DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed February 10, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. This action is made FINAL.
Applicant’s election without traverse of Group I and SEQ ID NO: 9 (miR-744-5p) in the reply filed on September 12, 2022 is reiterated for the record.
Claims 13, 22-26, and 29-31 are currently pending.
Claims 22-24, 26, and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter (either a nonelected invention or nonelected miRNAs), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 12, 2022.
Response To Arguments
3. In the response the Applicants argued that claim 26 should not be withdrawn. They argue that Claim 26 specifies the further use of at least one of the non-elected species (reference miRNAs other than SEQ ID NO: 9) in combination with the reference miRNA of SEQ ID NO: 9.
Importantly, claim 26 encompasses the elected reference miRNA of SEQ ID NO: 9, as claim 26 depends from claim 13, which requires the use of SEQ ID NO: 9. The additional reference miRNAs recited in claim 26 are used "in addition to" the elected species. Because claim 26 includes the elected species of SEQ ID NO: 9, the claim should not have been withdrawn.
This argument has been fully considered but is not persuasive. Applicants were asked to elect a single miRNA or a single combination of two or more miRNAs for examination. Applicants elected the single miRNA (SEQ ID NO: 9). Claims which require SEQ ID NO: 9 plus additional miRNAs do NOT read on the elected single miRNA. If claim 13 ever becomes allowable, this election of species requirement will be reconsidered. Until then, claims 26 and 30 are properly withdrawn as being drawn to nonelected subject matter (nonelected miRNAs).
Claim Rejections - 35 USC § 101
4. 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 13, 25, 29, 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The claims recite abstract ideas
The claims recite the following limitations:
-performing a sample quality assessment comprising:
(i) comparing the measured value of the reference miRNA to a predetermined threshold, and
(ii) determining whether the sample has good quality for gene expression analysis wherein the sample is determined to have good quality when the measured value of the reference miRNA is higher than the predetermined threshold
-wherein the sample quality assessment improves reliability of gene expression analysis by identifying and excluding degraded samples that would produce inaccurate expression data leading to misdiagnosis.
-wherein the good quality serum sample is a sample which has improved reliability of gene expression analysis by identifying and excluding degraded samples that would produce inaccurate expression data leading to misdiagnosis
-correcting said measured values obtained in the measuring step
The “performing” step which comprises “comparing” and “determining” steps are mental processes because they recite activities that humans can do with their minds. For example the “comparing” and “determining” steps could be performed by (i) reading a laboratory report comprising the measured value of the reference miRNA in the sample and the predetermined threshold, (ii) thinking about whether the measured value of reference miRNA in the sample is greater than or less than the predetermined threshold, and (iii) thinking that the serum sample has a good miRNA quality when the measured value of the reference miRNA is higher than the predetermined threshold. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The claims are considered to encompass “identifying” and “excluding”, even if these are not active process steps. The broadest reasonable interpretation of the “identifying” and “excluding” limitations is that they may be accomplished by a mental process. For example, “identifying” and “excluding” could be performed by (i) thinking that the serum sample is degraded when the abundance of the reference miRNA is lower than the predetermined threshold and (ii) thinking that the serum sample should not be used for further analysis. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
Regarding the “correcting” step the specification teaches that the correction method may be a conventional method. Examples of the method include the global normalization method and the quantile normalization method, wherein the correction is carried out using the measured values of all miRNAs detected (para 0094). Normalization require performing a mathematical calculation. Mathematical concepts such as performing calculations are abstract ideas.
The claims recite a law of nature.
