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 .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Applicant’s amendment to the claims submitted on 10/6/2025 is acknowledged. Claims 7-9 and 11-15 are pending and being examined on the merits.
Response to Amendment
The declaration under 37 CFR 1.132 filed 10/6/2025 is insufficient to overcome the rejection of claims 7-9 and 11-15 based upon Song et al. and Zhang et al. as set forth in the last Office action for the following reasons. The declaration addressed the 103 rejection of claims 7-9 and 11-15 over Song et al. in view of Zhang et al. This rejection under 35 USC 103 has been withdrawn and additional evidence has been provided in the new 35 USC 103 rejection of Song et al. in view of Matsumura et al. and Zhang et al. as discussed below. Matsumura et al., as detailed below, teaches an association between increased methylation levels of FAR1 and liver cancer. The evidence provided in the declaration confirms the increased methylation levels of FAR1 in liver cancer, as taught by Matsumura et al., and does not provide results that would be deemed unexpected in terms of diagnosis.
Specification
In light of Applicant’s amendments to the specification to amend typographical and grammatical errors, the objection to the specification is withdrawn.
Applicant’s amendment to the specification to properly denote trade names and marks used in commerce is acknowledged.
Claim Objections
The objections to claims 7, 12, 13, and 15 as detailed in the Office Action of 6/10/2025 are withdrawn in light of Applicant’s amendments to the claims.
New Objections – Necessitated by Amendment:
Claims 7, 12, 14, and 15 are objected to because of the following informalities:
Claim 7: Given the removal of “and treating the diagnosed patient”, the word “and” should be added after the step of “comparing” and before “diagnosing”. Claim 7 should then read “comparing the measured methylation levels with methylation levels of CpG sites of the same genes in a normal control sample; and diagnosing the patient who has increased methylation levels compared to the normal control sample as requiring treatment.” This indicates that each step of the claim is required.
Claims 12, 14, and 15: Claim 7, from which claims 12, 14, and 15 depend, has been amended to require the measurement of methylation levels of FAR1 and optionally one or more genes selected from the group consisting of FAM110A, VIM, LDHB, LIPE, INAFM1, ATL1, CELF6, MTHFD2, PAK1, NXPE3, SLC25A36 and VANGL2. However, claims 12, 14, and 15 have not been amended to require primers specific to methylated sequences of FAR1 and optionally one or more of said genes (claim 12), a kit comprising a primer pair for amplifying fragments of FAR1 and optionally one or more of said genes (claim 14), and probes capable of hybridizing with fragments including CpG sites of FAR1 and optionally one or more of said genes (claim 15). The examiner, with the amendment of claim 7 to require measurement of methylation of FAR1, is interpreting these claims to require primers and probes specific to FAR1 and optionally one or more genes from said group, but amendment to make this clear would provide more clarity and consistency throughout the claims.
Appropriate correction is required.
Withdrawn Claim Rejections
35 USC § 112a: The rejection of claims 7-9 and 11-15 under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement is withdrawn in light of Applicant’s amendments to the claims.
35 USC § 112b: The rejection of claims 8 and 11-13 under 35 U.S.C. 112(b) is withdrawn in light of Applicant’s amendments to the claims.
35 USC § 103: The rejection of claims 7-9 and 11-15 under 35 U.S.C. 103 as being unpatentable over Song et al. (PLOS One, 2013; cited on IDS submitted on 3/27/2025) in view of Zhang et al. (WO 2018161031 A1) is withdrawn in light of Applicant’s amendments to the claims.
New Claim Rejections – Necessitated by Amendments
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.
Claim 7-9 and 11-15 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (e.g.: a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) is/are directed to a judicial exception encompassing abstract ideas and natural phenomena. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception as set forth below. The judicial exception is not integrated into a practical application of the judicial exception.
The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S._, (2010) (slip op., at 5). “Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U. S. 63, 67 (1972).
Additionally, the unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Inti, 134 S. Ct. 2347, 2354 (2014).
The following inquiries are used to determine whether a claim is drawn to patent- eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter? Yes - the claims are directed to methods.
Step 2A, prong 1. Is the claim directed to a law of nature, a natural phenomenon, or an abstract idea (judicially recognized exceptions)? Yes — Where the claims are directed to a “diagnosing” a subject as having liver cancer by “comparing” measured methylation levels between the subject and a healthy control, the claims are directed to an abstract idea; it is the mental identification of a phenotype, or the correlation of data and information.
Furthermore, the claims are directed to an asserted correlation between increased methylation levels compared to a normal control and presence of a liver cancer; such a correlation is a natural phenomenon which is a genotype:phenotype relationship.
Step 2A, prong 2. Does the claim recite additional elements that integrate the judicial exception into a practical application? No - The judicial exception(s) to which the claims are directed are not integrated into a practical application because there are no required particular practical steps recited with specificity related to the increased methylation detection/diagnosis (as recited in the steps of the claims), such as applying a particular liver cancer treatment to the subject.
