DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5 March 2026 has been entered.
Comments
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
Claims 21, 23-29, 31-36, and 38-40 are pending and examined in the instant Office action.
In the instant claim listing of 3/5/2026, each of dependent claims 22, 30, and 37 in the prior claim listing of 9/25/2025 is now canceled and incorporated into independent claims 21, 29, and 26, respectively.
Even though the claims recite judicial exceptions, the claims are subject matter eligible because the claims result in the practical application of a more computationally efficient analysis of genetic data than conventional techniques with the analogous objective.
Information Disclosure Statement
The IDS of 3/5/2026 has been considered.
Disclosure
The disclosure is objected to because the disclosure contains sequences that require a sequence listing. The sequence listing is required as per 37 CFR 1.821(c) with an incorporated by reference statement (i.e. referring to the sequence listing) as per 37 CFR 1.77(b)(5).
Specifically, Figure 3 of the drawings illustrates multiple DNA sequences with lengths of 10 bases or greater.
Claim Rejections - 35 USC § 103
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.
The following rejection is reiterated:
35 U.S.C. 103 Rejection #1:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kural [WO 2015/058097 A1; on IDS of 11/30/2022] in view of Olsson et al. [EMBO Mol Med, volume 7, 18 May 2015, pages 1034-1047; on IDS of 11/30/2022] in view of Vogelstein et al. [WO 2011/103236 A2; on IDS of 11/30/2022].
Claim 21 is drawn to a method for monitoring a tumor of a patient over time. The method comprises creating a patient-specific genomic reference graph that represents at least one non-tumor sequence previously obtained by sequencing non-tumor DNA from the patient. The creating comprises updating an initial genomic reference graph to include the at least one non-tumor sequence. The updating comprises aligning the at least one non-tumor sequence to the initial genomic reference graph. The initial genomic reference graph represents a plurality of known human genomic sequences. The updating comprises identifying mutations of the at least one non-tumor sequence relative to the initial genomic reference graph. The updating comprises incorporating the identified mutations into the initial genomic reference graph to create the patient-specific genomic reference graph.
The patient-specific genomic reference graph comprises a directed acyclic graph having nodes and edges connecting the nodes. The method requires that the first node is stored as a first object. The method requires that the second node is stored as a second object. The method requires that a first edge of the edges is stored as a pointer from the first object to the second object. The method comprises aligning a first set of sequence reads, previously obtained by sequencing a first sample containing cell-free plasma DNA from the patient, to the patient-specific genomic reference graph to identify a first population of one or more mutations in the cell-free plasma DNA relative to the at least one non-tumor sequence from the patient. The method comprises aligning a second set of sequence reads, previously obtained by sequencing a first sample containing cell-free plasma DNA from the patient, to the patient-specific genomic reference graph to identify a second population of one or more mutations in the cell-free plasma DNA relative to the at least one non-tumor sequence from the patient. The method requires that the first sample is obtained at a first time and the second sample is obtained at a second time after the first time. The method comprises generating a report indicating a comparison between the first population of one or more mutations and the second population of one or more mutations.
Claim 29 is drawn to similar subject matter as claim 21, except claim 29 is drawn to a non-transitory computer readable medium.
Claim 36 is drawn to similar subject matter as claim 21, except claim 36 is drawn to a system.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. The abstract of Kural teaches aligning reference sequences with sequences of an individual progressing through a disease. Figures 2 and 6 of Kural illustrate graphs with nodes and pointed edges comparing healthy to diseased sequences. Figures 2 and 6 of Kural identify mutations in the diseased DNA that are not present in the healthy DNA. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic graph. The paragraph bridging pages 26-27 of Kural teaches the computer storage limitations of the claims. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Page 8 and Figure 9 of Kural suggests that multiple alignments are performed at different times, including a first alignment with a non-cancerous sequence and second alignments with cancerous clones. Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of Kural and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining Kural, Olsson et al., and Vogelstein et al. because all three studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is reiterated:
35 U.S.C. 103 Rejection #2:
Claims 27-28 and 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kural in view of Olsson et al. in view of Vogelstein et al. as applied to claims 21, 23-26, 29, 31-34, 36, and 38-40 above, in further view of Kerns et al. [Int. J. Radiation Oncology Biol. Phys., volume 78, 2010, pages 1292-1300; on attached 892 form].
