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 .
The preliminary amended claims dated 12/15/2025 are under consideration.
The amendments in the papers filed 12/15/2025 and arguments presented in the papers filed 12/2/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 9/2/2025 listed below have been reconsidered as indicated.
a) The rejections of claims 1-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in view of the amendments to the claims.
b) The rejections of claim(s) 1-12 under 35 U.S.C. 102(a)(1) and 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Zhang (US 2016/0210403 A1) are withdrawn in view of the amendments to the claims.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Election/Restrictions
The election of species requirement dated 5/2/2025 was previously withdrawn in its entirety.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on a submitted IDS, they have not been considered.
Drawings
High resolution copies of the drawings may be accessed via PAIR/Patent Center Retrieval using the Supplemental Content tab.
Claim Objections
Claim 1 is objected to because of the following informalities: in view of the amendments to the claims, it is suggested the preamble be amended to recite “A method for identifying and treating a subject with non-alcoholic steatohepatitis that is at risk of developing hepatocellular carcinoma” rather than “A method for identifying a subject, who has non- alcoholic steatohepatitis, who is at risk of developing hepatocellular carcinoma”.
Appropriate correction is required.
Claims 1 and 4 are objected to because of the following informalities: the claims identify the same CpG sites, but use different formats between the two claims. It is suggested a single format be used. If the format of claim 4 is chosen, it is suggested that the other dependent claims along with claim 1 be amended.
Appropriate correction is required.
Claim 1 is objected to because of the following informalities: it is suggested a comma or semicolon be used after the phrase “thereby identifying a subject at risk of…”.
Appropriate correction is required.
Claim 14 is objected to because of the following informalities: the claim lacks a comma after “The method of claim 1”, as was done in claim 13.
Appropriate correction is required.
Claim 15 is objected to because of the following informalities: the claim lacks a comma after “The method of claim 1”, as was done in claim 13.
Appropriate correction is required.
Claims 16-17 are objected to because of the following informalities: the claim lacks a semicolon after the words “comprises” and “comprising”, respectively, as was done in claim 1.
Appropriate correction is required.
Claim Interpretation
The claims include reference to positions within specified chromosomes and identifies them as being in reference to “Build 37”. This is understood to be referring to “GRCh37/hg19”.
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, 5, 10 and 13-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without significantly more.
Independent claims 1 and 18 are drawn to “methods” and thus are processes.
The claim(s) recite(s):
“detecting a decreased DNA methylation level of at least one target CpG site in genomic DNA compared to that of a control” (claim 1);
“detecting an increased DNA methylation level of at least one target CpG site in genomic DNA compared to that of a control” (claim 1);
“identifying a subject at risk of developing hepatocellular carcinoma” (claim 1);
“detecting whether the hepatocytes or the tissue comprising hepatocytes have a risk of developing into hepatocellular carcinoma” (claim 16);
“acquiring data on whether the hepatocytes, the tissue comprising hepatocytes, or the subject have a risk of developing hepatocellular carcinoma, from the detected DNA methylation level” (claim 17);
“detecting an abnormal DNA methylation level of a target CpG site in the genomic DNA compared to a control for at least one target CpG site” (claim 18).
The steps of “detecting DNA methylation level of a target CpG site in genomic DNA”, “detecting an increased DNA methylation level of at least one target CpG site in genomic DNA compared to that of a control” and “detecting an abnormal DNA methylation level of a target CpG site in the genomic DNA compared to a control for at least one target CpG site” broadly encompasses the analysis of raw data (para. 52 of original specification) and comparing it to another piece of data. The limited amount of data to be considered and compared, e.g., methylation data for a single CpG site, is able to be considered by the human mind, and thus encompasses an abstract idea.
The step of “identifying a subject at risk of developing hepatocellular carcinoma” broadly encompasses making a determination based on a limited amount of data that can be fully considered by the human mind.
The step of “detecting whether the hepatocytes or the tissue comprising hepatocytes have a risk of developing into hepatocellular carcinoma” broadly encompasses making a determination based on a limited amount of data, e.g., methylation data for a single CpG site. This amount of data is able to be considered by the human mind, and thus encompasses an abstract idea.
The step of “acquiring data on whether the hepatocytes, the tissue comprising hepatocytes, or the subject have a risk of developing hepatocellular carcinoma, from the detected DNA methylation level” broadly encompasses making a determination based on a limited amount of data, e.g., methylation data for a single CpG site. This amount of data is able to be considered by the human mind, and thus encompasses an abstract idea.
The claim also set forth the natural correlation that is the relationship between the methylation status of certain CpG sites and genomic DNA from hepatocytes or tissue comprising hepatocytes. This natural correlation is a judicial exception.
The judicial exceptions are not integrated into a practical application because the claims do not involve:
improvements to the functioning of a computer or to any other technology or technical field;
applying or using the judicial exceptions to effect a particular treatment or prophylaxis for a disease or medical condition;
applying the judicial exception with, or by use of, a particular machine; or
effecting a transformation or reduction of a particular article to a different state or thing.
The claimed limitations add insignificant extra-solution activity to the judicial exceptions. The step of obtaining a sample of hepatocytes or a sample comprising hepatocytes and isolating genomic DNA therefrom amounts to data a gather step (MPEP 2106.05(g)). The step of “treating the subject for hepatocellular carcinoma” in claim 1 and “treating the subject having an abnormal methylation level compared to the control for hepatocellular carcinoma” is not a particular treatment or prophylaxis and is generically recited such that it instructs a doctor to do a doctor would have done. Furthermore, there is a disconnect between “a subject” and the source of the “sample of hepatocytes or a sample comprising hepatocytes”. The source of the sample is not specified in the claim, and it unclear if the patient treated is the one in the preamble, or one that is “identified” as being “at risk of developing hepatocellular carcinoma”. The dependent claims do remedy these issues with the independent claims.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims encompass the use methods that are well-known and used in a conventional manner as described in paragraphs 33 and 35 of the instant specification.
