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 with traverse of Group I in the reply filed on January 13, 2026 is acknowledged. The traversal is on the ground(s) that the previous Office Action did not establish an undue search burden of the claims as specified by MPEP 803. This is not found persuasive because the instant application is a national stage entry filed under 35 U.S.C. 371 and is therefore not subject to US restriction practice but rather subject to lack of unity practice, see MPEP 1893.03(d). It is noted that undue search burden is not a criterion in lack of unity analysis. The test is whether or not special technical features can be established. It is noted that inventions listed as Groups I, II, III and IV do not relate to a single general inventive concept under PCT Rule 13.1 because, under PCT Rule 13.2, they lack the same or corresponding special technical features as set forth in paragraph 4 of the previous Office Action.
Claims 18, 21, 25-28, 30-31, 33, 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected method of treating a subject with pulmonary arterial hypertension (PAH), a non-transitory computer-readable medium and a kit for diagnosing a subject with a disease, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on January 13, 2026.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 10, 2024 is being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: “focuse” in line 20. This appears to be a typo. Appropriate correction is required. For examination purposes, examiner interpreted “focuse” as fucose.
Claim 6 is objected to because of the following informalities: “cholesterone” in line 5. This appears to be a typo. Appropriate correction is required. For examination purposes, examiner interpreted “cholesterone” as cholesterol.
Claim 16 is objected to because of the following informalities: “The method of claim 1, wherein the biological sample comprises plasma, serum, urine, obtained from the subject”. This claim lacks a coordinating conjunction. Appropriate correction is required. For examination purposes, examiner interpreted the claim as “plasma, serum or urine”.
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 7, 12, 13 and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 7 recites the limitation "are measured" in lines 1-2. The scope of the claim is unclear. It is unclear whether this recites a required step of the claimed method that actively performs measurement(s) longitudinally throughout time or merely states an intended use of the method. The claim does not recite any specific steps or criteria by which the measurement(s) are performed nor does it establish how the recited measurement is carried out.
Claim 12 recites the limitation “is used” in line 1. The scope of the claim is unclear. It is unclear whether this recites a required step of the claimed method that actively performs a determination of severity or merely states an intended use of the method. The claim does not recite any specific steps or criteria by which severity is determined nor does it establish how the recited “determining” is carried out.
Regarding claim 13, the phrase "classical metabolic disorders" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17 recites the limitation "is used" in line 1. The scope of the claim is unclear. It is unclear whether the claim recites a step of actively guiding treatment and/or care management or merely states intended use or result of performing the method. The claim does not recite any specific actions or steps by which treatment and/or care management is guided nor does it define how such guidance is implemented.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, 6-7, 9, 12-13 and 16-17 are rejected under U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more. Claim 1 recites a method of diagnosing a subject with a disease based on biomarkers present in the subject, which is dictated by law of nature. This judicial exception is not integrated into a practical application because nothing is done with the diagnosis. In addition, the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because even though the claim recites a step of inputting information into a computer, this is considered insignificant extra solution activity.
For the dependent claims 2, 4, 6-7, 9, 12-13 and 16-17, the claims do not cure the deficiency of claim 1 identified above. Specifically, the claims do not integrate the judicial exception into a practical application, and they do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 4, 6, 9, 12-13, 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. (Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension) in view of Itoi et al. (Serum Metabolomic Profiles for Human Pancreatic Cancer Discrimination).
Regarding claim 1, Lewis teaches a metabolic profiling right ventricular-pulmonary vascular (RV-PV) dysfunction in people with and without known pulmonary arterial hypertension (PAH) (pg. 175) and at least 5 metabolites selected from a group consisting of alpha-ketoglutarate, urate/uric acid, aconitate/aconitic acid, glucuronate/glucuronic acid (pg. 177), citrate/citric acid, fumarate/fumaric acid (pg. 179).
Lewis does not teach a computer-implemented method for diagnosing, inputting into a computer system expression data of a panel of metabolic biomarkers, determining whether expression of the metabolic biomarkers in the biological sample obtained from the subject is indicative of the disease using the computer system programmed with a trained machine learning classifier for distinguishing subjects with different diseases and without disease, wherein the machine learning classifier has been trained using expression data of a panel of metabolic biomarkers from subjects having the disease and from control subjects that do not have the disease; and diagnosing the subject if the expression data of the panel of metabolic biomarkers in the biological sample obtained from the subject is correlated by the computer system to be indicative of the disease; where the diagnostic accuracy is at least 90%.
