DETAILED ACTION
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 .
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.
Restriction election
Applicant’s election of Species 1 (liver inflammation) and Species 2 (the combination of LPL, STMN2, TREM2, FABP4, COMP, and CAPG) in the reply filed on 11/30/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 54-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claim Status
Claims 1-8, 16, 18, 27, 29, 31, 41-55, 56, and 58 are pending.
Claims 9-15, 17, 19-26, 28, 30, 32-40, 57, and 59-105 are canceled.
Claims 54-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, as described above.
Claims 1-8, 16, 18, 27, 29, 31, 41-53, 56, and 58 are under examination.
Claims 1-8, 16, 18, 27, 29, 31, 41-53, 56, and 58 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 63/291575, filed 12/20/2021 and US provisional application 63/292000, filed on 12/21/2021. Accordingly, each of claims 1-8, 16, 18, 27, 29, 31, 41-53, 56, and 58 are afforded the effective filing date of the 12/20/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 05/10/2023 and 06/06/2024 are in compliance with the provisions of 37 CFR 1.97 and have therefore been considered. Signed copies of the IDS documents are included with this Office Action.
Drawings
The Drawings submitted 12/19/2022 are accepted.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(b)
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.
Claims 1-8, 16, 18, 27, 29, 31, 41-53, 56, and 58 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1: Claim 1 is drawn to a method that has been amended to a method of treating with only one active step of administering a therapeutic agent or performing surgery. It provides several wherein clauses, however these do not appear to be active steps. It is unclear of the treatment is predicated or that the steps are required, or how they further limit the claim. The metes and bounds of the claims are unclear. The rejection may be overcome by clarifying what steps are required to be performed. For compact examination, it is assumed that the performance of the binding selection processes is required. Claim(s) 2-8, 16, 18, 27, 29, 31, 41-53, 56, and 58 is/are rejected for the same reason because they depend from claims 1, respectively, and do not resolve the indefiniteness issue in those claims.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8, 16, 18, 27, 29, 41-42, 52-53, 56, and 58 is/are rejected under 35 U.S.C. 102(a)1 as being anticipated by Gerhard et al. (EP23602477A1, published 08/24/2011, newly cited).
Claim 1 is directed to a method of treating a subject having liver inflammation and/or liver fibrosis in a , the method comprising: administering a therapeutic agent that treats or inhibits liver inflammation and/or liver fibrosis and/or conducting a surgery on the subject when the subject's Transcriptome Score (TS) is greater than a threshold TS determined from a reference population of subjects without liver inflammation and/or without liver fibrosis; wherein the TS comprises a value determined from RNA expression in a biological sample from the subject; wherein the threshold TS is determined by identifying a gene having a median transcript per million (TPM) value of 0.5; and wherein the therapeutic agent comprises an HSD17B13 inhibitor, a PNPLA3 inhibitor, a CIDEB inhibitor, or any combination thereof.
Gerhard discloses a panel of genes useful for diagnosing non-alcoholic steatohepatitis (NASH) [abstract]. Gerhard further discloses the invention also provides a method of diagnosing NASH in non-invasive assays based on the expression of particular genes in a panel of NASH-related genes [abstract]. Gerhard also discloses methods of treatment for NASH and compositions for treating NASH are also provided [abstract]. Gerhard further discloses a method for diagnosing a NASH disease state in a patient comprising determining a level of expression of a panel of genes associated with the onset or progression of NASH in a patient sample; comparing the level of expression with a predetermined value for NASH-associated gene expression in said panel of genes and correlating the level of expression with a NASH disease state [claim 1]. Gerhard also discloses a method for treating NASH in a mammalian subject comprising administering to a mammalian subject suspected of having or being susceptible to NASH, a therapeutically effective amount of an inhibitor of at least one NASH related gene or protein in an amount effective to reduce, eliminate or prevent NASH [claim 9].
Claim 2 is directed to the method according to claim 1, wherein the RNA expression comprises a quantification of RNA expression of at least one gene.
