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 without traverse of Group I (claims 1-7) in the reply filed on 09/11/2025 is acknowledged.
Claims 8-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claim Status
Claims 1-19 are pending.
Claims 8-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, as described above.
Claims 1-7 are under examination.
Claim 1 is objected to.
Claims 1-7 are rejected.
Priority
The instant Application claims domestic benefit to US provisional application 63/294,359, filed 12/28/2021. Accordingly, each of claims 1-7 are afforded the effective filing date of the 12/28/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 03/01/2024, 06/06/2024, and 01/25/2024 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 03/31/2023 are accepted.
Claim Objections
The claims are objected to for the following informalities:
Claim 1 recites “A development method of circulating biomarkers for cancer detection”. It is assumed that it means to identify circulating biomarker for cancer detection. If the assumption is correct please amend to “A development method of identifying circulating biomarkers for cancer detection”.
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 1-7 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 seems to have three unrelated limitations without context or steps as how they are used together which deems claim 1 as indefinite. The first limitation is directed to expression levels of normal and tumor samples, the second limitation is directed to tissue specific or group-enriched genes to plasma exosomes, and the third limitation is directed to expression level of plasma exosome of healthy and cancer people, please amend to show how these unrelated limitations are connected. Claim(s) 2-7 is/are rejected for the same reason because they depend from claim1 1, respectively, and do not resolve the indefiniteness issue in those claims.
Claim 1: The term “high expression levels” is a relative term which renders the claim indefinite. The term “high expression levels” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim(s) 2-7 is/are rejected for the same reason because they depend from claim1 1, respectively, and do not resolve the indefiniteness issue in those claims.
Claim 1 recites “using tissue-specific genes and group-enriched genes to calculate a weight of each human tissue's contribution to plasma exosomes”. It is unclear if both are used in the calculation or if it is one or the other as the specification states “if there are no tissue-specific genes in a tissue, several group-enriched genes are selected, that is, a group of genes with significantly increased expression level in this tissue and other tissues, so as to jointly determine the weight of each tissue [0032]. For compact examination, it is assumed that the they are used separately. If this assumption is correct, the rejection may be overcome by amending the recitation in claim 1 to "using tissue-specific genes or group-enriched genes". Claim(s) 2-7 is/are rejected for the same reason because they depend from claim1 1, respectively, and do not resolve the indefiniteness issue in those claims.
Claim 7 is indefinite as there is no specific calculation for the “overlapping index”, so the values for that index are unclear. Also, it is not clear whether the specific values require that the overlapping index be calculated as disclosed in the specification, or whether there’s some other acceptable/comparable calculation.
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 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to one or more judicial exceptions without significantly more.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (Prongs One and Two) and 2B as follows below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Framework with which to Evaluate Subject Matter Eligibility:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter;
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea;
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application (Prong Two); and
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept.
Framework Analysis as Pertains to the Instant Claims:
Step 1
With respect to Step 1: yes, the claims are directed to method, i.e., a process, machine, or manufacture within the above 101 categories [Step 1: YES; See MPEP § 2106.03].
Step 2A, Prong One
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. The MPEP at 2106.04(a)(2) further explains that abstract ideas are defined as:
mathematical concepts (mathematical formulas or equations, mathematical relationships and mathematical calculations);
certain methods of organizing human activity (fundamental economic practices or principles, managing personal behavior or relationships or interactions between people); and/or
mental processes (procedures for observing, evaluating, analyzing/ judging and organizing information).
The claims also recite a law of nature or a natural phenomenon. The MPEP at 2106.04(b) further explains that laws of nature and natural phenomena include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
With respect to the instant claims, under the Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mental processes (in particular procedures for observing, analyzing and organizing information) and mathematical concepts (in particular mathematical relationships and formulas) as well as a law of nature or a natural phenomenon are as follows:
Independent claim 1:
identifying expression levels of multiple genes in normal tissue samples and tumor tissue samples, and selecting genes with high expression levels in the tumor tissue samples;
using tissue-specific genes and group-enriched genes to calculate a weight of each human tissue's contribution to plasma exosomes; and comparing expression levels of plasma exosome genes of healthy people and cancer patients by an overlapping index, and
selecting circulating biomarkers and combinations thereof suitable for detection and evaluation of the plasma exosomes.
