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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group 2 (claims 6-9 directed to methods of diagnosing), and the particular combination of biomarkers that is miRNA-4449 and miRNA-151, in the reply filed on 10/03/2025 is acknowledged.
Claims 3, 4, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/03/2025.
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.
Claims 6-9 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.
Claims 6-9 are unclear over that stated purpose of the claimed methods as being a “method for identifying and diagnosing simple steatosis and nonalcoholic steatohepatitis”, as recited in the preamble of claim 6, from which claims 7-9 depend. The claims only recite a step of measuring miRNA expression levels (e.g.: the single practical step recited in claim 6) and a step of comparing an expression level (as recited in claim 8), but the claims do not set forth any practical step in which simple steatosis and nonalcoholic steatohepatitis is diagnosed or identified.
Claim 9 is unclear over recitation of the phrase “determining … nonalcoholic steatohepatitis when the expression level of each miRNA of patients in need of identification and diagnosis is 1.5 times higher than that of the simple steatosis patients”. The recitation of the term “when” appears to make the “determining conditional/dependent upon some particular compared amount (i.e.: 1.5 times higher in the patient as compared to a level in a simple steatosis subject), but it is unclear if this particular compared amount is in fact required to be present and detected. There is no recited step of detecting the amount, only a recitation of an asserted association between an expression level and a determination.
Claim Rejections – Improper Markush Group
Claims 6-9 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of alternative elements (i.e.: the different particular miRNAs recited in claims 6, and combinations thereof) in the limitations recited in the claims is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. Here it is noted that the election provides for the particular combination that is miRNA-4449 and miRNA-151. The different miRNAs are each unique markers, each expressed from a distinct genomic locus, with different sequences of nucleotides required for their detection and analysis. Additionally, the asserted biomarkers have different strengths of association with steatosis versus steatohepatitis (see for example Table 2 on pages 14-15 of the specification).
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 6-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas (e.g.: mental processes, mathematical calculations) and a natural phenomenon without significantly more.
The claim(s) recite(s) methods of identifying and diagnosing liver pathology (i.e.: simple steatosis and steatohepatitis) (as recited in claim 6) with a step measuring miRNA expression levels. The claims are thus directed to the assessment of collected data, which is and abstract idea that is a mental process (e.g.: MPEP 2106.04(a)(2)(III)(A)); it is the observation and evaluation of information to reach a judgment or conclusion, as set forth in claim 9. Claim 8 recites a step of “comparing”, which is a mental evaluation of data. Where the evaluation of data to reach a conclusion is based in the asserted correlation between gene expression and the presence of a particular pathology, such an association is accepted part of how a biological organism functions (i.e.: gene-expression:phenotype relationships), and as such this element of the claims is a natural phenomenon (e.g.: MPEP 2106.04(b)(I)).
This judicial exception is not integrated into a practical application because there are no practical steps related to the determination of simple steatosis or steatohepatitis in a subject. There are no additional steps of the claims that are directed to applying or using the judicial exception(s) noted above (e.g.: MPEP 2106.04(d)(I)). The claims end with an asserted association between a gene expression and the presence of a pathology, which is an abstract idea (as noted above).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only broadly recite steps of determining measuring an expression level of miRNA-4449 and miRNA-151 (as consonant with the election). However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example: Xin (2020) provides a review of methods including the detection and analysis of miRNA in serum samples related to NAFLD and NASH; Murakami et al (2012) teaches comprehensive analysis of miRNAs in peripheral blood; and Tan et al (2014) teaches the detection of miRNA levels using sequencing-based methods which detect all miRNA transcripts.
Claim Rejections - 35 USC § 112 – Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 6-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Nature of the invention and breadth of the claims
The methods of method for identifying and diagnosing simple steatosis and nonalcoholic steatohepatitis in a subject comprising measuring the expression level of miRNA-4449 and miRNA-151 in a sample form the subject.
The nature of the claims thus requires knowledge of an association between biomarker levels and the presence of particular pathology, as recited in the claims.
The claims encompass the diagnostic analysis of any subject organism, and the use of any levels of miRNA-4449 and miRNA-151 expression in the determination of pathology.
Direction provided by the specification and working example
The specification teaches an example (p.14 of the specification) of the analysis of miRNA expression level in serum samples form 24 human patients with NAFLD (12 with simple steatosis, and 12 with steatohepatitis).
The specification provides (e.g.: Table 2) that both miR-4449 and miR-151a-3p were found at higher levels in serum from subjects with steatohepatitis as compared to subjects with simple steatosis.
The specification teaches that the methods encompass non-human subjects (p.11), but there are no teachings related to expression levels in any non-human subject.
The specification teaches an analysis of gene expression levels of the particular miRNA that is hsa-miR-151a-3p, but does not teach any analysis of any other miRNA related to miR-151 (e.g.: miR-151b, miR-151a-5p).