The claims recite the following limitation:
- determining whether the sample has good quality for gene expression analysis wherein the sample is determined to have good quality when the measured value of the reference miRNA is higher than the predetermined threshold
The claims recite a correlation between the reference miRNA (SEQ ID NO: 9 which is miRNA-744-5p) and the quality of miRNA contained in a serum sample. The claims state that when the abundance of SEQ ID NO: 9 is higher than a threshold the serum sample is judged to have a good miRNA quality. In the instant case the claimed reference miRNA is naturally occurring in the sample. The miRNA’s deterioration is a natural property of the miRNA. The correlation with the sample degradation is a natural law because it is an inherent property of the degradation rates of the miRNA reference and the total miRNA in the sample. There is no human hand involved in the correlation, except for the discovery of it.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite the following limitations:
-preparing a microarray for miRNA expression analysis comprising a probe(s) for capturing a target miRNA(s) and a probe for capturing a reference miRNA consisting of SEQ ID NO: 9;
-applying miRNAs in the serum sample to the microarray;
-hybridizing miRNAs in the serum sample to the probes on the microarray;
-measuring, by microarray scanner, the abundance of the target miRNA(s) and the reference miRNA in the serum sample to obtain measured values thereof
These limitations do NOT integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Claim 13 also recites the following:
when the sample is determined to have good quality: validating the sample as suitable for gene expression analysis, generating expression data of the target miRNA(s) from the validated sample, and outputting the expression data for use in disease diagnosis
These limitations do NOT integrate the judicial exceptions into a practical application because they are not even required by the method. The “validating”, “generating”, and “outputting” steps are conditional and only performed when the sample is determined to have good quality. The claims encompass situations where the sample is determined to have bad quality and these additional steps are not performed.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, the claims recite the following limitations:
-preparing a microarray for miRNA expression analysis comprising a probe(s) for capturing a target miRNA(s) and a probe for capturing a reference miRNA consisting of SEQ ID NO: 9;
-applying miRNAs in the serum sample to the microarray;
-hybridizing miRNAs in the serum sample to the probes on the microarray;
-measuring, by microarray scanner, the abundance of the target miRNA(s) and the reference miRNA in the serum sample to obtain measured values thereof
These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The prior art of Chakravarti (US 2018/0002762 Pub 1/4/2018) demonstrates the well understood, routine, conventional nature of the additional elements because it teaches that the additional elements are well known. Chakravarti teaches the following:
The level of one or more miRNA biomarkers in a biological sample may be determined by any suitable method. Any reliable method for measuring the level or amount of miRNA in a sample may be used. Generally, miRNA can be detected and quantified from a sample (including fractions thereof), such as samples of isolated RNA by various methods known for mRNA detection, including, for example, amplification-based methods (e.g., Polymerase Chain Reaction (PCR), Real-Time Polymerase Chain Reaction (RT-PCR), Quantitative Polymerase Chain Reaction (qPCR), rolling circle amplification, etc.), hybridization-based methods (e.g., hybridization arrays (e.g., microarrays), NanoString analysis, Northern Blot analysis, branched DNA (bDNA) signal amplification, and in situ hybridization), and sequencing-based methods (e.g. next-generation sequencing methods, for example, using the Illumina or IonTorrent platforms). Other exemplary techniques include ribonuclease protection assay (RPA) and mass spectroscopy (para 0026).
miRNA may also be detected using hybridization-based methods, including but not limited to hybridization arrays (e.g., microarrays), NanoString™ analysis, Northern Blot analysis, branched DNA (bDNA) signal amplification, and in situ hybridization (para 0034).
Microarrays can be used to measure the expression levels of large numbers of miRNAs simultaneously. Microarrays can be fabricated using a variety of technologies, including printing with fine-pointed pins onto glass slides, photolithography using pre-made masks, photolithography using dynamic micromirror devices, ink-jet printing, or electrochemistry on microelectrode arrays (para 0035).
Axon B-4000 scanner and Gene-Pix Pro 4.0 software or other suitable software can be used to scan images. Non-positive spots after background subtraction, and outliers detected by the ESD procedure, are removed. The resulting signal intensity values may be normalized to per-chip median values and then used to obtain geometric means and standard errors for each miRNA. Each miRNA signal can be transformed to log base 2, and a one-sample t test can be conducted. Independent hybridizations for each sample can be performed on chips with each miRNA spotted multiple times to increase the robustness of the data (para 0037).