Step 2B. Does the claim recite additional elements that amount to significantly more than the judicial exception? No - The claims recite only routine steps related to measuring methylation levels.
Additionally, it is noted that the specification indicates that the practical steps of data collection were routinely practiced in the prior art. For example, the specification provides (pg 8, paragraph 3-4) that the measurement of methylation via modification of cytosine bases or methylation-sensitive restriction enzymes is well-known in the art.
So even where a practical step of the claim may require measuring methylation levels of CpG sites using conventional methods that have been practiced in the art, in University of Utah Res. Foundation v. Ambry Genetics Corp. (Fed Cir, 2014), the Court addressed claims that recite known methodological steps for collecting data (specifically genetic information) to be used in the application of a judicial exception, and held that:
Having determined that the comparison steps of claims 7 and 8 are abstract ideas, we move to the second step of Alice and ask whether the particular mechanism for the comparisons added by claims 7 or 8 renders the claims patent-eligible. For this step, Alice dictates that we ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “transform the nature of the claim’ into a patent-eligible application.” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297). There must be a further inventive concept to take the claim into the realm of patent-eligibility. Id. at 2355. The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add “enough” to make the claims as a whole patent- eligible.
Additionally, In University of Utah Research v. Ambry Genetics the courts stated, "Recently in Alice the Supreme Court reiterated its two-step test to determine patent eligibility for any claims that allegedly encompass abstract ideas. First, "we determine whether the claims at issue are directed to [a] patent-ineligible concept. If so, we then ask, ‘what else is there in the claims before us?" Id. at 2355 (quoting Mayo, 132 S. Ct. at 1296-97) (citations and punctuation omitted). That is, we next ask whether the remaining elements, either in isolation or combination with the other non-patent- ineligible elements, are sufficient to " ‘transform the nature of the claim’ into a patent- eligible application." Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further "inventive concept" to take the claim into the realm of patent eligibility."
For these reasons the claims are rejected under 35 USC 101 as directed to subject matter that is not significantly more than a judicial exception.
Claim Rejections - 35 USC § 103
Claims 7-9 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (PLOS One, 2013; cited on IDS of 3/27/2025) in view of Matsumura et al. (Human Cancer Biology 2012; cited on IDS of 11/3/2025) and Zhang et al. (WO 2018161031 A1; cited on PTO-892 of 6/10/2025).
Song et al. teaches measuring methylation levels of CpG sites of genes from samples of patients with liver cancer to determine differentially methylated loci associated with liver cancer (Abstract – Methods and Findings).
Regarding claims 7 and 14: Song et al. teach measuring methylation levels of CpG sites from samples isolated from patients with hepatocellular carcinoma and matched adjacent normal tissues (HCC, reads on liver cancer; Results – Methylation Analysis). Song et al. teaches comparing the methylation levels of the CpG sites to adjacent normal tissues (a normal control sample; Abstract – Methods and Findings). Song et al. measures the methylation levels of CpG sites in the genes FAM110A, FAR1, VIM, LDHB, ATL1, MTHFD2, PAK1, SLC25A36, and VANGL2 (Table 3, Tables S1 and S4). Song et al. teaches that CpG sites of genes PAK1, LDHB, and MTHFD2 are significantly hypermethylated in HCC samples compared to normal controls (Table 3).
Song et al. also indicates that some sites in FAR1 are significantly hypermethylated compared to controls (specific example for the gene FAR1 is the CpG site at chromosomal location 13690122 which is hypermethylated compared to normal controls, Table S4). Song et al. teaches measuring methylation levels of CpG sites of FAR1, in addition to FAM110A, VIM, LDHB, ATL1, MTHFD2, PAK1, SLC25A36, and VANGL2, as indicated above. Song et al. teaches comparing these methylation levels with methylation levels of CpG sites of the same genes in normal control samples.
While Song et al. does not explicitly teach FAR1 as a potential diagnostic biomarker of liver cancer, the tumor-specific hypermethylation and gene silencing of FAR1 in liver cancer is known in the art, as taught by Matsumura et al.
