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 .
DETAILED ACTION
Claims 2, 4-8, 10-11, 13-14, 17, 21-22, 25-27, 29-31 and 34 are pending.
Election/Restrictions
Applicant’s election without traverse of the species of taurodeoxycholic acid (TDCA) in the reply filed on 6/4/2026 is acknowledged.
Claims 2, 4-8, 10-11, 13-14, 17, 21-22, 25-27, 29-31 and 34 are examined herein.
Drawings
The drawings are objected to because in Fig. 1 it is not possible to distinguish between the two types of data points (male and female). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 22, 25, and 29-30 are objected to because of the following informalities:
Claims 22, 25, and 29-30 use hyphens as bullet points. Applicant should replace the hyphens with alphanumeric designations (e.g. (i), (a), or (1)).
In addition, claim 22 recites “determining if the subject has non-alcoholic fatty liver disease (NAFLD) by measuring the level of symmetric dimethylguanidino valeric acid (SDGV) in a biological sample obtained from the subject, and determining whether the subject has NAFLD disease based on the level of SDGV in the biological sample,” which is redundant. Applicant may consider amending the claim to recite instead “measuring the level of symmetric dimethylguanidino valeric acid (SDGV) in a biological sample obtained from the subject, and determining whether the subject has NAFLD disease based on the level of SDGV in the biological sample.” Likewise, Applicant should consider amending the second half of the claim to recite “measuring the level of taurodeoxycholic acid (TDCA) in a biological sample obtained from the subject, and determining whether the subject has HCC based on the level of TDCA in the body fluid biological sample.”
Appropriate correction is required.
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 4, 10-11, 13-14, 22, 25-27, 29-31, and 34 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.
Claim 4 is indefinite because the claim recites “The method according to claim 2 further comprising determining a change in liver fat level in a subject.” The claim is indefinite because it is unclear whether the subject is the same as the subject recited in claim 2.
Claim 10 recites wherein the level of symmetric dimethylguanidino valeric acid in the biological sample is compared to that of a SDGV control. It is unclear whether this limitation is further limiting the step of determining said presence or absence or level of liver fat based on the level of SDGV in the biological sample, or this limitation recites an additional method step. In addition, it is unclear whether the method further comprises measuring the level of the SDGV control.
Claim 11 recites optionally wherein the level of the further biological marker in the biological sample is compared to that of a further control. Claim 11 depends from claim 2, which does not recite a control. It is also unclear whether measuring the level of the control is within the scope of the claimed invention.
Claim 13 recites “clinically acceptable levels of liver fat.” Per MPEP 2173.05(b)(IV): A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. Here, whether or not a level of liver fat is “clinically acceptable” may vary depending on the clinic and requires the exercise of subjective judgment by the clinician.
Claims 13-14 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
In addition, claim 14 recites “wherein the standard control value or a set or standard control values indicative of the presence of liver fat is/are each:” and “wherein the standard control value or a set or standard control values indicative of the presence of liver fat is/are each:” Standard control value and a set of standard control values are both singular. However, the claim recites “is/are each” leading to ambiguity in the claim scope, since it is unclear whether there is a value, a set of values, or sets of values.
Claim 22 is indefinite because method steps do not match the method preamble. The preamble is drawn to diagnosing and/or prognosing HCC. However, the result of the method steps are determining whether the subject has NAFLD and determining whether the subject has HCC. Therefore, it unclear how the method is drawn to the prognosis of HCC.
Claim 22 is further indefinite because it is unclear whether the claim requires a single biological sample in which both SDGV and TDCA are measured or whether the claim requires two different biological samples, a first biological sample in which SDGV is measured and a second biological sample in which TDCA is measured. The indefiniteness arises because the claim recites “a biological sample obtained from the subject” in the first and second bullet points, but the claim also refers to “the biological sample” within each bullet point.
Claims 25-27, 29-31, and 34 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
Claim 25 recites the level of symmetric SDGV is compared to that of a SDGV control and/or the level of the TDCA is compared to that of a TDCA control. It is unclear whether these steps are additional method steps or whether these are further limiting the steps of determining whether the subject has NAFLD and determining whether the subject has HCC. It is further unclear whether measuring the level of SDGV or TDCA in the SDGV and TDCA controls are within the scope of the claim.
Claim 26 recites “clinically acceptable levels of liver fat.” Per MPEP 2173.05(b)(IV): A claim term that requires the exercise of subjective judgment without restriction may render the claim indefinite. Here, whether or not a level of liver fat is clinically acceptable” may vary depending on the clinic and requires the exercise of subjective judgment by the clinician.
