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 2-3, 5, 7, 9-10, 12, 16, 18, 21, 23-24, 27, 32, 34-38, and 40-41 are cancelled. Claims 1, 4, 6, 8, 11, 13-15, 17, 19-20, 22, 25-26, 28-31, 33, and 39 are pending and currently under examination.
Priority
The instant application 18/268,240 filed on 6/18/23 is a 371 US national phase PCT/US2021/064210 filed on 12/17/21, and claims domestic priority to provisional applications 63/126,863 filed on 12/17/20 and 63/246,306 filed on 9/20/21. The priority date is determined to be 12/17/20.
Claim Rejections - 35 USC § 112 – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 11 is 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.
Claim 11 recites tables. MPEP 2173.05(s) states:
Where possible, claims are to be complete in themselves. Incorporation by
reference to a specific figure or table "is permitted only in exceptional circumstances
where there is no practical way to define the invention in words and where it is more
concise to incorporate by reference than duplicating a drawing or table into the claim.
Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex
parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
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 1, 4, 6, 8, 11, 13-15, 17, 19-20, 22, 25-26, 28-31, 33, and 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claim is directed to the statutory category of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 1 recitations of “c) determining a proportion” and “d) characterizing the cfDNA”; claim 6 recitation of “fully methylated haplotypes determined in step c) are compared to”; claim 13 recitation of “determining a tissue”; claim 14 recitation of “b) determining a proportion”; claim 19 recitation of “fully methylated haplotypes determined in step c) are compared to”; claim 29 recitation of “determining a tissue”; claim 30 recitation of “c) determining a proportion”; claim 33 recitations of “determining a probability”, “estimate the probability distribution”, “e) determining one or”, and “prediction score”; and claim 39 recitations of “determining a tissue of origin” and “defining a tissue-specific index” are all abstract ideas. These limitations are abstract mental processes and/or mathematical concepts (see MPEP 2106.04(a)). The abstract mental processes of determination, comparison, characterization are concepts performed in the human mind. The mathematical concepts of proportions, probabilities, and scores/index require mathematical relationships, formulae, and calculations.
Additionally, the claims are directed towards laws of nature and natural phenomena through the correlations of methylated haplotypes (genotype) and tissue of origin/cancer (phenotype). Claim 1 recitation of “haplotypes of the genomic sequence that are fully methylated”; claim 6 recitation of “fully methylated haplotype signature(s)”; claim 13 correlation of methylation to tissues of origin; claim 14 recitation of “haplotypes of the genomic sequence that are fully methylated”; claim 19 recitation of “fully methylated haplotype signatures corresponding to one or more tumor types”; claim 30 recitation of “haplotypes of the genomic sequence that are fully methylated”; and claim 39 correlation of methylation to tissues of origin are all laws of nature and natural phenomena (see MPEP 2106.04(b)).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claims 1, 4, 6, 8, 11, 13-15, 17, 19-20, 22, 25-26, 28-31, 33, and 39 recite insignificant extra-solution activities directed towards mere data gathering (see MPEP 2106.05(g)).
Step 2B: The claim does not provide an inventive concept.
MPEP 2106.05(d)):
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S.
at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health
Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir.
2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs.
Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir.
2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115
USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78,
115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123
USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v.
Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic
variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119
USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah
Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d
1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d
at 1247.
The claims end with the judicial exceptions. Additionally, methods of characterizing cell-free DNA, detecting cancer/eradication, and tissues of origin are not inventive (Meissner et al. 2018; FOR citation 1 in IDS filed 11/7/24; WO 2018/209361 A2; and Zhang et al. 2016; USPGPub citation 6 in IDS filed 8/14/23; US 2016/0210403 A1).
For the reasons set forth above, claims 1, 4, 6, 8, 11, 13-15, 17, 19-20, 22, 25-26, 28-31, 33, and 39 are not directed to patent eligible subject matter.
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.
Claims 1, 4, 6, 8, 11, 13-15, 17, 19-20, 22, 25-26, 28-31, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Meissner et al. (2018; FOR citation 1 in IDS filed 11/7/24; WO 2018/209361 A2).
Relevant to claim 1 a), Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using whole-genome bisulfite sequencing (WGBS)" (paragraph 0040).