Claims 27 and 35 are further limiting wherein the second sample is obtained from the patient after administration of a treatment and wherein the method further comprises determining an effectiveness of the treatment based on the comparison between the first population of one or more mutations and the second population of one or more mutations.
Claim 28 is further limiting comprising determining presence and/or progression of the tumor based on the comparison between the first population of one or more mutations and the second population of one or more mutations.
Kural, Olsson et al., and Vogelstein et al. make obvious tumor analysis through analysis of patient-specific genomic graphs over time, as discussed above.
Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
Response to Arguments
Applicant's arguments filed 5 September 2026 have been fully considered but they are not persuasive.
Applicant argues that the amendments to the claims overcome the prior art. This argument is not persuasive Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph.
Applicant has no argument regarding Kerns et al.
Double Patenting
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.
The following rejection is newly applied:
Double Patenting Rejection #1:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 14-16, and 20 of U.S. Patent No. 11,447,828 B2 [on IDS of 3/5/2026] in view of Kural in view of Olsson et al. al. in view of Vogelstein et al.
Both the instant claims sand the claims of ‘828 involve using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer. The claims of ‘828 do not teach use of sequencing, cell free DNA, and a patient-specific genomic reference graph.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Figure 2 of Kural illustrates incorporating mutations into the graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘828 by use of the sequencing limitations of Kural wherein the motivation would have been that the sequencing of Kural provides authentic biological data to which to apply the genomic data analysis [paragraphs 16 and 29-30 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘828 and the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘828, the alignment of diseased to normal DNA in graphs to detect disease of Kural, and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining the claims of ‘828, Kural, Olsson et al., and Vogelstein et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #2:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8, 14, and 18-19 of U.S. Patent No. 10,053,736 B2 [on IDS of 11/30/2022] in view of Kural in view of Olsson et al. al. in view of Vogelstein et al.
Both the instant claims sand the claims of ‘736 involve using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer. The claims of ‘736 do not teach use of sequencing, cell free DNA, and a patient-specific genomic reference graph.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Figure 2 of Kural illustrates incorporating mutations into the graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘736 by use of the sequencing limitations of Kural wherein the motivation would have been that the sequencing of Kural provides authentic biological data to which to apply the genomic data analysis [paragraphs 16 and 29-30 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘736 and the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘736, the alignment of diseased to normal DNA in graphs to detect disease of Kural, and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining the claims of ‘736, Kural, Olsson et al., and Vogelstein et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #3:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7-9, 11, and 25 of U.S. Patent No. 9,898,575 B2 [on attached 892 form] in view of Kural in view of Olsson et al. al. in view of Vogelstein et al.
Both the instant claims sand the claims of ‘575 involve using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer. The claims of ‘575 do not teach use of sequencing, cell free DNA, and a patient-specific genomic reference graph.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Figure 2 of Kural illustrates incorporating mutations into the graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘575 by use of the sequencing limitations of Kural wherein the motivation would have been that the sequencing of Kural provides authentic biological data to which to apply the genomic data analysis [paragraphs 16 and 29-30 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘575 and the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘575, the alignment of diseased to normal DNA in graphs to detect disease of Kural, and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining the claims of ‘575, Kural, Olsson et al., and Vogelstein et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #4:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 13-15, and 19-20 of U.S. Patent No. 10,325,675 B2 [on attached 892 form] in view of Kural in view of Olsson et al. al. in view of Vogelstein et al.
Both the instant claims sand the claims of ‘675 involve using computer processors to apply graphs to analyze variations between reference and test sequences to analyze disease. The claims of ‘675 do not teach cancer, directed acyclic graphs, sequencing, cell free DNA, and a patient-specific genomic reference graph.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Figure 2 of Kural illustrates incorporating mutations into the graph. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply graphs to analyze variations between reference and test sequences to analyze disease of ‘675 by use of the directed acyclic graphs of Kural wherein the motivation would have been that the directed acyclic graphs of Kural provides an additional mathematical tool to facilitate the genomic data analysis [Figure 6 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply graphs to analyze variations between reference and test sequences to analyze disease of ‘675 by use of the sequencing limitations of Kural wherein the motivation would have been that the sequencing of Kural provides authentic biological data to which to apply the genomic data analysis [paragraphs 16 and 29-30 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply graphs to analyze variations between reference and test sequences to analyze disease of ‘675 and the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to using computer processors to apply graphs to analyze variations between reference and test sequences to analyze disease of ‘675, the alignment of diseased to normal DNA in graphs to detect disease of Kural, and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining the claims of ‘675, Kural, Olsson et al., and Vogelstein et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #5:
Claims 21, 23-26, 29, 31-34, 36, and 38-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-40 of copending Application No. 17/853,102 in view of in view of Kural in view of Olsson et al. al. in view of Vogelstein et al.