Claim 26 is further indefinite because there is a conjunction missing between “a series of biological samples from subjects without liver fat and without HCC, or without clinically acceptable levels of liver fat and without HCC” and “a standard control value or a set of standard control values indicative of the presence or absence of liver fat and/or HCC.”
Additionally, claim 26 is rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
Claim 27 is indefinite for “wherein said determining whether the subject has HCC comprises determining a concentration of the TDCA in a plasma from the subject of above, above 0.7 µM.” There appears to be a concentration missing after the first “above,” thus the metes and bounds of the claim are undefined.
Claim 29 recites the method comprises determining a concentration of the SDGV in plasma from the subject and determining a concentration of the TDCA in a plasma from the subject to thereby determine that the subject does not have HCC. Claim 29 depends from claim 22, which recites two separate determining steps: determining whether the subject has NAFLD based by measuring the level of SDGV in a biological sample obtained from the subject and determining whether the subject has HCC based on the level of TDCA in the biological sample. It is unclear whether claim 29 requires measuring TDCA and SDGV from the same plasma sample and it is further unclear whether the concentration of SDGV is required for determining whether the subject does not have HCC. Claim 29 recites determining SDGV and/or determining TDCA to thereby determine that the subject does not have HCC, but claim 22 recites determining whether the subject has HCC by measuring the level of TDCA in a biological sample.
Claim 30 recites determining a concentration of the SDGV in plasma and determining a concentration of TDCA in a plasma. Claim 30 depends from claim 22, which recites two separate determining steps: determining whether the subject has NAFLD based by measuring the level of SDGV in a biological sample obtained from the subject and determining whether the subject has HCC based on the level of TDCA in the biological sample. It is unclear whether claim 30 requires measuring TDCA and SDGV from the same plasma sample.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 30 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 30 fails to include all the limitations of the claim upon which it depends. Claim 30 recites determining a concentration of SDGV in plasma and determining a concentration of TDCA in plasma to thereby determine that the subject should be monitored due to a risk of developing HCC. However, claim 30 depends from claim 22, which recites measuring the level of TDCA in a biological sample obtained from a subject and determining whether the subject has HCC based on the level of TDCA in the biological sample.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 31 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating the subject to reduce liver fat in the subject and treating the subject to alleviate metabolic dysfunction-associated steatotic liver disease, does not reasonably provide enablement for the treatment of any other disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Per MPEP 2164.01(a), the following eight factors should be considered when determining whether the person of ordinary skill in the art would face undue experimentation to make and/or use the invention: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Nature of the invention. Claims 31 and 34 are drawn to methods for diagnosing and/or prognosing hepatocellular carcinoma in the subject but additionally recite the active method step of treating the subject to alleviate a disease arising at least in part from or characterized by excess liver fat.
Breadth of the claims. The claims are extremely broad in terms of the disease: “a disease arising at least in part from or characterized by excess liver fat.”
State of the prior art and unpredictability. Treatment of NAFLD may include any treatment that results in weight loss to reduce liver fat (Harvard health, 2020, website, page 3, “Weight loss is key to preventing complications of fatty liver” paragraph 1). However, there are other disorders characterized by excess liver fat: for example, Reiner et al. (Atherosclerosis 235.1 (2014): 21-30) teaches that lysosomal acid lipase deficiency is an under-recognized cause of dyslipidemia and liver dysfunction (Title) and no disease-specific treatments are currently available (page 27, right column, 7. Management and therapies in development, paragraph 1).
Guidance in the specification and working examples. The specification exemplifies some treatments that include lifestyle intervention (e.g. diet, exercise) to induce weight loss to reduce liver fat, as well as changing macronutrient composition, excluding fructose intake, limiting of alcohol consumption and/or increasing physical activity. The specification also discloses administering insulin sensitizers, vitamin E, a dual PPARα/δ agonist (e.g. elafibranor), and/or a Farnesoid X receptor (FXR) agonist (specification, bottom paragraph on page 17 through top paragraph on page 18).
Amount of experimentation necessary. Undue experimentation would be required by the person of ordinary skill in the art to practice the full scope of the invention due to the breadth of claims. First, the person of ordinary skill in the art would have had to catalog all diseases that arise at least in part from or are characterized by excess liver fat, which includes rare inherited genetic disorders. Second, the person of ordinary skill in the art would have had to develop a treatment for these disorders.