Further relevant to claim 1 a), Meissner et al. teaches "FIG. 1E provides genome browser tracks for WGBS, assay for transposase accessible chromatin with highthroughput sequencing (ATAC-seq) and RNA-seq data capturing three emblematic loci. Density refers to the projected number of methylated CpGs per 100 bp of primary sequence and highlights the extensive epigenetic signal present over these regions within ExE (Δ density refers to the difference compared to the epiblast)" (paragraph 0016).
Relevant to claim 1 b)-d), Meissner et al. teaches "In some embodiments, DNA methylation haplotypes corresponding to methylation patterns of CpGs are identified from the screening. The DNA methylation haplotypes may be classified into three groups, concordantly unmethylated haplotypes, disordered haplotypes, and concordantly methylated haplotypes. Haplotypes are also referenced to herein as sequencing reads." (paragraph 0041). Further relevant to claim 1 b)-d), Meissner et al. teaches "In certain embodiments, the inventions disclosed herein relate to methods of using proportion of concordantly methylated reads (PMR) (i.e., fully methylated haplotypes) to detect circulating tumor DNA (ctDNA) in a sample" (paragraph 0042).
Further relevant to claim 1 d), Meissner et al. teaches "The sample may comprises cell free DNA. In some aspects, 0.01 % to 1 % ctDNA, and more specifically 0.01 % ctDNA is detected in the sample" (paragraph 0006).
Further relevant to claim 1 d), Meissner et al. teaches "In some aspects described herein, for WGBS data, a CGI was considered differentially methylated if it was covered by at least 5 CpGs and 80% of them were significantly hyper/hypo-methylated" (paragraph 0040).
Relevant to claim 4, Meissner et al. teaches "Example 3: Detection of low-frequency tumors (0.01%) from cfDNA through simulation… Established herein is a novel way to predict ctDNA from cfDNA with a resolution as high as 0.01 %, in which five copies of tumor DNA are present (FIG. 16). According to the simulations, the presence of 0.01 % ctDNA can be predicted with 100% sensitivity and 95% specificity, with a p-value cutoff of 10^-4" (paragraphs 0101-0102).
Relevant to claim 6, Meissner et al. teaches "In one aspect, a methylation sequence for a sample is obtained, and at least one CpG Island (CGI) is identified on the methylation sequence. PMR for the identified CpG Island is calculated and compared to a control background of a normal tissue or epiblast. The presence of ctDNA is detected in the sample when the PMR of the sample is larger than the control background (e.g., signal is higher by bank sum test)" (paragraph 0005).
Relevant to claim 8, Meissner et al. teaches "Both systems display substantial methylation over ExE hyper CGIs as presented in FIG. 4 and FIG. 13. As a control, 'ExE hypo' CGIs demonstrate uniformly high H3K4me3 levels. Enrichment density heat maps are provided for the full ExE hyper CGI set and are ranked across plots according to their enrichment for H3K27me3 in HUES64. Normalized enrichment represents the fold chromatin immunoprecipitation-enrichment against sample matched whole cell extract (WCE)" (paragraph 0027).
Relevant to claim 11, Meissner et al. teaches "For example, with advances in sequencing technologies, longer reads that cover more CpGs may be sequenced" (paragraph 0099).
Further relevant to claim 11, Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using… TCGA Illumina Infinium HumanMethylation450K BeadChip sequencing (TCGA)" (paragraph 0040).
Relevant to claim 13, Meissner et al. teaches "In some aspects, the invention provides predictions of cancer tissues of origin using a DNA methylation signature" (paragraph 0056).
Relevant to claim 14, Meissner et al. teaches "Disclosed herein are methods for quantifying DNA methylation that may be utilized for screening for diseases (e.g., cancer), diagnosing diseases (e.g., cancer type), monitoring progression of a disease, and monitoring response to a treatment regimen" (paragraph 0036).
Relevant to claim 14 a), Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using whole-genome bisulfite sequencing (WGBS)" (paragraph 0040).
Further relevant to claim 14a), Meissner et al. teaches "FIG. 1E provides genome browser tracks for WGBS, assay for transposase accessible chromatin with highthroughput sequencing (ATAC-seq) and RNA-seq data capturing three emblematic loci. Density refers to the projected number of methylated CpGs per 100 bp of primary sequence and highlights the extensive epigenetic signal present over these regions within ExE (Δ density refers to the difference compared to the epiblast)" (paragraph 0016).