Dependent claim 2:
wherein a statistical analysis method is used to select the genes with high expression level in the tumor tissue samples, and the statistical analysis method includes a null hypothesis test and a fold change threshold.
Dependent claim 3:
using Welch's t-test to calculate a p value;
adjusting the p value by using a permutation test to increase a test validity; and
performing a screening by using a false discovery rate as a criterium to reduce a probability of selecting false high-expression genes.
Dependent claim 4:
comparing an exosome database and subcellular locations to see if the circulating biomarkers are expressed on the surface and/or inside exosome before calculating the weight of each human tissue's contribution to plasma exosomes.
Dependent claim 5:
using the calculated weight to simulate a plasma exosome expression level distribution of circulating biomarker in the healthy people and the cancer patients after calculating the weight of each human tissue's contribution to plasma exosomes.
Dependent claim 6:
wherein an intersection area of probability density functions of plasma exosome expression levels of the healthy people and the cancer patients are calculated according to the simulated plasma exosome expression level distributions, and the intersection area is the overlapping index.
Dependent claims 7 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 7 further limits the overlapping index of claim 1.
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind and/or by mathematical operation because the method only requires a user to manually identify, calculate, select, adjust, screen, compare and simulate. Without further detail as to the methodology involved in “identifying expression levels”, “calculate a weight of each human tissue's contribution “, “selecting circulating biomarkers “, “adjusting the p value by using a permutation test “, “performing a screening by using a false discovery rate “, and “calculate intersection area of probability density functions of plasma exosome expression levels”, under the BRI, one may simply, for example, use pen and paper to identify circulating biomarkers for cancer detection.
Therefore, claim 1 and those claims dependent therefrom recite an abstract idea and a law of nature/natural phenomenon [Step 2A, Prong 1: YES; See MPEP § 2106.04].
Step 2A, Prong Two
Because the claims do recite judicial exceptions, direction under Step 2A, Prong Two, provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d).I.; MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d).III).
Additional elements, Step 2A, Prong Two
With respect to the instant recitations, there are no additional elements
Considerations under Step 2A, Prong Two
Thus, none of the claims recite additional elements, therefore the judicial exceptions are not integrated into a practical application, and the claims are directed to one or more judicial exceptions [Step 2A, Prong 2: NO; See MPEP § 2106.04(d)].
Step 2B (MPEP 2106.05.A i-vi)
According to analysis so far, there are no additional elements.
Therefore, the instant claims are not drawn to eligible subject matter as they are directed to one or more judicial exceptions without significantly more. For additional guidance, applicant is directed generally to the MPEP § 2106.
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) 1-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lui et al (US 2018/0104187 A1, published 04/19/2018, cited on IDS dated 06/06/2023) in view of Loo et al. (Loo, L., et al. "New criteria for selecting differentially expressed genes." IEEE Engineering in Medicine and Biology Magazine 26.2 (2007): 17, newly cited), in further view of Frost et al. (Frost, H. Robert. "Computation and application of tissue-specific gene set weights." Bioinformatics 34.17 (2018): 2957-2964,newly cited), and in further view of Cho et al. (Cho, Oyeon, Do-Wan Kim, and Jae-Youn Cheong. “Screening Plasma Exosomal RNAs as Diagnostic Markers for Cervical Cancer: An Analysis of Patients Who Underwent Primary Chemoradiotherapy.” Biomolecules (Basel, Switzerland) 11.11 (2021): 1691. Web, newly cited)
Claim 1 is directed to a development method of circulating biomarkers for cancer detection, comprising:
Lui discloses the use of exosomes for biomarker analysis for early detecting and characterizing of disease progression of cancer [abstract]. Lui further discloses detecting expression of at least one cancer marker in the isolated extracellular vesicles [claim 1(c)]. Lui also discloses determining a differential expression profile for at least one cancer marker in the sample as compared to a control [claim 9]. Lui further discloses the strategic selection a CSC marker for exosome-based targeting, as CD44 is one the most characterized BCSC markers, it is also highly expressed on normal T cells [0165].