Taking these factors into account, undue experimentation would be required by one of ordinary skill in the art to practice the full scope of the claimed invention. Thus, the claims are not fully enabled by the disclosure.
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 2, 4-8, 10-11, 13-14, 17, 21-22, 25-27, 29-31, and 34 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of an abstract idea without significantly more.
The rationale for this determination is explained below.
A flowchart has been established to determine subject matter eligibility under 35 U.S.C. 101. See MPEP 2106 part (III) and 2106.04 part (II)(A). The flowchart comprises answering: Step 1) Is the claim to a process, machine, manufacture or composition of matter? Step 2A Prong One) Does the claim recite an abstract idea, law of nature or natural phenomenon? Step 2A Prong Two) Does the claim recite additional elements that integrate the judicial exception into a practical application? Step 2B) Does the claim recite additional elements that amount to significantly more than the judicial exception? The claims are analyzed for eligibility in accordance with their broadest reasonable interpretation.
Claim 2 recites a method for determining a presence or absence of liver fat in a subject or determining a subject’s level of liver fat comprising measuring the level of symmetric dimethylguanidino valeric acid in a biological sample obtained from the subject and determining the presence or absence or level of liver fat based on the level of SDGV in the biological sample.
Claim 2 is drawn to a process (Step 1: Yes). Claim 2 recites the judicial exception of a natural phenomenon: the level of symmetric dimethylguanidino valeric acid naturally correlates with the level of liver fat (Step 2A Prong One: Yes). The claim is not integrated into a practical application (Step 2A Prong Two: No) as there is no application recited in the claim. There are no additional elements recited in the claim (Step 2B: No).
Claim 4 recites the method further comprises determining a change in liver fat level in a subject comprising measuring the level of symmetric dimethylguanidino valeric acid in one or more biological samples obtained from the subject at multiple timepoints and determining whether there is a change in liver fat level in the subject over time based on a comparison of the level of SDGV in each said biological sample. Claim 4 recites the additional judicial exception of a mental process (abstract idea): “determining whether there is a change in liver fat level in the subject over time based on a comparison of the level of SDGV in each said biological sample” (Step 2A Prong One: Yes). Again, the judicial exception is not integrated into any practical application (Step 2A Prong Two: No). There are no additional elements recited in the claim (Step 2B: No).
Claim 5 further limits the subject. The analysis for claim 5 is the same as above for claim 2.
Claim 6 recites a method for diagnosing and /or prognosing fatty liver disease in a subject comprising measuring the level of symmetric dimethylguanidino valeric acid in a biological sample obtained from the subject and determining whether the subject has fatty liver disease based on the level of SDGV in the biological sample. Claim 6 recites the judicial exception of an abstract idea: determining whether the subject has fatty liver disease based on the level of SDGV in the biological sample (Step 2A Prong One: Yes). The judicial exception of an abstract idea is not integrated into any practical application because the outcome of performing the method is purely information: the disease state of the subject (Step 2A Prong Two: No). The claim recites the additional element of measuring the level of symmetric dimethylguanidino valeric acid in a biological sample obtained from the subject, which is recited at a high level of generality. This is insignificant, extra-solution activity (mere data gathering). Thus, the claim as a whole does not amount to significantly more than the judicial exception of an abstract idea (Step 2B: No).
Claim 7 limits the fatty liver disease to non-alcoholic fatty liver disease. The analysis for claim 7 is the same as for claim 6 above.
Claim 8 depends from claim 2. Claim 8 recites “wherein measuring the level of symmetric dimethylguanidino valeric acid in the biological sample is performed without measuring the level of asymmetric dimethylguanidino valeric acid in the biological sample and/or wherein said determining based upon the level of SDGV in the biological sample is performed without determining based on the level of asymmetric dimethylguanidino valeric acid in the biological sample.” Claim 8 is still drawn to the judicial exception of a natural phenomenon (Step 2A Prong One: Yes). The judicial exception is not integrated into any practical application (Step 2A Prong Two: No). The claim does not recite any additional element besides the judicial exception, which is the natural phenomenon of a correlation between the level of SDGV and the level of liver fat (Step 2B: No).
Claim 10 recites the additional judicial exception of an abstract idea: comparing the level of symmetric dimethylguanidino valeric acid in the biological sample to that of a SDGV control (Step 2A Prong One: Yes). The judicial exception is not integrated into a practical application and the claim does not recite any additional elements (Step 2A Prong Two: No, Step 2B: No).