Gerhard discloses gene expression at the nucleic acid level is detected in PBMCs by specific, quantifiable methods such as real-time PCR on RNA extracted from PBMCs [0065]. Gerhard further discloses the Taqman assay is well-known in the art as a means to quantify gene expression for analysis beginning with an RNA substrate [0065]. Gerhard also discloses any type of specific, quantifiable analysis known in the art may be used to detect gene expression and compare the expression level with normal levels to correlate either increased or decreased expression (depending on the gene of interest) with the diagnosis of NASH [0065]. Gerhard further discloses the Panel of genes of the invention may be used in a diagnostic screen for NASH by taking a sample from a patient and determining the level of expression of genes in the Panel and compare the results of the screen with a set of predetermined values for correlation of the results with likelihood of NASH in the patient [0058]. Gerhard also discloses in some embodiments, the Panel comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 genes [0057].
Claim 3 is directed to the method according to claim 2, wherein the at least one gene comprises a protein-coding gene, a long non-coding RNA, a mitochondrial rRNA, a mitochondrial tRNA, an RNA, a ribozyme, a B-cell receptor subunit constant gene, and/or a T-cell receptor subunit constant gene.
Gerhard discloses gene expression at the nucleic acid level is detected in PBMCs by specific, quantifiable methods such as real-time PCR on RNA extracted from PBMCs [0065].
Claim 4 is directed to the method according to claim 2, wherein the at least one gene comprises 10 genes.
Gerhard discloses multiple different probe sets sometimes map to the same gene or transcript, contributing to a final total of 39,000 best-characterized human genes on the HG-U133 array [0136].
Claim 5 is directed to the method according to claim 2, wherein the at least one gene comprises 50 genes.
Gerhard discloses multiple different probe sets sometimes map to the same gene or transcript, contributing to a final total of 39,000 best-characterized human genes on the HG-U133 array [0136].
Claim 6 is directed to the method according to claim 2, wherein the at least one gene comprises 100 genes.
Gerhard discloses multiple different probe sets sometimes map to the same gene or transcript, contributing to a final total of 39,000 best-characterized human genes on the HG-U133 array [0136].
Claim 7 is directed to the method according to claim 2, wherein the at least one gene comprises 200 genes.
Gerhard discloses multiple different probe sets sometimes map to the same gene or transcript, contributing to a final total of 39,000 best-characterized human genes on the HG-U133 array [0136].
Claim 8 is directed to the method according to claim 2, wherein the at least one gene comprises 1000 genes.
Gerhard discloses multiple different probe sets sometimes map to the same gene or transcript, contributing to a final total of 39,000 best-characterized human genes on the HG-U133 array [0136].
Claim 27 is directed to the method according to claim 2, wherein the reference population of subjects without liver inflammation and/or without liver fibrosis comprises a reference population of subjects without liver inflammation, and wherein the at least one gene is upregulated with respect to that of in the reference population of subjects without liver inflammation.
Gerhard discloses a method of diagnosing NASH by determining the expression levels of at least one of a panel of genes that are associated with NASH as compared to normal patients [0027] which reads on a reference without liver inflammation. Gerhard further discloses an elevated expression of some genes correlates with the incidence of NASH [0027]. Gerhard also discloses the expression level of CCL19 is compared with normal CCL19 expression and an increase in expression and the expression level of SCYA20 is compared with normal SCYA20 expression and an increase in expression correlates with NASH [0027]. Claims 16, 18, and 29 are obvious variants of claim 27.
Claim 41 is directed to the method according to claim 2, wherein the quantification comprises determining an RNA expression value for the at least one gene with respect to that of the reference population of subjects without liver inflammation and/or without liver fibrosis.
Gerhard discloses a method of diagnosing NASH by determining the expression levels of at least one of a panel of genes that are associated with NASH as compared to normal patients [0027] which reads on a reference without liver inflammation. Gerhard further discloses an elevated expression of some genes correlates with the incidence of NASH [0027]. Gerhard also discloses the expression level of CCL19 is compared with normal CCL19 expression and an increase in expression and the expression level of SCYA20 is compared with normal SCYA20 expression and an increase in expression correlates with NASH [0027].
Claim 42 is directed to the method according to claim 2, wherein the at least one gene comprises a plurality of genes, wherein the quantification comprises determining an expression value for each gene of the plurality of genes with respect to that of the reference population of subjects without liver inflammation and/or without liver fibrosis, thereby generating a plurality of stratified values.
