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 II (claims 21-23 and 31), and the particular biomarker that is hsa-miR-130b-5p, in the reply filed on 09/15/2025 is acknowledged. In light of the Examiner search and analysis of the claims, and in the interests of customer service and compact prosecution, the subject matter of claim 22 (i.e.: EVs comprising ASGR1) is rejoined with the elected biomarker. Claims 1, 3, 5-8, 10, 11, 14-18, 30 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 09/15/2025. Claim Objections Claim 31 is objected to because of the following informalities: the claim recites “ TGf -beta”, where “TGF-beta” is likely intended. Appropriate correction is required. 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 appl icant regards as his invention. Claim 31 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 31 contains the trademark/trade name OCALIVA . Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph. See Ex parte Simpson , 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a therapeutic reagent and, accordingly, the identification/description is indefinite. Claim 31 is unclear over the recitation of claim elements in parentheses as follows: anti-TGF- β1 monoclonal antibody (e.g. Fresolimumab ), LOXL2 monoclonal antibody (e.g. AB0023 or GS-6624) . It is unclear if the recited elements are intended to be required elements of the claim, or merely presented as a possible, but non-required, optional element. Claim Rejections – Improper Markush Group Claim 23 is rejected on the basis that it contains 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 the different biomarkers in claim 23 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The biomarker encompass structurally diverse biomolecules that are proteins (composed of amino acid monomers joined by peptide bonds) or polynucleotides (composed of nucleotide monomers joined by phosphodiester bonds) which may require different techniques and reagents (e.g.: western blots with antibodies; northern blots with oligonucleotide probes) . And each different element has a unique structure (e.g.: different amino acid or nucleotide sequences) required for its detection, and may be related to a different cellular process. In the instant case the claim may be amended to be directed to hsa-miR-130b-5p, as consonant with the election . 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 21-23 and 31 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 “assessing” (i.e.: claim 21) efficacy and comprise a step of “comparing” levels from a sample to another value. 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. Where the evaluation of data to reach a conclusion is based in the asserted correlation between a compared biomarker level and the functionality of a composition for treating a pathology, such an association is accepted part of how a biological organism functions (e.g.: transcriptomic: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 any assessed efficacy. There are no additional steps of the claims that are directed to a pplying or using the judicial exception (s) noted above (e.g.: MPEP 2106.04(d)(I)). The claims are only “Assessing” based on a step of “comparing” which are abstract ideas (as noted above). There are no additional practical steps based on the results of any assessment. 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 a biomarker level in a sample, recited at the highest level of generality. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example, the steps of marker analysis are recited at a high level of generality, and the instant specification indicates that such method are routine in the art (e.g.: specification at pages 12-13 ). Additionally in this regard it is noted that the practical step of the claims (e.g.: detecting biomarkers in a subject treated for a liver pathology) was established in the prior art (e.g.: Guo et al (2018); Lee et al (2018)) . 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. Claim(s) 21 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by McCreedy et al (US PG Pub 2015/0377910) cited on the IDS of 01/11/2023 . McCreedy teaches methods of assessing efficacy of compositions for treating fatty liver disease , including analyzing, from a subject having steatohepatitis and currently or previously being treated with a composition, a biological sample to determine the level(s) of one or more biomarkers for steatohepatitis , and comparing the level(s) of the one or more biomarkers in the sample to (a) levels of the one or more biomarkers in a previously-taken biological sample from the subject, where the previously-taken biological sample was obtained from the subject before being treated with the composition, (b) steatohepatitis-positive reference levels of the one or more biomarkers, and/or (c) steatohepatitis-negative reference levels of the one or more biomarker (e.g.: para: 0016-0018; 0024-0025; 0100-0111). 