Claim 11 recites the additional step of measuring further biological marker in the biological sample and requires that said determining the presence, absence or level of liver fat in the subject is additionally based on the level of the further biological marker, optionally wherein the level of the further biological marker in the biological sample is compared to that of a further control. Claim 11 recites the additional judicial exception of an abstract idea: comparing the level of the further biological marker to that of the further control (Step 2A Prong One: Yes). The judicial exception is not integrated into any practical application (Step 2A Prong Two: No). The claim recites the additional element of measuring further biological markers in the biological sample, which is data gathering and insignificant extra-solution activity (Step 2B: No).
Claims 13-14 further limit the SDGV control in the step of comparing the level of symmetric dimethylguanidino valeric acid in a biological sample to that of a SDGV control. The claims are still drawn to the judicial exception of a natural phenomenon (the natural correlation between the level of SDGV and the level of liver fat in a subject) and an abstract idea: comparing the level of SDGV in a biological sample to that of the SDGV control) (Step 2A Prong One: Yes). The claims are not integrated into a practical application (Step 2A Prong Two: No). The claims do not recite additional elements besides the judicial exception (Step 2B: No) because the SDGV control is only recited within the mental step of comparison.
Claim 17 recites the additional element of limiting the biological sample to blood, serum, plasma, urine, or liver and the method optionally further comprises culturing the biological sample and/or obtaining the biological sample from the subject. These additional elements are recited at a high level of generality and amount to insignificant, extra-solution activity (mere data gathering). In particular with respect to limiting the biological sample to blood, MPEP 2106.05(g) specifically exemplifies determining the level of a biomarker in blood as mere data gathering. Thus, claim 17 does not amount to significantly more than the judicial exception of a natural phenomenon (Step 2B: No).
Claim 21 limits the step of measuring the level of symmetric dimethylguanidino valeric acid to LC-MS/MS, GC-MS/MS or NMR. These measurement techniques are well-understood, routine, and conventional activity (Step 2B: No).
Claim 22 recites a method for diagnosing and/or prognosing hepatocellular carcinoma in a subject comprising determining if the subject has non-alcoholic fatty liver disease by measuring the level of symmetric dimethylguanidino valeric acid in a biological sample obtained from the subject and determining whether the subject has NAFLD based on the level of SDGV in the biological sample and determining whether the subject has HCC by measuring the level of taurodeoxycholic acid (TDCA) in a biological sample obtained from the subject, and determining whether the subject has HCC based on the level of TDCA in the sample. Claim 22 recites the judicial exception of a natural phenomenon: the natural correlation between the level of SDGV and the NAFLD state of the subject as well as the natural correlation between the level of taurodeoxycholic acid and the HCC disease state of the subject (Step 2A Prong One: Yes). Claim 22 does not integrate the judicial exception into a practical application (Step 2A Prong Two: No) because the outcome of performing the method is purely information (the diagnosis/prognosis of the subject). Claim 22 does not amount to significantly more than the judicial exception because the additional element of measuring the level of SDGV and TDCA in the biological sample is insignificant, extra-solution activity (mere data-gathering).
Claim 25 recites the additional judicial exception of an abstract idea: comparing the level of SDGV to that of a control and comparing the level of TDCA to that of a control. Claim 26 limits the SDGV control and/or the TDCA control. However, these are purely recited within the judicial exception of an abstract idea (comparison).
Claim 27 further limits the steps of determining if the subject has NAFLD and determining whether the subject has HCC. Claim 27 recites the additional judicial exception of an abstract idea (Step 2A Prong One: Yes): the comparison of the level of SDGV to recited ranges (e.g. above 0.4 µM) to determine if the subject has NAFLD and the comparison of the level of TDCA to the recited ranges (e.g. above 0.7 µM) to determine if the subject has HCC. The judicial exception is not integrated into any practical application (e.g. a particular treatment of NAFLD or HCC). There are no additional elements recited in the claim.
Claim 29 recites additional abstract ideas: determining a concentration of SDGV and TDCA in plasma below certain levels and concluding that the subject does not have HCC based on this comparison. The analysis is the same as for claim 27 (Step 2A Prong One: Yes, Step 2A Prong Two: No, Step 2B: No).
Claim 30 changes the mental comparison to determining the subject should be monitored due to risk of developing HCC based on a concentration of SDGV and TDCA in plasma. The analysis above is the same as for claim 27 (Step 2A Prong One: Yes, Step 2A Prong Two: No, Step 2B: No).