Itoi describes a computer-implemented method for diagnosing a subject with a disease, the method comprising:
Inputting into a computer system expression data of a panel of metabolic biomarkers in a biological sample obtained from the subject (pg. 10, “overall, 200 virtual datasets with the same sample number were generated…”);
Determining whether expression of the metabolic biomarkers in the biological sample obtained from the subject is indicative of the disease using the computer system programmed with a trained machine learning classifier for distinguishing subjects with different diseases and without disease (pg. 4, “to discriminate all diseases…from controls” “to discriminate pancreatic cancer…from other malignant diseases”);
Wherein the machine learning classifier has been trained using expression data of a panel of metabolic biomarkers from subjects having the disease and from control subjects that do not have disease (pg. 10, “to evaluate the versatility of the MLR models, we separated the data randomly into a training set…”); and
Diagnosing the subject if the expression data of the panel of metabolic biomarkers in the biological sample obtained from the subject is correlated by the computer system to be indicative of the disease (pg. 7, “the advantage of using multiple metabolite biomarkers for the diagnosis of PC…”);
where the diagnostic accuracy is at least 90% (pg. 7, “prediction accuracy…”)
Itoi describes the development of four multiple logistic regression models where Model 1 discriminates all diseases from controls (pg. 4). Model 1 used 5 biomarkers: glutamic acid/Glu, histidine/His, glutamine/Gln, trimethylamine N-oxide, and serine/Ser (pg. 5; 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 apply the machine learning techniques taught by Itoi to the metabolomic profiling of pulmonary arterial hypertension as disclosed by Lewis because Itoi demonstrates that machine learning models can be trained on metabolomic datasets to classify disease states with high diagnostic performance, including accuracies of at least 90%. One skilled in the art would have understood that such trained machine learning models operate by iterative optimization of model parameters to improve classification accuracy, efficiency and generalization to unseen data, and that performance (in this case accuracy of diagnosis) improves as a routine function of training, feature selection and model tuning when applied to separable biological datasets such as disease-specific metabolomic profiles. If the modification is made, then it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to train the machine learning models such that they can diagnose PAH with accuracy surpassing 90%.
Regarding claim 2, Lewis teaches the expression data of the panel of metabolic biomarkers is determined using standard clinical chemistry techniques, protein analytic techniques, nucleic acid techniques, and/or analytical techniques suitable for metabolite analysis (pg. 176, methods, ELISA and LC-MS).
Regarding claim 4, the modified method of Lewis in view of Itoi teaches that the trained machine learning classifier is a logistic regression (Itoi, pg. 10).
Regarding claim 6, Lewis describes the method of claim 1 wherein the metabolites further consist of adenosine-5-monophospate, 3-phenyllactic acid, pyrophosphate, maltotriose, glucose-1-phosphate, myristic acid, docosahexaenoic acid, aspartic acid, tocopherol gamma, 5-methoxytryptamine, arachidic acid, cystine, adipic acid, 3-hydroxybutyric acid, cholesterone, 2,4-diaminobutyric acid, and 3-aminoisobutyric acid.
Examiner is interpreting the claim to mean that the panel of metabolic biomarkers comprises at least 5 metabolites from the list mentioned in claim 1 plus the metabolites mentioned in claim 6. Lewis already describes at least 5 metabolites in claim 1. See supra (Claim 1).
Regarding claim 9, Lewis describes the disease comprises pulmonary arterial hypertension (PAH), Diabetes Mellitus (DM), left heart disease, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), head and neck cancer, thyroid cancer or colon cancer (pg. 177; “we performed metabolite profiling in 11 patients with PAH and 19 control subjects.”).
Regarding claim 12, Lewis teaches the method is used for determining the severity of PAH in the patient (pg. 188, conclusions).
Regarding claim 13, the modified method of Lewis in view of Itoi teaches the method can be used to discriminate between diseases including pulmonary arterial hypertension (PAH), and classical disorders such as diabetes mellitus (DM) or left heart diseases (pg. 181, multimarker scores).
Modified Lewis teaches diagnosing disease states using metabolomic biomarkers in combination with machine learning classification.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply such classification methods to discriminate PAH from other disease states, including diabetes and let heart disease because different diseases are known to exhibit distinct metabolomic signatures and Itoi demonstrates that machine learning analysis of metabolomic data can be used to distinguish between such disease states with a reasonable expectation of success (Itoi, pg. 4).
Regarding claim 16, the modified method of Lewis in view of Itoi teaches the biological sample comprises plasma, serum, urine, obtained from the subject (Lewis, pg. 176, “plasma”).
Regarding claim 17, Lewis teaches the method is used to guide treatment and/or care management of the subject diagnosed with pulmonary arterial hypertension (pg. 175, “inform selection of patients for PH-specific therapies”).
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. (Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension) in view of Itoi et al. (Serum Metabolomic Profiles for Human Pancreatic Cancer Discrimination) in further view of Rhodes et al. (Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension).
Regarding claim 7, the modified method of Lewis teaches that samples are obtained from the subjects at a single clinical timepoint and metabolite levels are measured from that sample (pg. 176, methods, “in the third PAH versus control validation cohort, peripheral venous plasma samples were obtained in the fasting state at 3 days from the time of right-sided heart catheterization documenting PAH”).
The modified method of Lewis does not describe that the samples were measured from the subject longitudinally throughout time as claimed.
Rhodes describes the metabolites are measured throughout time in samples obtained from the subject longitudinally throughout time, wherein the longitudinally throughout time comprises 1) an initial time comprising at time of no symptoms, at time of diagnosis, or at initial presentation of symptoms; 2) about weekly intervals post initial time; 3) about monthly intervals post initial time and/or 4) about yearly intervals (page 467, Analysis of Serial Samples).
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to measure metabolites throughout time in samples obtained from the subject longitudinally throughout time in order to observe changes in metabolite levels in individuals over time because correction of metabolite levels over time is linked to better clinical outcomes (Rhodes, page 461, Clinical Perspective, What Is New?).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brianna K. Slade whose telephone number is (571)272-8514. The examiner can normally be reached Monday - Friday 8:30 AM - 2:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Luan V. Van can be reached at (571) 272-8521. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/B.K.S./Examiner, Art Unit 1796
/PAUL S HYUN/Primary Examiner, Art Unit 1796
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