Gerhard discloses a method of diagnosing NASH by determining the expression levels of at least one of a panel of genes that are associated with NASH as compared to normal patients [0027] which reads on a reference without liver inflammation. Gerhard further discloses an elevated expression of some genes correlates with the incidence of NASH [0027]. Gerhard also discloses the expression level of CCL19 is compared with normal CCL19 expression and an increase in expression and the expression level of SCYA20 is compared with normal SCYA20 expression and an increase in expression correlates with NASH [0027].
Claim 52 is directed to the method according to claim 1, wherein the liver inflammation comprises inflammation associated with alcohol abuse, an alpha-1 antitrypsin deficiency, an autoimmune reaction, a decrease of a blood flow to the liver, a drug, a toxin, hemochromatosis, obstructive jaundice, a viral infection, Wilson's disease, or nonalcoholic fatty liver disease.
Gerhard discloses the main causes of liver fibrosis include chronic HCV infection, alcohol abuse, and NASH [0015]. Gerhard further discloses obvious inflammatory disorder (e.g. hepatitis, infection, connective tissue disease); History of NASH inducing conditions including lipodystrophies, peroxisomal diseases, mitochondrialopathies, Weber-Christian disease, Wilson’s Disease, industrial solvent exposure, medications [0122].
Claim 53 is directed to the method according to claim 52, wherein the viral infection comprises a hepatitis A viral infection, a hepatitis B viral infection, a hepatitis C viral infection, a hepatitis D viral infection, or a hepatitis E viral infection.
Gerhard discloses the genes was easily detectable GAPDH was used as a control gene, which has been used by others for analysis of gene expression in fibrotic liver samples from patients with hepatitis C [0149].
Claim 56 is directed the method according to claim 52, wherein the nonalcoholic fatty liver disease comprises nonalcoholic steatohepatitis.
Gerhard discloses a method of diagnosing NASH by determining the expression levels of at least one of a panel of genes that are associated with NASH as compared to normal patients [0027]
Claim 58 is directed to the method according to claim1, wherein: when the subject's TS is greater at the a later time point than the an earlier time point, the liver inflammation and/or the liver fibrosis has progressed in the subject; or when the subject's TS is greater at the earlier time point than the later time point, the liver inflammation and/or the liver fibrosis has regressed in the subject.
Gerhard discloses a method for diagnosing a NASH disease state in a patient comprising determining a level of expression of a panel of genes associated with the onset or progression of NASH in a patient sample; comparing the level of expression with a predetermined value for NASH-associated gene expression in said panel of genes and correlating the level of expression with a NASH disease state [claim 1] which reads on an initial determination or a follow-up progression determination.
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.
A. Claim(s) 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gerhard in view of Govaere et al (Govaere, Olivier, et al. "Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis."Science translational medicine 12.572 (2020), cited on IDS dated 05/10/2023).
Claim 31 is directed to the method according to claim, wherein the determination of the suitability for inclusion of the gene in a panel comprises calculating an area under a curve for the at least one gene in a panel comprises calculating an area under a curve for the at least one gene.
Gerhard discloses said predetermined value of NASH-associated gene expression represents an increase over normal expression of the genes by at least 4 fold, or by 4 to 12 fold [claim 2], but is silent on calculating an area under a curve for the at least one gene in a panel.
However, Govaere discloses transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis [title]. Govaere further discloses AUROC curves showing the combined predictive model with the single significant covariates as listed in fig. 4 [p. 7, fig. 4].
In regards to claim(s) 31, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Gerhard with Govaere as they both are directed to nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis. The motivation would have been to modify the fold change as inclusive measurement in the method of Gerhard with the AUROC of Govaere to develop better noninvasive means to diagnose and stratify patients for treatment or enrollment into clinical trials without the need for a liver biopsy. One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
B. Claims 43-51 are rejected under 35 U.S.C. 103 as being unpatentable over Gerhard, as applied to claims 42 as above, in view of Aryee et al. (WO2020055954A2, published 03/19/2020, newly cited), and in further view of Chaslasani et al. (Chalasani N, Toden S, Sninsky JJ, et al. Noninvasive stratification of nonalcoholic fatty liver disease by whole transcriptome cell-free mRNA characterization. Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G439-G449. doi:10.1152/ajpgi.00397.2020, newly cited).