identifying expression levels of multiple genes in normal tissue samples and tumor tissue samples, and selecting genes with high expression levels in the tumor tissue samples;
Liu is silent on expression levels of normal and tumor tissue samples.
However, Loo discloses filter-based feature selection techniques for better detection of changes in the distributions of expression levels [title]. Loo further discloses the databases consists of gene expression levels from 190 primary tumor samples representing 14 classes of common human cancer (the positive class) and 90 normal tissue samples (the negative class) [p. 19, col. 2, par. 2]. Loo also discloses the 14 classes of human cancer include breast adenocarcinoma, prostate adenocarcinoma, lung adenocarcinoma, colorectal adenocarcinoma, lymphoma, bladder transitional cell carcinoma, melanoma, uterine adenocarcinoma, leukemia, renal cell carcinoma, pancreatic adenocarcinoma, ovarian adenocarcinoma, pleural mesothelioma, and central nervous system [p. 19, col. 2, par. 2]. Loo further discloses identifying differentially expressed genes through multiple hypothesis testing, including a null hypothesis test[p. 20, col. 2, par. 3] , which reads on selecting genes with high expression levels in the tumor tissue samples as the specification discloses the genes with high expression level in tumor tissue samples are selected using statistical analysis methods, the statistical analysis methods include a null hypothesis test [0024].
using tissue-specific genes and group-enriched genes to calculate a weight of each human tissue's contribution to plasma exosomes; and
Lui and Loo are silent to tissue-specific genes and group-enriched genes to calculate a weight of each human tissue's contribution to plasma exosomes.
However, Frost discloses computation and application of tissue-specific gene set weights [title]. Frost further discloses tissue-specific gene set weights were computed using the 13 distinct MSigDB collections [p2959, col. 1, par. 2]. Frost further discloses the tissue-specificity of human protein coding genes was drawn from version 16 of the HPA [p. 2959, col. 1, par, 3]. Frost further discloses computation of tissue-specific gene set weights using both mRNA and protein evidence from the HPA [p. 2959, col. 2, par. 1], which reads on a weight of each human tissue's contribution to plasma exosomes, as the specification discloses a total of 69 types of tissues, organs, or blood cells, etc. that provide detection data in large human omics databases such as HPA, FANTOM5, and GTEx are expected to cover all sources of exosomes in the blood [0032].
comparing expression levels of plasma exosome genes of healthy people and cancer patients by an overlapping index, and selecting circulating biomarkers and combinations thereof suitable for detection and evaluation of the plasma exosomes.
Lui, Loo, and Frost are silent on expression levels of plasma exosome genes of healthy people and cancer patients by an overlapping index.
However, Cho discloses screening plasma exosomal RNAs as diagnostic markers for cervical cancer [title]. Cho further discloses statistical screening where the expression of plasma exosomal ncRNAs and mRNA was compared between the normal group and a group of six samples from patients with cervical adenocarcinoma adeno-squamous cell carcinoma before treatment (AC group). RNAs with |log2FC| >1.5 and p-values < 0.05 were selected from DEG analysis (C) [p. 3, par. 2]. Cho also discloses the significant DEGs were primarily selected when the RNAs of (A) were simultaneously included in those with |log2FC (B) + log2FC (C)| > 4 [p. 3, par. 2, and fig. 1].
Claim 2 is directed to the development method according to claim 1, wherein a statistical analysis method is used to select the genes with high expression level in the tumor tissue samples, and the statistical analysis method includes a null hypothesis test and a fold change threshold.
