DETAILED ACTION
The amendment filed on 12/01/2025 has been entered.
Claims 21, 30-33, 36, and 38-40 were amended in the claim set filed on 12/01/2025.
Claims 24-26, 34-35, and 37 were canceled in the claim set filed on 12/01/2025.
Claims 41-46 were added in the claim set filed on 12/01/2025. No new matter was added.
Election/Restrictions
Newly submitted claims 44-46 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: Claims 32-33, 36, 38-40, were amended from the original species, drawn to a method of quantifying cell free DNA (cfDNA) fragments based on anatomic origin, to be drawn to independent/distinct invention drawn to a nucleic acid sequencing system configured to quantify cell free DNA (cfDNA) fragments based on anatomic origin. The system is interpreted as a product.
Group I, claims 21-23, 27-31 and 41-43, drawn to a method of quantifying cell free DNA (cfDNA) fragments based on anatomic origin
Group II, claim 32-33, 36, 38-40, 44-46, drawn to a nucleic acid sequencing system configured to quantify cell free DNA (cfDNA) fragments based on anatomic origin.
The groups of inventions listed above do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
Groups I-II lack unity of invention because even though the inventions of these groups require the technical feature of quantifying cell free DNA (cfDNA) fragments based on anatomic origin as recited in claims 21 and 32, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018).
Liu discloses methods of analyzing DNA methylation in cell-free DNA (cfDNA) and genomic DNA (gDNA) from sequencing data. (Abstract)
Liu teaches a method of “characterizing DNA in a biological sample, the method involving isolating fragments of DNA from a biological sample, constructing a library comprising the fragments, sequencing the library… of cell free DNA” (Pg. 2 ln 16-18.). Liu teaches a method comprising “whole genome sequencing” (Pg. 3 ln 32). Liu teaches a method wherein “computer-implemented method… using a... window analysis and programming, to obtain the tissue of origin of the biological sample” (Pg. 5 ln 1-4). In this manner, the skilled person would arrive at the technical feature with a reasonable expectation of success.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 32-33, 36, 38-40 and 44-46 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claims 21-23, 27-31 and 41-43 in the claim set filed on 12/01/2025 are currently under examination.
Response to the Arguments
Objections to the claim 32 in the previously mailed non-final have been withdrawn in light of applicants amendments to the claims.
Applicant’s arguments regarding previous rejection(s) of claim(s) 21-23, 27-31 under 35 U.S.C. 101, have been fully considered but are not persuasive. The 35 U.S.C. 101 rejections documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 6-27. As necessitated by amendment to the claims, revised rejections for 21-23, 27-31 and 41-43 under 35 U.S.C. 101 are documented below, in this office action on Pg. 5-8.
Applicant’s arguments regarding previous rejection(s) of claim(s) 21-40 under 35 U.S.C. 103 have been fully considered but are not persuasive. Applicant’s argument on Pg. 12, states that “Liu, taken alone or in hypothetical combination with Gross, Hubbell, or Shendure fail to teach or suggest all of the elements of independent claims 21 and 32” The 35 U.S.C. 103 rejections documented in the previously mailed non-final have been maintained and revised in light of applicants claim amendments and arguments on Pg. 27-30. As necessitated by amendment to the claims, revised rejections for 21-23, 27-31 and 41-43 under 35 U.S.C. 103 are documented below, in this office action on Pg. 9-18.
The revised rejections for claims 21-23, 27-31 and 41-43 are documented below in this Final Office Action are necessitated by claim amendments filed on 12/01/2025.
Priority
This application claims priority to and the benefit of International Application No. PCT/US2022/015491, filed on February 7, 2022, which claims priority to and the benefit of U.S. Provisional Application No. 63/147,579, filed on February 9, 2021. Accordingly, the priority date of instant claims is determined to be February 9, 2021, the filing date of U.S. Provisional Application No. 63/147,579.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 21-23, 27-31 and 41-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards abstract ideas of data comparison, mathematical relationship using an algorithm, and routine and conventional methods, without significantly more. The claim(s) recite(s) abstract ideas, mathematical relationship and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 21 is directed towards: A method of quantifying cell free DNA (cfDNA) fragments based on anatomic origin, comprising the steps of: preparing a library using a sample acquired from a subject, wherein the sample comprises cfDNA fragments; performing a whole genome sequencing (WGS)-based assay using the library; based on an output of the WGS-based assay, generating a cfDNA profile for the subject, wherein the cfDNA profile comprises a plurality of copy number signals each corresponding to a respective cfDNA fragment and comparing the cfDNA profile of the subject to a plurality of reference profiles, wherein each reference profile corresponds to a different cell type or tissue type: and determining a relative contribution of each cell type or tissue type for the cfDNA fragments of the sample based on the comparison.