Total RNA containing the miRNA extracted from a sample can also be used directly without size-selection of the miRNAs. For example, the RNA can be 3′ end labeled using T4 RNA ligase and a fluorophore-labeled short RNA linker. Fluorophore-labeled miRNAs complementary to the corresponding miRNA capture probe sequences on the array hybridize, via base pairing, to the spot at which the capture probes are affixed. The fluorescence intensity of each spot is then evaluated in terms of the number of copies of a particular miRNA, using a number of positive and negative controls and array data normalization methods, which will result in assessment of the level of expression of a particular miRNA (para 0040).
Additionally the prior art of Beaudenon (WO 2019/036332 Pub 3/19/2009) discloses a miRNA consisting of SEQ ID NO: 9 (see SEQ ID NO: 549 on page 16). Beaudenon teaches that the disclosed miRNAs can be used in array analysis (para 0084). Beaudenon describes methods of array preparation (paras 00135-00139). Beaudenon describes methods of array hybridization and using arrays for differential expression analyses (paras 00141-00153).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
5. In the response the Applicants traversed the rejection under 35 USC 101. In the response the Applicants argue that the claims do not recite a mental process because the claims as amended no longer recite the “judging” step.
This argument has been fully considered. The claims as amended recite a step of “performing” a sample quality assessment comprising “comparing” and “determining”. The claims also encompass “identifying” and “excluding”, even if these are not active process steps. For the reasons discussed above, each of these steps could be performed by a human using mental steps or basic critical thinking. Thus the claims as amended still recite mental processes which are considered to be abstract ideas.
In the response the Applicants argue that the claims are not directed to a law of nature. They argue that rather than merely claiming the correlation between reference miRNA abundance and sample quality, the claims recite a practical laboratory method that utilizes this correlation to prepare a sample for analysis.
These arguments have been fully considered but are not persuasive. It is noted that the PTAB has already determined on page 10 of the Patent Board Decision that was mailed on July 14, 2025 that the correlation between the reference miRNA (SEQ ID NO: 9 which is miRNA-744-5p) and the quality of miRNA contained in a serum sample is a natural phenomenon. The Board found that this is a natural phenomenon because the claimed reference miRNA is naturally occurring in the sample. The miRNA’s deterioration is a natural property of the miRNA. The correlation with the sample degradation is a natural law because it is an inherent property of the degradation rates of the miRNA reference and the total miRNA in the sample. There is no human hand involved in the correlation, except for the discovery of it. It is maintained that the amended claims recite a law of nature.
Regarding Step 2A, Prong two, the Applicants argue that the claims are integrated into a
practical application. They argue that the claims require providing a chip for miRNA expression analysis, contacting the chip with an RNA sample to allow hybridization, and measuring abundances using a microarray scanner. These are not merely routine data-gathering steps but specific physical steps that transform the sample. They argue that the assay is limited to a specific reference miRNA (SEQ ID NO: 9) and a specific requirement for high abundance to indicate good quality. The use of SEQ ID NO: 9 is not arbitrary but reflects the inventors discovery that this specific miRNA is sensitive to degradation that occurs within a very short period of several hours to one day, enabling detection of quality deterioration that was undetectable by conventional techniques. Further they are that the method provides a technical improvement. The method improves the reliability of gene expression analysis by identifying and excluding degraded samples that would otherwise produce inaccurate data, thereby preventing misdiagnosis. This is a concrete technical improvement to the field of miRNA expression analysis.
These arguments have been fully considered but are not persuasive. Herein the steps of “preparing”, “applying”, “hybridizing”, and “measuring” are data gathering steps that are necessary to use the judicial exception. The fact that the claims are limited to SEQ ID NO: 9 is noted, but SEQ ID NO: 9 is not an step/element recited in addition to the judicial exception, because it is part of the judicial exception, i.e., the correlation between SEQ ID NO: 9 and the quality of miRNA contained in a serum sample. Further it is noted that the PTAB has already addressed the argument the claims result in an improvement in the technical field of miRNA expression analysis on pages of 10-11 of the Patent Board Decision that was mailed on July 14, 2025. It is reiterated that the claims do not recite additional elements that result in the improvement in the functioning of a computer, or an improvement to other technology or technical field Herein the “technology” used by the claim is using a chip comprising probes to detect miRNA levels in a sample. The additional elements cited in the claims, do not improve this technology or any other technology. The additional elements cited in the claims, do not make this technology or any other technology work better. Herein, the improvement is an improvement on a judicial exception. The inventors have discovered that the reference miRNA (SEQ ID NO: 9) is a better marker of miRNA degradation because it can be used to detect degradation that occurs within a very short period of several hours to one day. It is noted that even specific correlations are laws of nature when they occur naturally. This exception does not improve the technology of using a chip comprising probes to detect miRNA levels in a sample or any other technology. Therefore, there is no improvement nor is the exception integrated into a practical application. Thus it is maintained that the claims do NOT integrate the judicial exceptions into a practical application.