This is a provisional nonstatutory double patenting rejection.
Both the instant claims sand the claims of ‘102 involve using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer. The claims of ‘102 do not teach use of sequencing, cell free DNA, and a patient-specific genomic reference graph.
The document of Kural studies methods and systems for identifying disease-induced mutations [title]. Pages 29-30 of Kural teach the sequencing limitations of the claims, including sequencing genes in blood plasma. The first full paragraph on page 16 of Kural teaches sequencing a tumor cell of an individual. Figure 2 of Kural illustrates incorporating mutations into the graph.
Kural does not teach cell free DNA. Kural does not teach patient specific genomic data.
The document of Olsson et al. studies serial monitoring of circulating tumor DNA in patients with primary cancer for detecting of occult metastatic disease [title]. The abstract of Olsson et al. teaches that interrogating ctDNA in blood plasma in a convenient manner of detecting cancer metastases. The full paragraph on page 1037 of Olsson et al. teaches assessing cancer state and disease progression at different time points.
Kural and Olsson et al. do not teach patient specific genomic data.
The document of Vogelstein et al. studies personalized tumor biomarkers [title]. Paragraph 33 of Vogelstein et al. studies the pros and cons to finding patient-specific alterations in a genome.
With regard to claims 25, 33, and 40, Figure 9 of Kural illustrates aligning a reference sequence to a plurality of known non-cancerous sequences to detect variants/mutations. Figure 6 of Kural has a notation update to point to placement of the healthy, non-tumor sequence within the directed acyclic (and linear) graph. Figure 2 of Kural illustrates incorporating mutations into the graph. It is interpreted that this incorporation could be accomplished prior to or after the second alignment.
With regard to claims 23-24, 26, 31-32, 34, and 38-39, Figure 2 of Kural teaches a first path through the graph representing a tumor associated mutation. The first paragraph on page 10 of Kural teaches a reference population and subpopulations, and the second paragraph of page 10 of Kural teaches a breast cancer population and subpopulations, which at least suggests a ratio of healthy to diseased populations of both people and genes within an individual.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘102 by use of the sequencing limitations of Kural wherein the motivation would have been that the sequencing of Kural provides authentic biological data to which to apply the genomic data analysis [paragraphs 16 and 29-30 of Kural].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘102 and the alignment of diseased to normal DNA in graphs to detect disease of Kural by use of the ctDNA of Olsson et al. wherein the motivation would have been that detection of diseased DNA in ctDNA is an additional tool making more efficient the detection of metastases of cancer [abstract of Olsson et al.].
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify using computer processors to apply directed acyclic graphs to analyze variations between reference and test sequences to analyze cancer of ‘102, the alignment of diseased to normal DNA in graphs to detect disease of Kural, and the ctDNA of Olsson et al. by use of the patient-specific DNA of Vogelstein et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [paragraph 33 of Vogelstein et al.].
There would have been a reasonable expectation of success in combining the claims of ‘102, Kural, Olsson et al., and Vogelstein et al. because all four studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #6:
Claims 27-28 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 14-16, and 20 of U.S. Patent No. 11,447,828 B2 [on IDS of 3/5/2026] in view of Kural in view of Olsson et al. in view of Vogelstein et al. as applied to Double Patenting Rejection #1 above, in further view of Kerns et al.
The claims of ‘828, Kural, Olsson et al., and Vogelstein et al., make obvious the use of computer processors to process patient-specific directed acyclic graphs analyzing patient-specific cfDNA to analyze the genes for tumor markers and cancer, as discussed in Double Patenting Rejection #1 above.
The claims of ‘828, Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of the claims of ‘828 and Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining the claims of ‘828, Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all five studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #7:
Claims 27-28 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 8, 14, and 18-19 of U.S. Patent No. 10,053,736 B2 [on IDS of 11/30/2022] in view of Kural in view of Olsson et al. in view of Vogelstein et al. as applied to Double Patenting Rejection #2 above, in further view of Kerns et al.
