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 .
This Office Action is in reply to Applicants’ correspondence of 04/01/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
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.
Election/Restrictions
In the reply filed on 10/03/2025 Applicants elected, without traverse, the invention of Group 2 (claims directed to methods of diagnosing), and the particular combination of biomarkers that is miRNA-4449 and miRNA-151.
Claims 3, 4, and 15 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 2 of the Office action of 01/07/2026.
Withdrawn Claim Rejections – 35 USC § 112 – Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 2-3 of the Office Action of 01/07/2026 are withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 6, 7 and 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, 7 and 9 are unclear over recitation of the limitation “to the measured miRNA in the simple steatosis patients” because there is no antecedent basis for any “simple steatosis patients”. The recitation in the unclear phrase appears to be directed to a control population of patients known to have the particular phenotype that is “simple steatosis”, but there is no antecedent basis in the claimed method for this plurality of specific patients.
Claim 9 is unclear over recitation of the phrase “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 after the comparing step, the method further comprises determining the nonalcoholic steatohepatitis”. Initially it is noted the recitation of the plural “patients” in the phrase “level of each miRNA of patients in need of” is unclear where the claim depends form claim 6 and claim 6 is a method performed on a single patient (i.e.: claim 6 recites “measuring expression levels of … from a biological sample of a patient in need of”). Furthermore the claim is unclear where 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, or if the limitation is only a statement of an asserted association between a compared level and a phenotype.
Maintained Claim Rejections – Improper Markush Group
Modified as Necessitated by Claim Amendments
Claims 67, and 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).
Response to Remarks
Applicants have traversed the rejection of claims as directed to an improper Markush style group of alternatively useable elements, as maintained above. Applicants’ arguments (p. 5-6 of the Remarks of 04/01/2026) have been fully and carefully considered but ae not persuasive to withdraw the rejection. Applicants have argued that the rejection does not set forth that the first element of a proper Markush Group (i.e.: that all are 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). This argument is not persuasive. Initially it is noted that the argument improperly interprets the “first” and “second” (as addressed in MPEP 2117) requirements of a proper Markush group as alternative requirements. These are not “two different ways” (as argued by Applicant) that a proper Markush group is recognized. The requirement for both aspects is clear from MPEP 2117 which provides:
A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use.
In the instant case it is clear that the different recited elements (i.e.: distinct miRNAs) do not share a single structure that is mainly responsible for their use in the claimed methods. As detailed in the rejection, 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. Furthermore, the Examiner maintains that where the rejection details that the asserted biomarkers have different strengths of association with steatosis versus steatohepatitis, this analysis of the claims is relevant to different alternatively claimed elements not meeting the requirement of being functionally equivalent.
Maintained Claim Rejections - 35 USC § 101
Modified as Necessitated by Claim Amendments
Claims 6, 7 and 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 6 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.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 101 as directed to a judicial exception to patentability without significantly more, as maintained above. Applicants’ arguments (p. 6-7 of the Remarks of 04/01/2026) have been fully and carefully considered but ae not persuasive to withdraw the rejection. Applicants have argued that the claims are amended to overcome the rejection. The examiner maintains that, as detailed in the rejection, the claims are directed to abstract ideas and natural phenomenon with only routine and conventional steps of gathering data to be used in a comparison to make a diagnosis. The diagnosis is not integrated into a practical application of the diagnosis because there are no practical steps (such as administering some specific treatment) that are performed upon the patient after a particular diagnosis is provided.
Maintained Claim Rejections - 35 USC § 112 – Enablement
Modified as Necessitated by Claim Amendments
Claims 6, 7 and 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.
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.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 as directed to subject matter that is not enabled by the application as originally filed, as maintained above. Applicants’ arguments (p. 7-8 of the Remarks of 04/01/2026) have been fully and carefully considered but ae not persuasive to withdraw the rejection. Applicants have argued that the claims are amended to provide the methods that are enabled by the application. Initially it is noted that where the claims are amended to recite a comparison to miRNA levels in simple steatosis patients, the portion of the rejection that was applied to the generical nature of the comparisons encompassed by the previous claims (e.g.: page 9 of the Office Action of 01/07/2026 which references the teachings of Cheung et al) has been withdrawn. The examiner maintains that the claims generically encompass the diagnosis of any subject organism, and that the application as filed provides only teachings relevant to human gene expression values. This aspect of the claims has not been addressed by amendment or by Applicants arguments. Applicants argue that where the claims recite miRNA-151, the teachings in the Application as originally field which are directed to expression of hsa-miR-151a-3p would direct the skilled artisan to the particular miRNA analysis detailed in the application. The Examiner maintains that the recitation of the claimed subject matter is considerably broader than the particular teachings of the specification, and the specification does not “expressly identify miRNA-151 and miRNA-151a-3p”; there is no limiting definition of the generically claimed miRNA-151 to direct the scope of the claims to the particular miRNA that is miRNA-151a-3p.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claim under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al (2020), as set forth on pages 10-11 of the Office Action of 01/07/2026, is withdrawn in light of the certified translation of the foreign priority application provided with the response of 04/01/2026. In light of the provided translation, the cited reference is no longer considered to be prior art.
Requirement for Information
In response to the Requirement for Information, Applicants have provided with the response of 04/01/2026 a certified translation of the foreign priority application. As such the referenced Abstract (Lee et al (2020)) is no longer considered to be prior art and the Requirement is moot.
Conclusion
No claim is 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 STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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