The generating a cfDNA profile for the subject, comparing the cfDNA profile of the subject to a plurality of reference profiles, and determining a relative contribution of each cell type or tissue type for the cfDNA fragments of the sample based on the comparison are identified as an abstract idea directed to an idea of itself related to data comparisons that can be performed mentally or analogous to human mental work aided by a computer algorithm. See MPEP 2106.04 (a)(2).
The preparing a library and performing whole genome sequencing (WGS) are considered active steps. The active steps are routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the sample, preparation of library, WGS-based assay, analysis, algorithm, reference profiles, and contributions of cell type or tissue type.
The instant claim 30 is directed towards: The method of claim 21, wherein a WGS tissue quantification algorithm is used to quantify each cfDNA fragment and accommodates the output of the WGS- based assay having a coverage of 0.2x coverage.
The using WGS tissue quantification algorithm is considered a considered to be active steps requiring a computer algorithm, thus having a mathematical relationship.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract ideas.
The generating a cfDNA profile for the subject, comparing the cfDNA profile of the subject to a plurality of reference profiles, and determining a relative contribution of each cell type or tissue type for the cfDNA fragments of the sample based on the comparison are identified as an abstract idea directed to an idea of itself related to data comparisons that can be performed mentally or analogous to human mental work aided by a computer algorithm. See MPEP 2106.04 (a)(2).
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claims 21-23, 27-31 and 41-43, the claims are similar to the methods of preparing a sample, performing WGS and comparing sample to reference(s) to determine the tissue origin of the cfDNA as that of Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018)
Liu discloses methods of analyzing DNA methylation in cell-free DNA (cfDNA) and genomic DNA (gDNA) from sequencing data. (Abstract) Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require sample, preparation of library, WGS-based assay, analysis, algorithm, reference profiles, and contributions of cell type or tissue type, which are all routine and conventional based on Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018) in view Gross et al. (“Gross”; (2019). Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease. Genetics in Medicine, 21(5), 1121–1130.), Hubbell et al. (“Hubbell”; Patent App. Pub. No. WO 2020132499 A2, Jan. 28, 2016), and Shendure et al. (“Shendure”; Patent App. Pub. No. WO 2016015058 A2, Jan. 28, 2016).
Response to Arguments
Applicant's arguments filed 12/01/2025 (Pg. 11-12) with respect to claims 1, 5, 19-22, 24-27 and 50 have been fully considered but are not persuasive. To clarify some instances argued in the response filed 12/01/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “, the present pending claims are not directed to an abstract idea.” (Pg. 12)
Response: Applicant’s arguments have been fully considered but are unpersuasive because applicants amendments do not overcome the lack of patentably matter under U.S.C. 35 101. The previously presented and amended claims recite abstract idea. Furthermore. the generating a cfDNA profile for the subject, comparing the cfDNA profile of the subject to a plurality of reference profiles, and determining a relative contribution of each cell type or tissue type for the cfDNA fragments of the sample based on the comparison are identified as an abstract idea directed to an idea of itself related to data comparisons that can be performed mentally or analogous to human mental work aided by a computer algorithm. See MPEP 2106.04 (a)(2). The newly added claim recites an abstract idea of comparing. These judicial exceptions are not integrated into a practical application because the claims provide no specific limitations to integrate the judicial exception into a practical application (See MPEP 2106.04(d)). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims provide no specific limitations that provide significantly more (See MPEP 2106.05).
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.
Claim(s) 21-22, 27, 30-31 and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018).
Liu discloses methods of analyzing DNA methylation in cell-free DNA (cfDNA) and genomic DNA (gDNA) from sequencing data. (Abstract)
Regarding claim 21, Liu teaches a method of “characterizing DNA in a biological sample, the method involving isolating fragments of DNA from a biological sample, constructing a library comprising the fragments, sequencing the library… of cell free DNA” (Pg. 2 ln 16-18.). Thus, Liu teaches a method comprising the step of preparing a library using a sample acquired from a subject, wherein the sample comprises cfDNA fragments.