The claims of ‘736, Kural, Olsson et al., and Vogelstein et al., make obvious the use of computer processors to process patient-specific directed acyclic graphs analyzing patient-specific cfDNA to analyze the genes for tumor markers and cancer, as discussed in Double Patenting Rejection #2 above.
The claims of ‘736, Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of the claims of ‘736 and Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining the claims of ‘736, Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all five studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #8:
Claims 27-28 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7-9, 11, and 25 of U.S. Patent No. 9,898,575 B2 [on attached 892 form] in view of Kural in view of Olsson et al. in view of Vogelstein et al. as applied to Double Patenting Rejection #3 above, in further view of Kerns et al.
The claims of ‘575, Kural, Olsson et al., and Vogelstein et al., make obvious the use of computer processors to process patient-specific directed acyclic graphs analyzing patient-specific cfDNA to analyze the genes for tumor markers and cancer, as discussed in Double Patenting Rejection #3 above.
The claims of ‘575, Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of the claims of ‘575 and Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining the claims of ‘575, Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all five studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #9:
Claims 27-28 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 13-15, and 19-20 of U.S. Patent No. 10,325,675 B2 [on attached 892 form] in view of Kural in view of Olsson et al. in view of Vogelstein et al. as applied to Double Patenting Rejection #4 above, in further view of Kerns et al.
The claims of ‘675, Kural, Olsson et al., and Vogelstein et al., make obvious the use of computer processors to process patient-specific directed acyclic graphs analyzing patient-specific cfDNA to analyze the genes for tumor markers and cancer, as discussed in Double Patenting Rejection #4 above.
The claims of ‘676, Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of the claims of ‘675 and Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining the claims of ‘675, Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all five studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
The following rejection is newly applied:
Double Patenting Rejection #10:
Claims 27-28 and 35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-40 of copending Application No. 17/853,102 in view of Kural in view of Olsson et al. in view of Vogelstein et al. as applied to Double Patenting Rejection #5 above, in further view of Kerns et al.
This is a provisional nonstatutory double patenting rejection.
The claims of ‘102, Kural, Olsson et al., and Vogelstein et al., make obvious the use of computer processors to process patient-specific directed acyclic graphs analyzing patient-specific cfDNA to analyze the genes for tumor markers and cancer, as discussed in Double Patenting Rejection #5 above.
The claims of ‘102, Kural, Olsson et al., and Vogelstein et al. do not teach that the second sample is obtained after treatment.
The document of Kerns et al. is genome-wide association study to identify SNPs associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer [title]. The Materials and Methods section on page 1293 of Kerns et al. teaches sequencing analysis for SNPs in two sets of men after radiation treatment for prostate tumors. The first set of men is men without erectile dysfunction before and after treatment with radiation for prostate tumors. The second set of men is men with erectile dysfunction after treatment with radiation for prostate tumors, but without erectile dysfunction before the radiation. Table 2 on page 1296 of Kerns et al. lists the SNPs most likely responsible for the change.
It would have been obvious to someone of ordinary skill in the art at the time of the effective filing date of the instant application to modify the alignment of diseased to normal DNA in graphs to detect disease of the claims of ‘102 and Kural, the ctDNA of Olsson et al., and the patient-specific DNA of Vogelstein et al. by use of the sequencing after cancer treatment of Kerns et al. wherein the motivation would have been that the additional patient specific DNA adds to the pool of DNA data used to differentiate between normal and diseased DNA [abstract of Kerns et al.].
There would have been a reasonable expectation of success in combining the claims of ‘102, Kural, Olsson et al., Vogelstein et al., and Kerns et al. because all five studies analogously pertain to the problem of detecting disease in diseased patient by measuring variations in DNA.
Related Prior Art
The prior art documents of Kural [WO 2015/058093; on IDS] and [WO2015/058095; on IDS] also teach alignment of DNA molecules using graph theory. However, alignment and graphing as pertaining to disease is not as prominent as in the document of Kural cited in the rejections of the instant Office action.
E-mail Communications Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300):
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Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Russell Negin, whose telephone number is (571) 272-1083. This Examiner can normally be reached from Monday through Thursday from 8 am to 3 pm and variable hours on Fridays.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s Supervisor, Larry Riggs, Supervisory Patent Examiner, can be reached at (571) 270-3062.
/RUSSELL S NEGIN/ Primary Examiner, Art Unit 1686 29 March 2026