Claims 31 and 34 recite the method further comprises either treating the subject to reduce liver fat in the subject or treating the subject to alleviate a disease arising at least in part from or characterized by excess liver fat. The additional limitations do not integrate the judicial exception into a practical application because they are recited at a high level of generality and are not a particular treatment (Step 2A Prong Two: No). Treatment to reduce liver fat in diseases arising at least in part or characterized by excess liver fat is well-understood, routine, and conventional activity (Step 2B: No). For example, treatment of NAFLD may include any treatment that results in weight loss to reduce liver fat (Harvard health, 2020, website, page 3, “Weight loss is key to preventing complications of fatty liver” paragraph 1).
Therefore, none of the claim are eligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 2, 5, 10, 13, 17, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by O’Sullivan et al. (The Journal of clinical investigation 127.12 (2017): 4394-4402; cited on the IDS filed 6/16/2026) as evidenced by Jarzebska et al. (International journal of molecular sciences 20.18 (2019): 4592; cited on the IDS filed 6/16/2026).
Regarding claim 2, O’Sullivan teaches measuring the level of DMGV, which is the level of both symmetric and asymmetric dimethylguanidino valeric acid (metabolite 1 in Table 2) in plasma (page 4400, right column, Metabolic profiling, Hybrid platform, paragraph 1) and that the level of DMGV correlates with liver fat (Table 2 and page 4399, left column, paragraph 2). Although O’Sullivan refers to metabolite 1 as DMGV, the measurement includes the amount of both symmetric and asymmetric dimethylguanidino valeric acid as evidenced by Jarzebska (page 7, paragraph 1). There are two overlapping peaks in the chromatogram: one peak at RT 7.85 and the other peak at RT 7.95 (Figure 2B). Therefore, O’Sullivan teaches determining the relative level of liver fat based on the amount of DMGV, which includes both symmetric and asymmetric dimethylguanidino valeric acid.
Regarding claim 5, O’Sullivan measures the level of DMGV (symmetric and asymmetric dimethylguanidino valeric acid) in patients with NASH (Figure 3A), which is a type of fatty liver disease.
Regarding claim 10, O’Sullivan compares the level of DMGV (SDGV + ADGV) to that of a control (Figure 3A).
Regarding claim 13, O’Sullivan’s control is normal (Table 3) and is thus a standard control value indicative of the absence of liver fat.
Regarding claim 17, O’Sullivan sample is plasma (page 4400, right column, Metabolic profiling, Hybrid platform, paragraph 1).
Regarding claim 21, O’Sullivan measures the level of DMGV (SDGV + ADGV) by LC-MS/MS (page 4401, left column, DMGV assay on the targeted MS platform, paragraph 2 and Figure 2C).
Claim 14 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by O’Sullivan et al. (The Journal of clinical investigation 127.12 (2017): 4394-4402; cited on the IDS filed 6/16/2026) as evidenced by Jarzebska et al. (International journal of molecular sciences 20.18 (2019): 4592; cited on the IDS filed 6/16/2026), as applied to claims 2, 5, 10, 13, 17, and 21 above, further evidenced by Petäjä et al. (International journal of molecular sciences 17.5 (2016): 633).
See discussion of O’Sullivan and Jarzebska above, which is incorporated into this rejection as well.
Regarding claim 14, normal liver fat is less than 5% in normal biopsies of liver cells as evidenced by Petäjä (Abstract).
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.
Claims 4, 6-7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over O’Sullivan et al. (The Journal of clinical investigation 127.12 (2017): 4394-4402; cited on the IDS filed 6/16/2026) as evidenced by Jarzebska et al. (International journal of molecular sciences 20.18 (2019): 4592; cited on the IDS filed 6/16/2026).
See above discussion of O’Sullivan and Jarzebska above, which is incorporated into this rejection as well.
Regarding claim 4, O’Sullivan teaches monitoring the level of DMGV (SDGV+ADGV) in patients over time following weight loss surgery (Figure 3B).
O’Sullivan does not explicitly teach determining a change in liver fat level in the subject based on a comparison of the level of SDGV in each biological sample.
However, O’Sullivan teaches that DMGV (includes SDGV and ADGV) correlates with liver fat (Table 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to determine a relative change in liver fat level of the subject based on the level of DMGV (SDGV + ADGV) measured at each time point. The person of ordinary skill in the art would have been motivated by the teaching of O’Sullivan, who teaches both measuring the level of DMGV over time and the correlation of liver fat with the level of DMGV.