Matsumura et al. teach measuring CpG methylation levels in HCC cell lines and normal controls using MeDIP-chip analysis with concurrent expression analysis to identify novel tumor suppressor genes (TSGs) for HCC (live cancer; Abstract). Matsumura et al. teach that through the integration of both MeDIP-chip and expression analyses, 11 genes were significantly differentially methylated and exhibited differential expression in tumor cells as compared to normal cells. Of these 11 genes, FAR1 was hypermethylated in over 50% of cancer cell lines compared to normal tissue and was downregulated in all cell lines that exhibited hypermethylation (Results - Integration and validation of results in two microarray-based analyses). While Matsumura et al. determined that MZB1 was the “most probable” candidate for a gene silenced through tumor-specific methylation, FAR1 was hypermethylated in almost the same number of cases and exhibited decreased expression in over 50% of these cases (Results - MZB1 is frequently silenced through CpG island methylation in primary tumors).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Song et al. to specifically look at the methylation status of FAR1, as taught by Matsumura et al. One would be motivated to do so given the teaching by Matsumura et al. that FAR1 is hypermethylated in over 50% of tumors as compared to normal controls and exhibits hypermethylation/tumor-specific downregulation of expression, indicating its potential status as a novel tumor suppressor gene and thus an important diagnostic biomarker. One would have a reasonable expectation of successfully diagnosing liver cancer with increased levels of FAR1 methylation given the high correlation between FAR1 hypermethylation and liver cancer status.
Song et al. in view of Matsumura et al. does not explicitly teach diagnosing patients with the increased methylation levels of FAR1 and optionally one or more of the genes listed in claim 7, but does teach that understanding these epigenetic changes “may eventually lead to identification of molecular markers for liver cancer diagnosis” (Song et al., Conclusion). Song et al. in view of Matsumura et al. also does not teach providing necessary reagents for assessing methylation levels in a kit (claim 14). However, use of methylation markers specific to HCC to diagnose a patient as needing treatment and inclusion of the necessary reagents for doing so in a kit is known in the art, as taught by Zhang et al.
Zhang et al. teach determining methylation levels at specific genomic sites and using these methylation levels, determining if the sample indicates presence of HCC (claim 7; paragraph [0004]). Additionally, Zhang et al. teach including reagents necessary for assessment of methylation levels in a kit comprising a plurality of primers to measure methylation status of specific biomarkers used for diagnosis of HCC (claim 14; paragraph [0175]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Song et al. in view of Matsumura et al. to include diagnosis of a patient determined to have liver cancer, as taught by Zhang et al. One would be motivated to use hypermethylation of genes with a significant association with liver cancer (as taught by Song et al. and Matsumura et al.) to diagnose a subject with liver cancer and administer an appropriate treatment, as taught by Zhang et al., given the assertion by Zhang et al. that differential methylation is often “one of the first neoplastic changes” and “has higher clinical sensitivity” compared to mutation analysis as well as a high correlation with prognosis of a cancer (paragraphs [0065 and 0067]). One would have a reasonable expectation of success given that Zhang et al. exhibit successful diagnostic modeling of liver cancer using methylation biomarkers and identify appropriate treatment regimes. Additionally, one skilled in the art would recognize the obvious advantage of including the reagents necessary for assessing methylation levels of specific biomarkers in a kit due to the convenience of having all of the required assay materials provided together in one location.
Regarding claim 8: Song et al. teach measuring methylation levels of genes using pyrosequencing (Materials and Methods – Methylation Analysis, paragraph 4).
Regarding claim 9: Song et al. teach measuring methylation levels of CpG sites in samples consisting of liver tissues (Materials and Methods – Patient Specimens).
Regarding claim 11: Song et al. teach measuring methylation levels of CpG sites that are between +/- 2000 bases from a transcription start site (TSS1500 and TSS200 of the HumanMethylation450 BeadChip, Materials and Methods – Methylation Analysis; specific example for the gene FAR1 is the CpG site at chromosomal location 13690122 which is hypermethylated compared to normal controls, Table S4).
Regarding claims 12 and 13: Song et al. teaches measuring methylation levels of CpG sites by using a compound that is capable of modifying an unmethylated cytosine, bisulfite (Materials and Methods – DNA Extraction and Bisulfite Conversion).
Regarding claim 15: Song et al. teaches using a nucleic acid chip that has immobilized probes capable of hybridizing to fragments of DNA that contain CpG sites from genes including FAM110A, FAR1, VIM, LDHB, ATL1, MTHFD2, PAK1, SLC25A36, and VANGL2 (HumanMethylation450 BeadChip from Illumina, Materials and Methods – Methylation Analysis).
Response to Remarks
Applicant's arguments filed 10/6/2025 have been fully considered but they are not deemed persuasive for the following reasons.
Applicant’s arguments traversing the rejection of claims 7-9 and 11-15 under 35 USC 103 as obvious over Song et al. in view of Zhang et al. (pg 5 of Remarks) are moot in light of Applicant’s amendments to the claims. The additional limitation of measuring methylation levels of FAR1 for diagnosis of liver cancer has been addressed in the new 103 rejection above.
Applicant points to the additional data provided in the declaration under 37 CFR 1.132 which “highlight[s] the importance of measurement of methylation in FAR1” (pg 5 of Remarks). The association of increased FAR1 methylation levels and liver cancer is taught by Matsumura et al. in the new 103 rejection detailed above. The ability of this biomarker to diagnose liver cancer is not an unexpected result of measuring methylation levels of this biomarker, according to the teachings of Matsumura et al.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683