Relevant to claim 14 b)-d), Meissner et al. teaches "In some embodiments, DNA methylation haplotypes corresponding to methylation patterns of CpGs are identified from the screening. The DNA methylation haplotypes may be classified into three groups, concordantly unmethylated haplotypes, disordered haplotypes, and concordantly methylated haplotypes. Haplotypes are also referenced to herein as sequencing reads." (paragraph 0041). Further relevant to claim 14 b)-d), Meissner et al. teaches "In certain embodiments, the inventions disclosed herein relate to methods of using proportion of concordantly methylated reads (PMR) (i.e., fully methylated haplotypes) to detect circulating tumor DNA (ctDNA) in a sample" (paragraph 0042).
Further relevant to claim 14 d), Meissner et al. teaches "The sample may comprises cell free DNA. In some aspects, 0.01 % to 1 % ctDNA, and more specifically 0.01 % ctDNA is detected in the sample" (paragraph 0006).
Further relevant to claim 14 d), Meissner et al. teaches "In some aspects described herein, for WGBS data, a CGI was considered differentially methylated if it was covered by at least 5 CpGs and 80% of them were significantly hyper/hypo-methylated" (paragraph 0040).
Relevant to claim 15, Meissner et al. teaches "For example, with advances in sequencing technologies, longer reads that cover more CpGs may be sequenced" (paragraph 0099).
Relevant to claim 17, Meissner et al. teaches "Example 3: Detection of low-frequency tumors (0.01%) from cfDNA through simulation… Established herein is a novel way to predict ctDNA from cfDNA with a resolution as high as 0.01 %, in which five copies of tumor DNA are present (FIG. 16). According to the simulations, the presence of 0.01 % ctDNA can be predicted with 100% sensitivity and 95% specificity, with a p-value cutoff of 10^-4" (paragraphs 0101-0102).
Relevant to claim 19, Meissner et al. teaches "In one aspect, a methylation sequence for a sample is obtained, and at least one CpG Island (CGI) is identified on the methylation sequence. PMR for the identified CpG Island is calculated and compared to a control background of a normal tissue or epiblast. The presence of ctDNA is detected in the sample when the PMR of the sample is larger than the control background (e.g., signal is higher by bank sum test)" (paragraph 0005).
Further relevant to claim 19, Meissner et al. teaches "In some aspects, the presence of ctDNA indicates the presence of a tumor" (paragraph 0007).
Relevant to claim 20, Meissner et al. teaches "The cancer may be selected from the group comprising bladder urothelial carcinoma, breast invasive carcinoma, colon adenocardinoma, colorectal adenocarcinoma, oseophageal carcinoma, head and neck squamous cell carcinoma, kidney rental clear cell carcinoma, kidney renal papillar cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, stomach and oesophageal carcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, and chronic lymphocytic leukaemia" (paragraph 0007).
Relevant to claim 22, Meissner et al. teaches "Both systems display substantial methylation over ExE hyper CGIs as presented in FIG. 4 and FIG. 13. As a control, 'ExE hypo' CGIs demonstrate uniformly high H3K4me3 levels. Enrichment density heat maps are provided for the full ExE hyper CGI set and are ranked across plots according to their enrichment for H3K27me3 in HUES64. Normalized enrichment represents the fold chromatin immunoprecipitation-enrichment against sample matched whole cell extract (WCE)" (paragraph 0027).
Relevant to claim 25, Meissner et al. teaches "Example 3: Detection of low-frequency tumors (0.01%) from cfDNA through simulation… Established herein is a novel way to predict ctDNA from cfDNA with a resolution as high as 0.01 %, in which five copies of tumor DNA are present (FIG. 16). According to the simulations, the presence of 0.01 % ctDNA can be predicted with 100% sensitivity and 95% specificity, with a p-value cutoff of 10^-4" (paragraphs 0101-0102).
Relevant to claim 26, Meissner et al. teaches "The cancer may be selected from the group comprising bladder urothelial carcinoma, breast invasive carcinoma, colon adenocardinoma, colorectal adenocarcinoma, oseophageal carcinoma, head and neck squamous cell carcinoma, kidney rental clear cell carcinoma, kidney renal papillar cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, prostate adenocarcinoma, stomach and oesophageal carcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, and chronic lymphocytic leukaemia" (paragraph 0007).