Examiner’s response to the traversal of the 101 rejections
The Remarks argue the rejections cannot be sustained in light of the amendment of claim 1 which now requires identification and treatment of subject at risk of hepatocarcinoma and requires that an increased level or decreased level of CpG methylation is determined with reference to a control. The Remarks argue new claim 18 requires detection of an abnormal level of methylation at specific positions. The Remarks argue claim 1 and its dependents are not directed to the judicial exception alone but require particular concrete detection steps and concrete application of the detection steps to patient treatment, and such treatment goes beyond any natural correlation and is not insignificant. The Remarks argue claim 1 refers to a practical application with defined step-detecting a level of methylation at specific genomic DNA sites and does not simply recite a natural correlation along or an instruction to "apply it". See p. 10.
The arguments have been fully considered but are not persuasive. The amended steps of “treating” are generic and do not require a particular treatment or prophylaxis. Amending the claim to recite “treating the subject at risk of developing hepatocellular carcinoma with regular checkups, diagnostic imaging, liver biopsy, lifestyle guidance, diet therapy and/or exercise therapy”, may aid in overcoming this rejection. This generic step broadly amounts to adding the words “apply it” to the claim. Furthermore, it is noted the claim does not specify where the sample is obtained from, e.g. that is obtained from the “subject” of the preamble of the claim.
The Remarks argue the claimed method provides an improvement over prior art methods as explained in the specification and it provides new, concrete, and non-routine diagnostic steps for the identification and treatment of patients at risk of hepatocarcinoma. See p. 10.
The arguments have been fully considered but are not persuasive. There is no indication that the claimed methods improved the prior art. There is no comparison between the two demonstrating that any patients identified and treated in the context of the claimed methods is different in scope from those currently being treated for NASH and/or hepatocellular carcinoma.
Claim Rejections - 35 USC § 112
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.
Claims 1, 4, 5, 10, 13, 14, 15, 16 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, it is unclear if the “subject” in the last line is “a subject, who has non-alcoholic steatohepatitis” as set forth in the preamble, or “a subject at risk of developing hepatocellular carcinoma” as a result of the “detecting” steps”. This issue is compounded by the fact that the source of “a sample” is not identified as being “a subject” described in the preamble.
Regarding claim 1, if the “subject” identified and treated is the same “subject” as set forth in the preamble, then the claim is incomplete because “a sample” is not identified as being from “a subject” set forth in the preamble.
Regarding claim 1, the claim recites “thereby identifying a subject at risk of developing hepatocellular carcinoma”. It is unclear if the claim is only describing results of the second “detecting” step” from which it follows in the text.
Regarding claim 1, the claim recites “treating the subject for hepatocellular carcinoma”. However, the patient is never diagnosed with “hepatocellular carcinoma”. Thus, the claim is incomplete because the patient is not identified as having “hepatocellular carcinoma” to treat.
Claims 4, 5, 10, 13, 14, 15, 16 and 17 depend from claim 1 and are rejected for the same reason.
Regarding claim 13, the claim recites analogous language to the first “detecting” step of claim 1. It is unclear if the claim is intended to require the first “detecting” step, which in claim 1 is not specifically required based on the use of “and/or” between the first and second “detecting” steps. The language of claim 13 is contrasted with that of claim 14 that states the method of claim 1 “comprising detecting a DNA methylation…”.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1, 5, 14, 16, 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Murphy (Gastroenterology. 2013. 145:1076-1087 and Supplemental Materials).
The following are new rejections necessitated by amendment.
Regarding claims 1, 14 and 18, Murphy teaches obtaining a sample of frozen liver biopsies and isolating genomic DNA for the Illumina HumanMethylation450 beadchip platform (p. 1077, Study Samples and Generation of Genomic Data; and Supplemental Materials, p. 2 of 167, Generation of genomic data). The frozen liver biopsies comprise hepatocytes. The patients have NAFLD, which includes NASH or “non-alcoholic steatohepatitis”, based on having portal inflammation and ballooning (p. 1077, Patient and Sample Characteristics; and Table 1).
Murphy teaches detecting “increased” of hypermethylation using the cg05861743 probe (Supplemental Materials, p. 10 of 167), which according to Table 3 of the specification corresponds to chromosome 6, position 31624387. The claim states that as a result of detecting increased methylation at chromosome 6, position 31624387, one has detected a risk of developing hepatocellular carcinoma. This level of hypermethylation is “abnormal” as compared to mild NAFLD as a control.
Murphy further teaches patients identified with advanced NAFLD should be treated (paragraph spanning p. 1076-1077). The cg05861743 probe corresponds to the APOM gene (Supplemental Materials, Table 1), which is hypermethylated in advanced versus mild NAFLD (Supplemental Materials, Table 5 and Table 6)
Thus, it would have been prima facie obvious to the ordinary artisan to have treated patients with advanced NAFLD/NASH for their hepatocellular carcinoma risk.
Regarding claim 5, Murphy teaches detecting methylation involves using bisulfite treated genomic DNA (Supplemental Materials, p. 2 of 167, Generation of genomic data).
Regarding claim 16, Murphy teaches detecting the cells as being advanced NAFLD/NASH as described above, which have a risk of developing into hepatocellular carcinoma.
Regarding claim 17, Murphy teaches the cg05861743 probe is hypermethylated in patients with advanced NAFLD/NASH, thus, acquiring data on whether the patients are at risk of developing hepatocellular carcinoma.
Conclusion
No claims allowed.
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 JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
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/JOSEPH G. DAUNER/ Primary Examiner, Art Unit 1682