Regarding claim 21, Liu teaches a method of “sequencing the library… of cell free DNA” (Pg. 2 ln 18.) and “whole genome sequencing” (Pg. 3 ln 32). Thus, Liu teaches a method comprising the step of performing a whole genome sequencing (WGS)-based assay using the library.
Regarding claim 21, Liu teaches a method wherein “computer-implemented method… using a... window analysis and programming, to obtain the tissue of origin of the biological sample” (Pg. 5 ln 1-4). Liu teaches a method wherein “A machine learning approach was used to infer the base pair resolution DNA methylation level from fragment size information in whole genome sequencing (WGS)” (Pg. 23 ln 8-12) and “cfDNA's tissue-of-origin status was deconvoluted by inferred DNA methylation level at ULP-WGS from the cell lines” (Pg. 23 ln 16-17). Liu teaches a method wherein “diagnostic methods of the invention are used to detect changes in copy number and/or methylation in a biological sample relative to a reference” (Pg 17 ln 18-19). Liu teaches a method wherein “The tissue-of-origin profiles were inferred in each sample and found high concordance of the tumor fraction estimated based on predicted DNA methylation and measured based on analysis of somatic copy number alterations using ichorCNA” (Pg. 22 ln 23-26). Liu teaches a method wherein “ Liu teaches a method wherein “comparing the subject's alterations in the fragmentation pattern in methylated and unmethylated DNA of cell free DNA and genomic DNA to a healthy reference sample where the detection of differences in the fragmentation pattern between the subject and the reference sample indicates that the subject does have a disease or cancer, and failure to detect such alterations indicates that the subject does not have a disease or cancer" (Pg. 3 ln 18-23). Liu teaches a method wherein “using hundreds of WGBS datasets from different tumor and normal tissues/cells as the reference map, cfDNA's tissue-of-origin status was deconvoluted" (Pg. 23 ln 15-16). “computer-implemented method… using a... window analysis and programming” reads on generating a cfDNA profile. Thus, Liu teaches a method comprising the step of based on an output of the WGS-based assay, generating a cfDNA profile for the subject, wherein the cfDNA profile comprises a plurality of copy number signals each corresponding to a respective cfDNA fragment and comparing the cfDNA profile of the subject to a plurality of reference profiles, wherein each reference profile corresponds to a different cell type or tissue type: and determining a relative contribution of each cell type or tissue type for the cfDNA fragments of the sample based on the comparison.
Furthermore, Liu teaches the limitations of dependent claims 22, 27 30-31 and 41-43 which depend on claim 21.
Regarding claim 22, Liu teaches a method wherein “a liquid biological sample selected from the group consisting of blood, plasma, serum, cerebrospinal fluid… saliva, urine… breast milk, and tears” (Pg 4 ln 5-7). Thus, Liu teaches a method wherein the sample comprises blood, blood plasma, serum, urine, cerebrospinal fluid, saliva, lymphatic fluid, aqueous humor, vitreous humor, cochlear fluid, tears, milk, sputum, vaginal discharge, or any combination thereof.
Regarding claim 27, Liu teaches a method wherein “the sequencing is at about 0.01-30X genome sequencing coverage” (Pg. 5 ln 15-16). “about …30X” reads on 30x-40x. Thus, Liu teaches a method wherein the whole genome sequencing (WGS)- based assay comprises a 30x - 40x whole genome sequencing operation.
Regarding claim 30 and 31, Liu teaches a method wherein “It was sought to determine whether DNA methylation levels could be predicted using ultra-low-pass whole-genome sequencing (0.1× coverage, ULP-WGS) and infer tissue-of-origin” (Pg. 22 ln 6-8). Thus, Liu teaches a method wherein the WGS tissue quantification algorithm is used to quantify each cfDNA fragment and accommodates the output of the WGS having a coverage of 0.2x coverage and further comprising generating an indication of a tissue or organ based on the relative contribution of each cell type or tissue type.