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. Claim (s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCreedy et al (US PG Pub 2015/0377910) cited on the IDS of 01/11/2023 in view of Li et al (2019) cited on the IDS of 01/11/2023 . McCreedy et al teaches methods of assessing efficacy of compositions for treating fatty liver disease , as detailed earlier in this Office Action . Further relevant to the instantly rejected claim, McCreedy et al addresses samples that are suitable for analysis, including that the sample may be any biological material suitable for detecting the desired biomarkers, and may be isolated from blood or blood plasma (e.g.: 0045) . McCreedy et al does not specifically teach samples comprising extracellular vesicles (EVs) comprising ASGR1, but the use of extracellular vesicles (EVs) comprising ASGR1 in the detection of liver-related biomarkers was known in the art as it taught b y Li et al. Li et al teaches that circulating extracellular vesicles (EVs) are a potential blood-based biomarker with for diagnostic utility in NAFLD, and that changes in EV numbers of EV cargoes in disease states may serve as disease-specific signatures. Li et al teaches that asialoglycoprotein receptor 1 (ASGR1) is a marker of hepatocyte-derived EVs; and teaches that the detection of ASGR1 + EVs is associated with the presence of liver pathology (e.g.: Fig 1). It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have performed the efficacy assessment of McCreedy et al using a sample comprising ASGR1+ EVs, as taught by Li et al. Where Li et al teaches that ASGR1 + EVs are derived from hepatocytes and are themselves a biomarker of liver pathology, the use of ASGR1 + EVs in the methods of McCreedy et al would have been the simple substitution of one known element for another with predictable results. Claim (s) 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCreedy et al (US PG Pub 2015/0377910) cited on the IDS of 01/11/2023 in view of Li et al (2019) cited on the IDS of 01/11/2023, as applied to claim 22 above, and further in view of Shen et al (2017) . McCreedy et al in view of Li et al renders obvious the detection of a level of a biomarker for liver disease in a sample comprising ASGR1 + EVs from a subject being treated with a composition for treating liver disease, and comparing the detected level to a control level, as required by claims 21 and 22. McCreedy et al in view of Li et al does not teach a liver disease biomarker that is hsa-miR-130b-5p (as recited in claim 23, as consonant with the election). However, detection of hsa-miR-130b-5p in liver disease related samples, and the comparison of the level to controls related to the presence or disease and the treatment of the disease phenotype , was known in the prior art and is taught by Shen et al. Relevant to the limitations of the rejected claim, Shen et al teaches the detection of miRNAs in human hepatoma cell line HepG2 control cells (Group 1), as well as Free fatty acid (FFA)-induced steatosi s model cells (Group 2) and FFA cells treated with a therapeutic drug (i.e.: L iraglutide ) (Group 3) (e.g.: p.4857 – Materials and methods) . Shen et al teaches that hsa-miR-130b-5p is detected at decreased levels in Group 2 as compared to Group 1 (Table S2), and that the level of hsa-miR-130b-5p in pathological model cells is increased in response to drug treatment (Table S3). It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have measured the particular biomarker hsa-miR-130b-5p in a subject with NAFLD being treated with L iraglutide , as taught by Shen et al, in a sample from the subject comprising ASGR1 + EVs and a control subject, as rendered obvious by McCreedy et al in view of Li et al. the skilled artisan would have been motivated to apply the teachings of McCreedy et al in view of Li et al to hsa-miR-130b-5p in a subject with NAFLD being treated with L iraglutide based on the expressed teachings of McCreedy et al that such methods can be used to determine the efficacy of a treatment regimen, and the expressed teachings of Li et al that the cargo of ASGR1 + EVs are potential biomarkers of liver pathology. The skilled artisan would have had a reasonable expectation of success based on the expressed teachings of Shen et al that hsa-miR-130b-5p in hepatocyte cells has measurable pathology- and treatment-related, and the expressed teachings of Li e tal that hepatocyte-derived EVs are ASGR1 + . Claim (s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over McCreedy et al (US PG Pub 2015/0377910) cited on the IDS of 01/11/2023 in view of Sturzeneker et al (2019) . McCreedy et al teaches methods of assessing efficacy of compositions for treating fatty liver disease , as detailed earlier in this Office Action. McCreedy et al does not specifically teach subjects treated with an ACE inhibitor, but the use of an ACE inhibitor related to fatty liver disease was known in the art and is taught by Sturzeneker et al (2019) . Sturzeneker et al teaches administration of r amipril , an ACE-inhibitor , to attenuate the development of the whole NAFLD histopathological spectrum. It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have performed the efficacy assessment of McCreedy et al using a sample from a subject at risk of fatty liver disease that is treated with r amipril , as taught by Sturzeneker et al. The skilled artisan would have been motivated to test a sample from the subject of Sturzeneker et al according to the methods of McCreedy et al based on the expressed teachings of McCreedy et al that such methods allow for the non-invasive assessment of treatment efficacy. The skilled artisan would have had a reasonable expectation of success because McCreedy et al teaches biomarkers associated with liver pathology, and Sturzeneker et al teaches measurement of serum biochemical markers in response to drug treatment. Conclusion No claim is allowed. 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