Regarding Step 2B, the Applicants argue that the claims provide an inventive concept. They argue that the technical core of the invention lies in the use of the reference miRNA of SEQ ID NO: 9 specifically for quality control purposes. While the prior art references (Chakravarti and Beaudenon) cited by the Examiner teach the use of reference miRNAs for normalization and the use of microarrays for miRNA detection, they neither disclose nor suggest using such markers for quality control. They argue that the present invention adopts an unconventional approach by "actively utilizing sensitivity to degradation." A person of ordinary skill in the art would typically select a stable, non-fluctuating miRNA as a reference, because stability is generally desirable for normalization purposes. The present invention purposefully selects SEQ ID NO: 9, which is sensitive to degradation, and utilizes the relationship where its high abundance indicates good quality. This selection is contrary to conventional wisdom in the field. As a result of this technical feature, the invention achieves the unexpected effect of detecting "short-term degradation"-specifically, quality loss occurring within several hours to one day-which was difficult to detect using prior art techniques. This leads to a significant increase in diagnostic accuracy. Therefore, the use of SEQ ID NO: 9 for quality control is not a "well-understood, routine, or conventional activity" and constitutes "significantly more" than any judicial exception.
This argument has been fully considered but is not persuasive. At Step 2B, we evaluate whether the claims (a) add a specific limitation beyond the judicial exception that is not well-understood, routine, conventional in the field or (b) simply appends well-understood, routine activities previously known to the industry, specified at a high level of generality. Herein the prior arts cited supports a finding that the steps of “preparing”, “applying”, “hybridizing”, and “measuring”, add only well understood, routine activities previously known to the industry, specified at a high level of generality, to the judicial exception. The discovery of the reference miRNA of SEQ ID NO 9 used to determine the quality of the miRNA in a serum sample cannot be relied upon to show that the claims provide an inventive step because it is the judicial exception. For these reasons the rejection is maintained.
Claim Rejections - 35 USC § 112
6. 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 13, 25, 29, and 31 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.
Claims 13, 25, 29, and 31 recite “a probe for capturing a reference miRNA consisting of SEQ ID NO: 9”. This recitation is indefinite because it is unclear what consists of SEQ ID NO: 9. Is it the probe, the reference miRNA, or both that consist of SEQ ID NO: 9? Clarification is required.
Claims 13, 25, 29 are rejected over the recitation of the phrase “wherein the sample quality assessment improves reliability of gene expression analysis by identifying and excluding degraded samples that would produce inaccurate expression data leading to misdiagnosis”. This recitation is confusing because the claims recite an active process step of “performing” a sample quality assessment, but this step only requires “comparing” measured values to a threshold and “determining” whether a sample has good quality. There are no active process steps of identifying and excluding degraded samples. Therefore it is unclear how “performing” the sample quality assessment step improves reliability of gene expression analysis by identifying and excluding degraded samples that would produce inaccurate expression data leading to misdiagnosis. Clarification is required.
Regarding 31 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites “A method of preparing a good quality serum sample for gene expression analysis, wherein the good quality serum sample is a sample which has improved reliability of gene expression analysis by identifying and excluding degraded samples that would produce inaccurate expression data leading to misdiagnosis”. However, the method only recites active process steps of “preparing”, “applying”, “hybridizing”, “measuring”, and “performing”. Thus it is not clear if applicant intends to cover only a method of “preparing”, “applying”, “hybridizing”, “measuring”, and “performing” OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
7. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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