The specification teaches the analysis of expression levels in serum from subjects with steatohepatitis as compared to subjects with simple steatosis, but does not teach any analysis of miRNA expression levels in healthy controls.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to detecting a biomarker in any particular sample is advanced, the unpredictability with regard to associating the presence of any biomarker with the presence of a pathology is high. This unpredictability is demonstrated by the related art.
Because the claims generically encompass the analysis of any organism, and the specification teaches that the “invention is not limited as long as the subject is mammals”, whereas the instant specification provides only teachings of human biomarkers and samples, it is relevant to point out that there is a large amount of unpredictability with regard to comparing results from biomarker analysis data in humans to other even closely related animals. Enard et al (2002) teaches that large numbers of quantitative changes in gene expression can be detected between closely related mammals (p.342, middle col., last paragraph).
Because the claims are broadly directed to “miRNA-151” (as recited in claim 6, as consonant with the election), and the specification teaches only the particular miRNA that is hsa-miR-151a-3p, it is relevant to point out that different miRNAs have different structures (i.e.: distinct polynucleotide sequences, see output from miRbase for hsa-mir-151b and hsa-mir-151a) and as such the different miRNAs that may be considered “miRNA-151” (as recited in the claim) have different gene targets for regulation and may not be associated with the same biological function and pathology as the disclosed hsa-miR-151a-3p.
Because the specification provides only an analysis of miRNA expression levels in pathological subject samples (i.e.: subjects with steatohepatitis as compared to subjects with simple steatosis), it is relevant to point out that there is no indication of any miRNA expression levels in normal healthy controls. Cheung et al (2003) teaches that there is natural variation in gene expression among different individuals. Thus, it is unpredictable as to whether any compared gene expression level is in fact specifically indicative of the pathological phenotype, or is associated with a non-pathological normal/healthy phenotype. For example, the specification indicates that miR-4449 is lower in NAFL as compared to NASH; but it is unknown if mir-4449 is higher in normal as compared to NASH. As such it is unpredictable what conclusion can reliably be drawn from comparing mir-4449 in a sample from a subject to the level in a NAFL (i.e.: simple steatosis) subject.
Quantity of experimentation required
A prohibitively large an amount of experimentation would be required to make and use the claimed invention. Such experimentation would include large case:control analyses of different expression levels in any subject organism, and comparison expression levels of various miRNAs to any type of reference levels from different case and control subjects. Even if such experimentation were to be performed, there is no indication that any associations beyond those exemplified by the instant application would be identified.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
In the instant rejection of claims as anticipated by the cited prior art, it is noted that the claims have been previously rejected in this Office Action under 35 USC 112(a) for lack of embalmment related to the intended use of the claimed methods in identifying and diagnosing simple steatosis and nonalcoholic steatohepatitis. The rejection of claims under 35 USC 102 is made in the interests of customer service and compact prosecution where the cited prior art teaches the same practical steps as required by the methods of the rejected claims.
The cited reference is available as prior art where the cited reference includes additional authors who are not joint inventors of the Application (i.e.: the reference includes authors that are not: Lee, Young-Sun; Gim, Jeongan; Lee, Yoonseok).
Additionally, Applicant cannot rely upon the certified copy of the foreign priority application (KR-10-2020-0093534) to overcome this rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim(s) 6-9 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (2020).
Lee et al teaches methods including the measurement of miR-4449 and miR-151a-3p (relevant to claim 6) in serum samples from subjects diagnosed with NAFLD (relevant to claim 7), and the detection of increased expression levels of the miRNAs in samples form subject with non-alcoholic steatohepatitis as compared to subjects with non-alcoholic fatty liver (relevant to claim 8 and 9).
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
The Examiner has identified the following citation/reference that is relevant to the instantly claimed subject matter:
Lee, Young-sun; Kim, Taehyung; Kang, Seong Hee; Jung, Young Kul; Seo, Yeon Seok; Kim, Ji Hoon; Yim, Hyung-Joon; Yeon, Jong Eun; Um, Soon Ho; Byun, Kwan Soo. “SERUM miRNA AS A USEFUL BIOMARKER FOR DIAGNOSIS OF NASH” (Meeting Poster), Liver Meeting of the American Association for the study of Liver Diseases (AASLD). November 13-16, 2020. Amer Assoc Study Liver Dis.
The authorship of the cited reference includes inventors of the instant application, and appears to be the abstract associated with a virtual poster presentation that was part of the 2020 AASLD conference.
The Examiner requires additional information in order to make further determinations about the patentability to the instant claims. In response to this requirement, please provide:
1. Any material (e.g.: poster panels; figures; descriptive paragraphs) that was presented in association with the cited abstract as a part of the poster presentation of the AASLD conference.
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement.
Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.58. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Conclusion
No claim is allowed.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683