Vol. 43, pages 27-34, January 2011), as cited on the IDS dated 04/05/2023.
The teachings of Snyder with respect to claim 1 is discussed above and incorporated herein.
Regarding claims 8 & 9, Snyder does not teach that the TF binding sites comprises a map of FOXA1 binding sites (see claim 8) or a map of estrogen binding (ER) binding sites (see claim 9).
Hurtado teaches that estrogen receptor (ER) is a defining feature of breast cancer as it functions as a transcription factor to regulate cell division and further that FOXA1 is found at many ER binding regions and is sufficient to permit ER-chromatin interactions and transcriptional activity in diverse target tissues (pg. 27 column 1 1st full paragraph lines 1-2; pg. 27 column 1 2nd full paragraph 6-7; pg. 27 paragraphs bridging column 1 & 2 lines 6-11). In addition, Hurtado teaches that FOXA1 can predict outcome in patients with ER-positive breast cancer (pg. 27 column 1 2nd full paragraph lines 12-13).
Snyder and Hurtado are considered to be analogous to the claimed invention because they are all in the same field of transcription factor activity in breast cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method obtaining a map of TF binding sites in cfDNA breast cancer samples in Snyder to incorporate including a map of FOXA1 binding sites (see claim 8) and a map of ER binding sites (see claim 9) as taught in Hurtado because Hurtado teaches that doing so would provide a method to analyze transcriptional activity in target tissues and predict clinical outcome in patients with ER-positive breast cancer.
Claim(s) 23-27, 32-37, & 40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Snyder (Snyder et al.; Cell, Vol. 164, pages 57-68, January 2015), as cited on the IDS dated 04/05/2023, in view of Abdueva (WO 2018/009723 A1, January 2018), as cited on the IDS dated 03/17/2023.
Regarding amended claim 23, it is noted that the pg. 14 of the instant specification teaches that cfDNA fragments shorter than about 147 bp are fragments associated with subnucleosomes (pg. 14 of instant specification).
Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (obtaining a map of subnucleosomes at promoters associated with a map of TF binding sites through the sequencing of cfDNA) to infer cell types contributing to pathological states such as cancer and to determine patterns of nucleosome spacing that correlate with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (determining whether the subject has the disease or disorder if the map for the subject matches a signature for an individual having the disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11). In addition, Snyder teaches that cfDNA fragments of nucleosomes peak at a range around 147 bp and that the method of single-stranded sequencing library preparation used in the method results in enrichment of short fragments of cfDNA ranging from 50-120 bp (subnucleosomes has a fragment length distribution of less than about 147 basepairs) (pg. 57 paragraph bridging column 1 & 2 lines 11-13; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-7; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5;Figure 1(D)). In addition, Snyder teaches this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4).
Snyder does not teach determining whether treatment of the subject is effective if the map of subnucleosomes at promoters associated with the map of TF binding sites for the subject starts to approximate a signature for an individual that is free of the disease or disorder.
Abdueva teaches a method for obtaining sequence information of cfDNA fragments from a subject, both healthy and diseased subjects, and performing analysis on the cfDNA sequence information including a likelihood that a mappable base-pair position will appear within a sequenced DNA fragment as a consequence of differential nucleosome occupancy occurring at one or more transcription start sites of promoter regions for transcription factor binding site (TFBS) occupancy analysis (obtaining a map of subnucleosomes at promoters associated with a map of TF binding sites through sequencing) and that this method can be used to assess therapeutic intervention and disease score as a health status indicator of the subject (determining whether the treatment of the subject is effective if TF binding sites of the subject starts to approximate a signature for an individual that is free of the disease or disorder) (paragraph [0004] lines 1-2; paragraph [0017] lines 1-6; paragraph [0018] lines 5-7; paragraph [0022] lines 5-8; paragraph [0264] lines 1-5; paragraph [00265] lines 1-5; paragraph [00266] lines 1-5; paragraph [00268] lines 13-14). In addition, Abdueva teaches that this method for analyzing nucleosomal positioning can yield a for more comprehensive assessment of tumor status (paragraph [0002] lines 4-11).