Relevant to claim 28, Meissner et al. teaches "Also disclosed herein are methods of treating a subject in need of treatment for cancer comprising using proportion of concordantly methylated reads (PMR) of a sample to detect ctDNA in the sample, wherein the presence of ctDNA is indicative of the subject having cancer; and treating the subject for cancer" (paragraph 0009).
Relevant to claim 29, Meissner et al. teaches "In some aspects, the invention provides predictions of cancer tissues of origin using a DNA methylation signature" (paragraph 0056).
Relevant to claim 30, Meissner et al. teaches "Also disclosed herein are methods of monitoring progression or amelioration of cancer in a subject, the method comprising using proportion of concordantly methylated reads to identify ctDNA from cfDNA of the subject, wherein if ctDNA is present the subject is at risk of developing cancer, and monitoring the amount of ctDNA in the cfDNA over time, wherein alteration of the amount of ctDNA in the cfDNA is indicative of progression or amelioration of the condition" (paragraph 0011).
Relevant to claim 30 a), Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using whole-genome bisulfite sequencing (WGBS)" (paragraph 0040).
Further relevant to claim 30 a), Meissner et al. teaches "FIG. 1E provides genome browser tracks for WGBS, assay for transposase accessible chromatin with highthroughput sequencing (ATAC-seq) and RNA-seq data capturing three emblematic loci. Density refers to the projected number of methylated CpGs per 100 bp of primary sequence and highlights the extensive epigenetic signal present over these regions within ExE (Δ density refers to the difference compared to the epiblast)" (paragraph 0016).
Relevant to claim 30 b)-d), Meissner et al. teaches "In some embodiments, DNA methylation haplotypes corresponding to methylation patterns of CpGs are identified from the screening. The DNA methylation haplotypes may be classified into three groups, concordantly unmethylated haplotypes, disordered haplotypes, and concordantly methylated haplotypes. Haplotypes are also referenced to herein as sequencing reads." (paragraph 0041). Further relevant to claim 30 b)-d), Meissner et al. teaches "In certain embodiments, the inventions disclosed herein relate to methods of using proportion of concordantly methylated reads (PMR) (i.e., fully methylated haplotypes) to detect circulating tumor DNA (ctDNA) in a sample" (paragraph 0042).
Further relevant to claim 30 d), Meissner et al. teaches "The sample may comprises cell free DNA. In some aspects, 0.01 % to 1 % ctDNA, and more specifically 0.01 % ctDNA is detected in the sample" (paragraph 0006).
Further relevant to claim 30 d), Meissner et al. teaches "Also disclosed herein are methods of monitoring progression or amelioration of cancer in a subject, the method comprising using proportion of concordantly methylated reads to identify ctDNA from cfDNA of the subject, wherein if ctDNA is present the subject is at risk of developing cancer, and monitoring the amount of ctDNA in the cfDNA over time, wherein alteration of the amount of ctDNA in the cfDNA is indicative of progression or amelioration of the condition" (paragraph 0011).
Relevant to claim 31, Meissner et al. teaches "For example, with advances in sequencing technologies, longer reads that cover more CpGs may be sequenced" (paragraph 0099).
Relevant to claim 39, Meissner et al. teaches "In some aspects, the invention provides predictions of cancer tissues of origin using a DNA methylation signature" (paragraph 0056).
Relevant to claim 39 a), Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using whole-genome bisulfite sequencing (WGBS)" (paragraph 0040).
Further relevant to claim 39 a), Meissner et al. teaches "FIG. 1E provides genome browser tracks for WGBS, assay for transposase accessible chromatin with highthroughput sequencing (ATAC-seq) and RNA-seq data capturing three emblematic loci. Density refers to the projected number of methylated CpGs per 100 bp of primary sequence and highlights the extensive epigenetic signal present over these regions within ExE (Δ density refers to the difference compared to the epiblast)" (paragraph 0016).
Relevant to claim 39 b), Meissner et al. teaches "The bisulfite-converted DNA fragments were PCR amplified according to the following thermocycler settings…" (paragraph 0116).