Lui discloses statistical analysis was done by following Unpaired Student's t-test [0129], but is silent on a null hypothesis test and a fold change threshold.
However, Loo discloses identifying differentially expressed genes through multiple hypothesis testing, including a null hypothesis test[p. 20, col. 2, par. 3]. Loo further discloses gene and its distributions of expression levels obtained under different conditions[p. 18, fig. 1(b)] which reads on a fold change. Loo also discloses depending on the gene selection threshold, they are unlikely to select differentially expressed but irrelevant genes [p. 17, col. 2, par. 2]. It would be obvious to one in the art to choose a fold change threshold as a filtering step.
Claim 3 is directed to the development method according to claim 2, wherein the null hypothesis test includes: using Welch's t-test to calculate a p value; adjusting the p value by using a permutation test to increase a test validity; and performing a screening by using a false discovery rate as a criterium to reduce a probability of selecting false high-expression genes.
Lui discloses statistical analysis was done by following Unpaired Student's t-test [0129], but is silent on a null hypothesis test and a fold change threshold.
However, Loo discloses identifying differentially expressed genes can be stated as a multiple hypothesis testing problem [p. 20, col. 2, par. 3]. Loo further discloses a common gene selection criteria include the Welch t-statistic (WTS) [p. 18, col. 1, par. 1]. Loo also discloses to estimate the distribution empirically by using resampling methods, such as permutation [p. 20, col. 2, par. 4]. Loo further discloses the probability of committing a false alarm increases quickly with the number of tested hypotheses [p. 18, col. 2, par. 5]. Loo also discloses the remedy is to adjust the raw p-values, obtained for each gene, to account for the large number of hypotheses [p. 18, col. 2, par. 5]. Loo further discloses a detailed comparison of various p-value adjustment procedures for multiple hypothesis testing, in particular, Benjamini and Hochberg’s step-up procedure for controlling the false discovery rate has been shown to retain substantially more power than other family-wise error rate controlling procedures [p. 18, col. 2, par. 5]. Loo also discloses after the p-values have been adjusted through the Benjamini and Hochberg’s procedure, differentially expressed genes are identified as those with adjusted p-values smaller than a predetermined threshold [p. 18, col. 2, par. 5].
Claim 4 is directed to the development method according to claim 1, further comprising comparing an exosome database and subcellular locations to see if the circulating biomarkers are expressed on the surface and/or inside exosome before calculating the weight of each human tissue's contribution to plasma exosomes.
Liu discloses the present invention provides a method for readily detecting and profiling surface molecules of EVs and exosomes which can be used as biomarkers for specific diseases, specifically cancer [0044]. Lui further discloses EVs may be identified by the expression of one or more exosomal markers on the exosomes surface [0057]. The creation of data from an assay is considered a database and therefore reads on determining if the biomarkers are expressed on the surface and being able to select those biomarkers.
In regards to claim(s) 1-4, 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 Lui with Loo as they both exosomes for biomarker analysis for early detecting and characterizing of disease progression of cancer. The motivation would have been to modify the method of Lui with the filter-based feature selection techniques of Loo for better detection of changes in the distributions of expression levels as the gene selection is potentially helpful to improve the quality of the genetic network built and reduce the computational time needed to build the network as disclosed by Loo [p. 17, col. 1, par. 2].
In regards to claim(s) 1-4, 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 Lui and Loo with Frost as they disclose gene set testing, or pathway analysis, has become a critical tool for the analysis of high-dimensional genomic data. The motivation would have been to modify the method of Lui with the computation and application of tissue-specific gene set weights the tissue-specific gene set weights can also be used to improve the performance of standard gene set testing as disclosed by Frost [p. 2960, col. 2 par. 2].
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dawn M. Bickham whose telephone number is (703)756-1817. The examiner can normally be reached M-Th 7:30 - 4:30.
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/D.M.B./Examiner, Art Unit 1685
/Soren Harward/Primary Examiner, TC 1600