Snyder and Abdueva are considered to be analogous to the claimed invention because they are all in the same field of analysis of sequenced cfDNA to obtain a map of subnucleosomes associated with a map of TF binding for analysis of cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints for disease analysis in healthy individuals and cancer patients in Snyder to incorporate the use of this method for determining whether therapeutic intervention is successful and the health status of the subject as taught in Abdueva because Abdueva teaches that doing so would provide a method that can yield a more comprehensive assessment of tumor status.
Regarding claim 24, Snyder teaches that a map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in healthy individuals correlates with particular tissue or cell types of lymphoid and myeloid cell lines (the signature for an individual that is free of disease or disorder comprises sites in lymphoid and myeloid cells) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61 paragraph bridging column 1 & 2 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11; pg. 62-63 paragraph bridging pg. 62 & pg. 63 lines 15-19).
Regarding claim 25, Snyder teaches that a map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in cancer patients correlates with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (the signature for an individual having the disease or disorder comprises sites in cells associated with the disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11).
Abdueva teaches that the method of obtaining mappable nucleosomal positioning through base-pair position appearing within a sequenced DNA fragment as a consequence of differential nucleosome occupancy occurring at one or more transcription start sites of promoter regions for transcription factor binding site (TFBS) occupancy analysis can be used to determine treatment options and selection of treatment (subject is determined to require further, or alternate, treatment) (paragraph [00264] lines 1-5).
Regarding claims 26 & 27, Snyder teaches the disease is ductal carcinoma in situ breast cancer (disease or disorder is breast cancer) (pg. 63 column 1 1st full paragraph lines 1-8 & 14-19).
Regarding claims 32 & 33, Snyder teaches the cfDNA is sequenced on a single-stranded cfDNA sequencing library derived from the subject comprising identifying fragment length distribution that is enriched for shorter fragments (identifying an enrichment of cfDNA fragments associated with subnucleosomes over fragments associated with nucleosome and/or chromatosomes), obtaining a map of nucleosome occupancy and footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (obtaining a map of cfDNA fragments identifying transcription start sites (TSS)) in which TSS of shorter cfDNA indicates a map of transcription factor binding sites and gene expression (provides a map of TF binding and a map of gene expression) (pg. 58 column 1 2nd full paragraph lines 5-16; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11; pg. 63 column 1 1st full paragraph lines 1-6; pg. 65 column 2 3rd full paragraph lines 6-7; Figure 1).
Regarding claim 34, Snyder teaches that cfDNA fragments of nucleosomes peak at a range around 147 bp and that the method of single-stranded sequencing library preparation results in enrichment of short fragments of cfDNA ranging from 50-120 bp (cfDNA associated with TF binding has a fragment length distribution of less than about 147 basepairs) (pg. 57 paragraph bridging column 1 & 2 lines 11-13; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-7; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5; Figure 1(D)).
Regarding claim 35, Snyder teaches that this method enables observations in nucleosome footprints to infer cell types contributing to cfDNA in pathological states in which the nucleosome footprint in healthy individuals correlates with particular tissue or cell types of lymphoid and myeloid cell lines compared to the footprint in cancer patients that correlates with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (comparing the map of subnucleosomes at promoters and TF binding sites for the subject to a map for a healthy individual to a map of an individual having disease or disorder) (abstract lines 1-21; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17).
Abdueva teaches that the method of obtaining mappable nucleosomal positioning through base-pair position appearing within a sequenced DNA fragment as a consequence of differential nucleosome occupancy occurring at one or more transcription start sites of promoter regions for transcription factor binding site (TFBS) occupancy analysis can be used to determine treatment options and selection of treatment and indication of health status through assessing one or more healthy reference models and one or more diseased reference models (determining whether treatment is effective comprising comparing the map of individual free of disease or disorder to map of individual having the disease or disorder) (paragraph [00264] lines 1-5; paragraph [00266] lines 1-5).
Regarding claims 36 & 37, Snyder teaches the samples comprises human plasma from healthy individuals and breast cancer patients (patient-derived xenograft (PDX) is breast cancer PDX) (pg. 63 column 1 1st full paragraph lines 1-6; pg. 65 column 2 2nd full paragraph lines 1-10).