Regarding claims 6-7, O’Sullivan teaches that DMGV (SDGV + ADGV) is a biomarker for NAFLD (page 4395, left column, paragraph 1 and Figure 3A).
Therefore, although O’Sullivan does not explicitly teach diagnosing the subject with NASH (a type of NAFLD) based on the level of DMGV (SDGV + ADGV), it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to do so based on the teachings of O’Sullivan and the person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
Regarding claim 11, O’Sullivan does not teach determining the presence of liver fat in a subject based on ALT or AST and DMGV (SDGV+ADGV).
O’Sullivan also measures elevated levels of ALT and AST in NASH subjects relative to normal subjects (Table ).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of O’Sullivan by determining the presence of liver fat in a subject by measuring ALT or AST and DMGV (SDGV+ADGV) in a plasma sample from the subject. The person of ordinary skill in the art would have been motivated to include ALT and/or AST because they are both positively correlated with NASH status and thus are both indicative of liver fat. The person of ordinary skill in the art would have had a reasonable expectation of success in the combination of biomarkers each correlated with NASH status.
Claims 22, 25-26, 29, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over O’Sullivan et al. (The Journal of clinical investigation 127.12 (2017): 4394-4402; cited on the IDS filed 6/16/2026) as evidenced by Jarzebska et al. (International journal of molecular sciences 20.18 (2019): 4592; cited on the IDS filed 6/16/2026), as applied to claims 4, 6-7, and 11 above, in view of Thomas et al. (Cancers 13.11 (2021): 2648; published May 28, 2021).
See discussion of O’Sullivan and Jarzebska above, which is incorporated into this rejection as well.
Regarding claim 22, O’Sullivan teaches that DMGV (SDGV + ADGV) is a biomarker for NAFLD (page 4395, left column, paragraph 1 and Figure 3A).
Therefore, although O’Sullivan does not explicitly teach diagnosing the subject with NASH (a type of NAFLD) based on the level of DMGV (SDGV + ADGV), it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to do so based on the teachings of O’Sullivan and the person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
O’Sullivan does not teach measuring the level of TDCA in a biological sample obtained from the subject and determining whether the subject has HCC based on the level of TDCA in the sample.
Thomas teaches that the rising incidence of hepatocellular carcinoma (HCC) may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development (Abstract). Thomas teaches that the serum level of TDCA, among other bile acids, is elevated in patients with HCC (Title and Table 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add a step of measuring the level of TDCA in O’Sullivan’s plasma sample in order to determine whether the subject has HCC. The person of ordinary skill in the art would have been motivated by the teaching of Thomas, who suggests an association between metabolic dysfunction-associated fatty liver disease and the development of HCC. The person of ordinary skill in the art would have had a reasonable expectation of success given that TDCA is elevated in patients with HCC.
Regarding claim 25¸ O’Sullivan does not teach comparing the level of TDCA to a control.
Thomas compares the level of TDCA to a control (Table 4).
It would have been further obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to measure the level of TDCA in a control and compare the level of TDCA in the subject’s plasma sample to that of the control in order to determine if the TDCA is elevated and thus whether the subject has HCC. The person of ordinary skill in the art would have had a reasonable expectation of success in adding a step of measuring the level of TDCA in a control and comparing the level of TDCA in the sample to that of the control.
Regarding claim 26, Thomas teaches that the controls do not have HCC (Table 1). The geometric mean of the level of TDCA in the controls is 45 nM, whereas the geometric mean of the level of TDCA in the HCC cases is 124 nM (Table 4). Thus, Thomas teaches the TDCA control has a standard control value (45 nM), which is indicative of the absence of HCC.
Regarding claim 29, O’Sullivan does not teach determining a concentration of TDCA in plasma below 0.8 µM to determine that the subject does not have HCC.
However, given that the geometric mean of level of TDCA in the controls is 45 nM (Thomas Table 4), it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to determine that the subject does not have HCC when the concentration of TDCA in the plasma from the subject is 45 nM or below. Below 45 nM overlaps with the claimed ranges of below 0.8 µM, below 0.75 µM, and below 0.7 µM.
Regarding claim 34, O’Sullivan teaches performing weight loss surgery that reduces DMGV (SDGV+ ADGV) and thus necessarily reduces liver fat (Table 1 and Figure 3B).
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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