Relevant to claim 39 c), Meissner et al. teaches "FIG. 19 shows precise molecular detection for predicting cancer tissues of origin using a novel methylation signature" (paragraph 0034).
Meissner et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that "[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious," the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR at 1741. The Court emphasized that "[a] person of ordinary skill is... a person of ordinary creativity, not an automaton." Id. At 1742.
Consistent with this reasoning, it would have been prima facie obvious to have
selected various combinations of various disclosed elements — including genomic sequences, cancers, and techniques — for a method, to arrive at compositions "yielding no more than one would expect from such an arrangement."
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Meissner et al. (2018; FOR citation 1 in IDS filed 11/7/24; WO 2018/209361 A2) in view of Zhang et al. (2016; USPGPub citation 6 in IDS filed 8/14/23; US 2016/0210403 A1).
Relevant to claim 33 a), Meissner et al. teaches "In certain embodiments, a sample (e.g., a fluid sample) is screened. The sample may be screened using whole-genome bisulfite sequencing (WGBS)" (paragraph 0040).
Further relevant to claim 33 a), Meissner et al. teaches "FIG. 1E provides genome browser tracks for WGBS, assay for transposase accessible chromatin with highthroughput sequencing (ATAC-seq) and RNA-seq data capturing three emblematic loci. Density refers to the projected number of methylated CpGs per 100 bp of primary sequence and highlights the extensive epigenetic signal present over these regions within ExE (Δ density refers to the difference compared to the epiblast)" (paragraph 0016).
Relevant to claim 33 b), Meissner et al. teaches "In some embodiments, DNA methylation haplotypes corresponding to methylation patterns of CpGs are identified from the screening. The DNA methylation haplotypes may be classified into three groups, concordantly unmethylated haplotypes, disordered haplotypes, and concordantly methylated haplotypes. Haplotypes are also referenced to herein as sequencing reads." (paragraph 0041). Further relevant to claim 33 b), Meissner et al. teaches "In certain embodiments, the inventions disclosed herein relate to methods of using proportion of concordantly methylated reads (PMR) (i.e., fully methylated haplotypes) to detect circulating tumor DNA (ctDNA) in a sample" (paragraph 0042).
Relevant to claim 33 e), Meissner et al. teaches "Disclosed herein are methods for quantifying DNA methylation that may be utilized for screening for diseases (e.g., cancer), diagnosing diseases (e.g., cancer type), monitoring progression of a disease, and monitoring response to a treatment regimen" (paragraph 0036).
Meissner et al. is silent to specifics regarding training or validation set and machine learning. However, these limitations were known in the prior art and taught by Zhang et al.
Zhang et al. teaches “DNA methylation data from initial training set and first testing set were obtained from The Cancer Genome Atlas (TCGA). The methylation status of 470,000 sites was generated using the Infinium 450K Methylation Array. DNA methylation data of the second cohort of Chinese cancer patients were obtained using a bisulfite sequencing method” (paragraph 0481).
Zhang et al. paragraphs 0482 – 0483 teach the application of machine learning methods such as support vector machines towards the classifications of samples. Additionally, Zhang et al. paragraph 0231 teaches “In certain embodiments, the methylation values measured for markers of a biomarker panel are mathematically combined and the combined value is correlated to the underlying diagnostic question… Well-known mathematical methods for correlating a marker combination to a disease status employ methods like… Random Forest Methods…”
Although Meissner et al. does not teach the Zhang et al. computational limitations, they would have been prima facie obvious to the skilled artisan. Meissner et al. and Zhang et al. are analogous disclosures to the instant methylation analyses. The skilled artisan would have been motivated to combine the analogous disclosures.
The skilled artisan would have been motivated to include the Zhang et al. computational limitations within the methodologies rendered obvious by Meissner et al. because Zhang et al. teaches that “The learning algorithms described above are useful both for developing classification algorithms for the biomarker biomarkers already discovered, and for finding new biomarker biomarkers. The classification algorithms, in tum, form the base for diagnostic tests by providing diagnostic values (e.g., cut-off points) for biomarkers used singly or in combination” (paragraph 0280).
The skilled artisan would have a reasonable expectation of success given the teachings of Meissner et al. in view of Zhang et al., as discussed in the preceding paragraphs.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682