Regarding claim 41, Liu teaches a method wherein “diagnostic methods of the invention are used to detect changes in copy number and/or methylation in a biological sample relative to a reference (e.g., a reference determined by an algorithm, determined based on known values...” (Pg. 17 ln 18-20). Thus, Liu teaches a method wherein the plurality of reference profiles comprise a plurality of reference copy number signal profiles.
Regarding claim 42, Liu teaches a method wherein “By "disease" is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ” (Pg. 7 ln 3-4). Thus, Liu teaches a method wherein the relative contribution of cell type or tissue type is indicative of a source of cell damage, tissue damage, or organ damage in a subject from which the sample was acquired.
Regarding claim 43, Liu teaches a method wherein “To infer tissue of origin from low-pass WGBS or inferred WGBS patient data, patient WGBS data was modeled as a linear combination of reference methylomes.” (Pg. 28 ln 19-20). Thus, Liu teaches a method wherein determining the relative contribution of each cell type or tissue type comprises quantifying different respective tissue fractions by linearly projecting the cfDNA profile onto the plurality of reference profiles.
Therefore, the invention as recited in claims 21-22, 27, 30-31 and 41-43 are prima facie obvious over the prior art Liu et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to provide a method of quantifying cfDNA fragments based on anatomic origin according to the limitations of the instant application claims 21-22, 27, 30-31 and 41-43 based on Liu et al. (Patent App. Pub. No. WO 2018/027176 A1) with the predictable outcome of quantifying cfDNA fragments based on anatomic origin.
Response to Arguments
Applicant' s arguments filed 12/01/2025 (Pg. 27-30) with respect to claims 21-22, 27, 30-31 and 41-43 have been considered but are not persuasive. To clarify some instances argued in the response filed 12/01/2025 see responses to each argument made by Applicant below:
Applicants’ argument: “Liu, taken alone… fail to teach or suggest all of the elements of independent claims 21” (Pg. 28)
Response: Applicants’ argument filed 12/01/2025 does not apply to the revised rejections, documented above, based on Liu. Liu does teach the limitations according to amended claim 21.
Claims 21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018) in view Gross et al. (“Gross”; (2019). Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease. Genetics in Medicine, 21(5), 1121–1130.).
The teachings of Liu are documented above in the rejection of claims 21 under 35 U.S.C. 103. Claim 23 depends on claim 21. Liu does not explicitly teach the limitations of claim 23 , wherein no PCR amplification is performed on the sample.
Gross discloses CNV calling from cGS is robust and can benefit patients with a suspected genetic disease. Further algorithmic improvements, and the availability of large PCR-free genome reference sets, are likely to further increase both the sensitivity and the specificity of the assay and improve its diagnostic efficacy. (Discussion last para.)
Regarding claim 23, Gross teaches a method wherein “DNA samples from … patients … were prepared using the Illumina TruSeq PCR-free kit and sequenced” (Pg. 1122 Col. 1, Genome sequencing and CNV calling, Para. 1). Gross also teaches a method wherein “modern PCR-free library preparations minimize the hazard of capture and PCR-based artifacts” (Pg. 1122 Col. 1 Para. 1). Thus, Liu and Gross teach a method wherein no PCR amplification is performed on the sample.
Liu and Gross are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a patient sample. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method of PCR-free sequencing as taught by Gross and provide a method of wherein no PCR amplification is performed. Doing so would decrease the number of artifacts introduced into the sample during whole genome sequencing.
Response to Arguments
Applicants’ argument: “Liu, taken alone or in hypothetical combination with Gross, Hubbell, or Shendure fail to teach or suggest all of the elements of independent claims 21” (Pg. 28)
Response: See response above regarding Liu alone. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated on Pg. 13 of the non-final office action and documented above, Liu and Gross are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a patient sample. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method of PCR-free sequencing as taught by Gross and provide a method of wherein no PCR amplification is performed. Doing so would decrease the number of artifacts introduced into the sample during whole genome sequencing.
In response to applicants’ arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 21 and 28, are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018) in view of Hubbell et al. (“Hubbell”; Patent App. Pub. No. WO 2020132499 A2, Jan. 28, 2016).
The teachings of Liu are documented above in the rejection of claim 21 under 35 U.S.C. 103. Claim 28 depends on claim 21. Liu does not explicitly teach the limitations of claim 28, wherein the sample comprises mitochondria cfDNA.