Claim 43 is directed to the method according to claim 42, wherein the quantification further comprises determining an expression value for the at least one gene with respect to that of the reference population of subjects without liver inflammation and/or without liver fibrosis, and wherein the TS is within a percentile of the plurality of stratified values.
Gerhard is silent on wherein the TS is within a percentile of the plurality of stratified values.
However, Aryee discloses methods for detecting liver diseases [title]. Aryee further discloses relates to a method of detecting and/or evaluating a liver disease, e.g. Hepatocellular carcinoma (HCC) by measuring expression levels of hepatocellular carcinoma (HCC) classifier genes in circulating epithelial cells (CECs) of subjects [summary]. Aryee also discloses the expression levels of HCC classifier genes are used to calculate a HCC score, and the calculated HCC score is compared with a reference score, where the presence of HCC is determined based on the presence of an HCC score above the reference score (from a non-diseased counterpart cell or tissue) [claim 6]. Aryee further discloses sampling was stratified according to disease status using a comparator classifier, a multivariable logistic regression model was created using the 10 most significant genes [p. 28, par. 1]. Aryee is silent on a percentile.
However, Chalasani discloses noninvasive stratification of nonalcoholic fatty liver disease by whole transcriptome cell-free mRNA characterization [title]. Chalasani further discloses the predicted probability of having clinically significant fibrosis on the y-axis as a function of the percentile of the biomarker score on the x-axis [p. 445, col. 2, par. 1], which reads on a TS score within a percentile of the plurality of stratified values.
Claims 43-51 are directed to the method according to claim 43, wherein the TS is within the fiftieth percentile – ninety-fifth percentile.
Gerhard is silent on wherein the TS is within a percentile of the plurality of stratified values.
However, Aryee discloses methods for detecting liver diseases [title]. Aryee further discloses relates to a method of detecting and/or evaluating a liver disease, e.g. Hepatocellular carcinoma (HCC) by measuring expression levels of hepatocellular carcinoma (HCC) classifier genes in circulating epithelial cells (CECs) of subjects [summary]. Aryee also discloses the expression levels of HCC classifier genes are used to calculate a HCC score, and the calculated HCC score is compared with a reference score, where the presence of HCC is determined based on the presence of an HCC score above the reference score (from a non-diseased counterpart cell or tissue) [claim 6]. Aryee further discloses sampling was stratified according to disease status using a comparator classifier, a multivariable logistic regression model was created using the 10 most significant genes [p. 28, par. 1]. Aryee is silent on a percentile.
However, Chalasani discloses noninvasive stratification of nonalcoholic fatty liver disease by whole transcriptome cell-free mRNA characterization [title]. Chalasani further discloses the predicted probability of having clinically significant fibrosis on the y-axis as a function of the percentile of the biomarker score on the x-axis [p. 445, col. 2, par. 1], which reads on a TS score within a percentile of the plurality of stratified values including the 50%, 60%, 70%, 80%, 90% and 95% [p. 446, fig. 5].
In regards to claim(s) 43-51, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Gerhard with Aryee as they both disclose methods for detecting liver diseases. The motivation would have been to include the metrics that indicate the degree of differential expression of Gerhard with the HCC score of Aryee to accurately detect the presence of cancer such as hepatocellular carcinoma (HCC) and/or to accurately characterize the different stages (e.g., early or late stages) of liver diseases or conditions such as liver fibrosis [p. 2, par. 5].
In regards to claim(s) 43-51, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Gerhard and Aryee and Chalasani as they all are directed to nonalcoholic fatty liver disease by whole transcriptome RNA characterization. The motivation would have been to include the percentile of the biomarker score of Chalasani with the HCC score of Aryee to develop effective classifiers for liver fibrosis as disclosed by Chalasani (p. 446, col. 1, par. 1]. One of ordinary skill in the art would have recognized that the results of the combination were predictable.
Conclusion
No claims are allowed.
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/D.M.B./Examiner, Art Unit 1685
/Soren Harward/Primary Examiner, TC 1600