Regarding amended claim 40, it is noted that the pg. 14 of the instant specification teaches that cfDNA fragments shorter than about 147 bp are fragments associated with subnucleosomes (pg. 14 of instant specification).
Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) (obtaining a map of subnucleosomes at promoters associated with a map of TF binding sites through the sequencing of cfDNA) to infer cell types contributing to pathological states such as cancer and to determine patterns of nucleosome spacing that correlate with non-hematopoietic tissue or cell lines that often match with the anatomical origin of a patients cancer (determining whether the subject has the disease or disorder if the map for the subject matches a signature for an individual having the disease or disorder) (abstract lines 1-21; pg. 57 paragraph bridging column 1 & 2 lines 11-17; pg. 57 column 2 3rd full paragraph lines 1-8; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-17; pg. 61-62 paragraph bridging pg. 61 & pg. 62 lines 1-11). In addition, Snyder teaches that cfDNA fragments of nucleosomes peak at a range around 147 bp and that the method of single-stranded sequencing library preparation used in the method results in enrichment of short fragments of cfDNA ranging from 50-120 bp (subnucleosomes has a fragment length distribution of less than about 147 basepairs) (pg. 57 paragraph bridging column 1 & 2 lines 11-13; pg. 57-58 paragraph bridging pg. 57 & pg. 58 lines 1-7; pg. 59-60 paragraph bridging pg. 59 & pg. 60 lines 3-5;Figure 1(D)). In addition, Snyder teaches this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4).
Snyder does not teach determining whether the subject is having a recurrence of the disease or disorder if the map of subnucleosomes at promoters and TF binding sites for the subject matches the signature for an individual having the disease or disorder.
Abdueva teaches a method for obtaining sequence information of cfDNA fragments from a subject, both healthy and diseased subjects, and performing analysis on the cfDNA sequence information including a likelihood that a mappable base-pair position will appear within a sequenced DNA fragment as a consequence of differential nucleosome occupancy occurring at one or more transcription start sites of promoter regions for transcription factor binding site (TFBS) occupancy analysis (obtaining a map of subnucleosomes at promoters associated with a map of TF binding sites through sequencing) and that this method can be used to assess tumor recurrence (determining whether the subject is having a recurrence of the disease or disorder if the map of subnucleosomes at promoters and TF binding sites for the subject matches the signature for an individual having the disease or disorder) (paragraph [0004] lines 1-2; paragraph [0017] lines 1-6; paragraph [0018] lines 5-7; paragraph [0021] lines 1-11; paragraph [0022] lines 5-8; paragraph [0264] lines 1-5; paragraph [00265] lines 1-5; paragraph [00266] lines 1-5; paragraph [00268] lines 13-14). In addition, Abdueva teaches that this method for analyzing nucleosomal positioning can yield a for more comprehensive assessment of tumor status (paragraph [0002] lines 4-11).
Snyder and Abdueva are considered to be analogous to the claimed invention because they are all in the same field of analysis of sequenced cfDNA to obtain a map of subnucleosomes associated with a map of TF binding for analysis of cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints for disease analysis in healthy individuals and cancer patients in Snyder to incorporate the use of this method for assessing tumor recurrence as taught in Abdueva because Abdueva teaches that doing so would provide a method that can yield a more comprehensive assessment of tumor status.
Claim(s) 29 & 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Snyder (Snyder et al.; Cell, Vol. 164, pages 57-68, January 2015), as cited on the IDS dated 04/05/2023, and Abdueva (WO 2018/009723 A1, January 2018), as cited on the IDS dated 03/17/2023 as applied to claims 23-27, 32-37, & 40 above, and further in view of Hurtado (Hurtado et al.; Nature Genetics, Vol. 43, pages 27-34, January 2011), as cited on the IDS dated 04/05/2023.
The teachings of Snyder and Abdueva with respect to claim 23 is discussed above.
Regarding claims 29 & 30, Snyder and Abdueva does not teach that the TF binding sites comprises a map of FOXA1 binding sites (see claim 29) or a map of estrogen binding (ER) binding sites (see claim 30).