Hubbell discloses methods for determining relevant medical information about a cancer based on the distribution of fragment lengths of cell-free DNA sequenced from a biological fluid sample. In certain embodiments, the systems and methods are useful for segmenting a cancer genome, phasing alleles in a cancer genome, detecting the loss of heterozygosity in a cancer genome, assigning an origin of a variant allele, validating a sequencing mapping, and validating use of an allele in a cancer classifier. (Abstract)
Regarding claim 28, Hubbell teaches a method wherein “cell-free nucleic acids include but are not limited to… mitochondrial DNA” (Para.127). Thus, Liu and Hubbell teach a method wherein the sample comprises mitochondria cfDNA.
Liu and Hubbell are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a biological fluid sample. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method of the cell-free nucleic acid sample comprising mitochondrial DNA as taught by Hubbell and provide a method wherein the sample comprises mitochondria cfDNA. Doing so would allow for further cellular and/or disease characterization of the sample.
Response to Arguments
Applicants’ argument: “Liu, taken alone or in hypothetical combination with Gross, Hubbell, or Shendure fail to teach or suggest all of the elements of independent claims 21” (Pg. 28)
Response: See response above regarding Liu alone. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated on Pg. 14 of the non-final office action and documented above, Liu and Hubbell are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a biological fluid sample. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method of the cell-free nucleic acid sample comprising mitochondrial DNA as taught by Hubbell and provide a method wherein the sample comprises mitochondria cfDNA. Doing so would allow for further cellular and/or disease characterization of the sample.
In response to applicants’ arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Claims 21 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (“Liu”; Patent App. Pub. No. WO 2018/027176 A1, Feb. 08, 2018) in view of Shendure et al. (“Shendure”; Patent App. Pub. No. WO 2016015058 A2, Jan. 28, 2016).
The teachings of Liu are documented above in the rejection of claims 21 under 35 U.S.C. 103. Claim 29 depends on claim 21.
Regarding claim 29, Liu teaches a method wherein “detecting alterations in the fragment length, fragment coverage, and distance to fragment end” (Para. 9). Thus, Liu teaches a method wherein preparing the library comprises determining a size distribution of DNA fragments.
Liu does not explicitly teach the limitations of claim 29, wherein preparing the library comprises treating a blood plasma sample with a circulating nucleic acid kit.
Shendure discloses methods of determining one or more tissues and/or cell-types contributing to cell-free DNA ("cfDNA") in a biological sample of a subject. In some embodiments, the present disclosure provides a method of identifying a disease or disorder in a subject as a function of one or more determined more tissues and/or cell-types contributing to cfDNA in a biological sample from the subject. (Abstract)
Regarding claim 29, Shendure teaches a method wherein “cfDNA was extracted from plasma using QIAAMP Circulating Nucleic Acid” (Para.415). Thus, Liu and Shendure teach a method wherein preparing the library comprises treating a blood plasma sample with a circulating nucleic acid kit and determining a size distribution of DNA fragments.
Liu and Shendure are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a patient sample and determining the tissue origin of cfDNA. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method using a circulating nucleic acid kit as taught by Shendure and provide a method of treating a blood plasma sample with a circulating nucleic acid kit. Doing so would allow for high-quality cfDNA to be isolated from the biological sample without any harsh chemicals or precipitation.
Response to Arguments
Applicants’ argument: “Liu, taken alone or in hypothetical combination with Gross, Hubbell, or Shendure fail to teach or suggest all of the elements of independent claims 21” (Pg. 28)
Response: See response above regarding Liu alone. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as stated on Pg. 15 of the non-final office action and documented above, Liu and Shendure are both considered to be analogous to the claimed invention because they are in the same field of clinical genome sequencing of a patient sample and determining the tissue origin of cfDNA. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of quantifying cfDNA fragments based on anatomic origin as taught by Liu to incorporate the method using a circulating nucleic acid kit as taught by Shendure and provide a method of treating a blood plasma sample with a circulating nucleic acid kit. Doing so would allow for high-quality cfDNA to be isolated from the biological sample without any harsh chemicals or precipitation.
In response to applicants’ arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion of Response to Arguments
In view of the amendments, the revised rejections and above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
THIS ACTION IS MADE FINAL. 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 KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682