Hurtado teaches that estrogen receptor (ER) is a defining feature of breast cancer as it functions as a transcription factor to regulate cell division and further that FOXA1 is found at many ER binding regions and is sufficient to permit ER-chromatin interactions and transcriptional activity in diverse target tissues (pg. 27 column 1 1st full paragraph lines 1-2; pg. 27 column 1 2nd full paragraph 6-7; pg. 27 paragraphs bridging column 1 & 2 lines 6-11). In addition, Hurtado teaches that FOXA1 can predict outcome in patients with ER-positive breast cancer (pg. 27 column 1 2nd full paragraph lines 12-13).
Snyder, Abdueva, and Hurtado are considered to be analogous to the claimed invention because they are all in the same field of transcription factor activity in breast cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method obtaining a map of TF binding sites in cfDNA breast cancer samples in Snyder to incorporate including a map of FOXA1 binding sites (see claim 29) and a map of ER binding sites (see claim 30) as taught in Hurtado because Hurtado teaches that doing so would provide a method to analyze transcriptional activity in target tissues and predict clinical outcome in patients with ER-positive breast cancer.
Response to Arguments
The response traverses the rejection. The response asserts that claims 8 and 9 include all limitations of independent claim 1 and that independent claim 1, as amended herein, is patentable over Snyder at least for the reasons set forth hereinabove. Further, the response asserts that Hurtado fails to cure the deficiencies of Snyder in teaching the method of the instant claims comprising estimating a cfDNA fragment length distribution. This argument has been thoroughly reviewed but was not found persuasive as, as discussed above, Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in which this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4). Therefore, Snyder teaches the limitation of estimating fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy as currently amended in claim 1.
The response also asserts that independent claims 23 and 40, as amended herein, more particularly points out that obtaining the map of subnucleosomes at TF binding sites comprises estimating cfDNA fragment length distribution, generating clusters of TF binding sites based on the estimated cfDNA fragment length distributions to identify a subset of TF biding sites having a fragment length distribution characteristic of TF occupancy and that Snyder fails to teach the method of independent claims 23 and 40 as amended herein and Abdueva fails to cure the deficiencies of Snyder in generating clusters of TF binding sites based on estimated cfDNA fragment length distributions. This argument has been thoroughly reviewed but was not found persuasive as, as discussed above, Snyder teaches a method for deep-sequencing cell-free DNA to yield a genome-wide map of nucleosome occupancy and footprints in which short cfDNA fragments harbor footprints of transcription factor binding sites in the vicinity of transcriptional start sites (TSS) in which this method comprises determining fragment length distributions of the cfDNA comprising clustering fragment length distributions into short lengths and long lengths in which short cfDNA fragment length distribution directly footprint occupancy of DNA-bound TFs (estimating a cfDNA fragment length distribution at each individual TF binding site and generating clusters of TF binding sites based on the estimated fragment length distributions to identify a subset of TF binding sites having a fragment length distribution characteristic of TF occupancy) (pg. 58 column 1 1st full paragraph lines 1-15; pg. 58 column 1 2nd full paragraph lines 5-16; pg. 58 column 2 2nd full paragraph lines 1-5; pg. 59-60 paragraph bridging pg. 59 & 60 lines 16; pg. 61 column 1 1st full paragraph lines 1-10; Figure 1; Figure 2; Figure 4). Therefore, Snyder teaches every limitation of amended claims 23 and 40.
The response also asserts that independent claims 23 and 40, and dependent claims 24-27 and 32-37, which depend either directly or indirectly from and include all the limitations of claims 23, are patentable over Snyder in view of Abdueva. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
The response also asserts that claims 29 and 30 depend from and include all the limitations of independent claim 23 and that independent claim 23, as amended herein, is patentable over Snyder in view of Abdueva at least for the reasons set for hereinabove and that Hurtado fails to cure the deficiencies of Snyder and Abdueva in teaching the method of the instant claims. This argument has been thoroughly reviewed but was not found persuasive for the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 1-6, 8, 9, 11-16, 23-27, 29, 30, 32-37, & 40 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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