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 .
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on August 21, 2026. No claims amendment are made in the response filed on 08/21/2026.
In the amended claims filed on 02/15/2024, claims 1-23 are currently pending, with claims 9-23 withdrawn.
Claims 1-8 are under examination. This is the first action on the merits.
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on June 08, 2026 is acknowledged:
Species of method of detecting micro RNA: A) a method for diagnosing hepatocellular carcinoma (HCC) in a subject (claim 1) 1.
Applicant’s election without traverse of the following species in the reply filed on August 21, 2026 is acknowledged:
Species of reference sample: G) the reference sample is a sample from a subject having cirrhosis (claim 2)2.
Claims 9-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Examination on the merits commences on claims 1-8.
Priority
The priority date of the instant claims 1-8 is 02/04/2021, filling date of the US provisional application NO. 63/145,718.
Claim Objections
Claim 1 is objected to because of the following informalities:
In claim 1, lines 9-11, it should read: "determining whether the at least one miRNA in the saliva sample is differentially expressed as compared to a reference saliva sample," to properly refer back to the earlier recited "at least one microRNA (miRNA)" at lines 4-5, and remove redundant phrases to improve clarity.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
Regarding claim 4 reciting "optionally further comprising one or more of hsa-mir-6512-5p, hsa-mir-505, hsa-mir-8059, and/or hsa-mir-193a-3p." The application's disclosure does not expressly define "optionally" or "optional." Thus, the term "optional" is interpreted according to its ordinary meaning as identifying a feature that is permitted but not required.
For the purpose of applying prior art, claim 5 recites "wherein the at least one miRNA is selected from the group consisting of hsa-mir-148b-3p, hsa-mir-30d-5p, hsa-mir-6806, hsa-mir-6512-5p, hsa-mir-126-3p, hsa-mir-505, hsa-mir-8059, and hsa-mir-193a-3p as compared to a reference expression sample."
The phrase "consisting of" is interpreted as limiting the particular miRNA marker selected for comparison of a determined miRNA expression level to a particular reference (e.g., in specification, Table 6). However, the claimed method is not interpreted as excluding the determination and/or analysis of expression levels of additional miRNAs beyond the recited group.
This interpretation is applied in light of the specification, which teaches performing small RNA-seq to detect 695 differentially expressed miRNAs ([0079]; [0084]). The sequencing data are then further analyzed to select 8 miRNAs as markers for differentiating HCC from cirrhosis ([0090]). Accordingly, the closed group limits the selected marker or markers used for the recited, particular comparison step, but does not exclude the detection or analysis of additional miRNAs as part of the overall method.
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 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Independent claim 1 recites:
A method for diagnosing or prognosticating hepatocellular carcinoma (HCC) in a subject, or for assessing the risk of developing hepatocellular carcinoma, or for monitoring the effectiveness of an anti-tumor therapy against hepatocellular carcinoma, comprising
determining, in an isolated sample of saliva, the expression level of at least one microRNA (miRNA) having at least 90% sequence identity with an miRNA selected from the group comprising or consisting of hsa-mir-148b-3p, hsa-mir-148b-5p, hsa-mir-30d-3p, hsa-mir-30d-5p, hsa-mir-6806-3p, hsa-mir-6806-5p, hsa-mir-6512-3p, hsa-mir-6512-5p, hsa-mir-126-3p, hsa-mir-126-5p, hsa-mir-505-3p, hsa-mir-505-5p, hsa-mir-8059, hsa-mir-193a-3p, and hsa-mir-193a-5p and
determining whether the miRNA in the saliva sample is differentially expressed as compared to as compared to a reference saliva sample,
wherein the differential expression of miRNA is an upregulation or a downregulation of miRNA expression, in order to determine whether the subject has HCC, is at elevated risk of having HCC, or is receiving effective treatment for HCC, and
treating the subject diagnosed with HCC or having elevated risk of having HCC, or as needing further effective treatment for HCC with a compound or other therapy to improve the HCC.
Claim 1 is drawn to a method for diagnosis of hepatocellular carcinoma (HCC) in a subject, comprising the steps to determine and analyze expression level of miRNA marker(s) in a sample.
Following the analysis below the claims are not patent eligible under 35 U.S.C. 101.
Step 1 - Whether the Claim is to a Statutory Category: YES. The claims are drawn to a method, therefore to one of the of statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: Yes. The claim recites a judicial exception, namely a law of nature of natural phenomenon. Specifically, the claim recites the natural correlation between microRNA biomarker expression level in a sample from a subject and the subject having a condition (e.g. HCC).
As stated in MPEP 2106.04(b)(I), laws of nature and natural phenomena, as identified by the courts, 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.
Here, according to the specification, the inventors observed that certain miRNAs in saliva samples are differentially expressed between individuals having different conditions (e.g., between HCC and cirrhosis samples, see [0084]), and proposed that the miRNA expression levels are indicative of the subject's condition ([0090]-[0092]).
A subject naturally possesses a microRNA expression pattern, associated with a physiological condition is classified as naturally occurring principles/relations. Thus, the claimed diagnosis method relies on a judicial exception, which is a naturally occurring correlation microRNA biomarker expression level in a sample from a subject and the subject having a condition (e.g. HCC).
In conclusion, the claims recite laws of nature and natural phenomena.
Step 2A Prong 2 - Whether the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application: No. The claim as a whole do not integrates the exception into a practical application of that exception.
The additional element in the claim do not transform the claimed natural phenomena to something that are markedly different than their naturally occurring counterparts in their natural state, nor does it integrate the recited judicial exception into a practical application of the exception.
Claim 1 involves a natural correlation (miRNA expression level and the subject's medical condition), and a comparison to a reference value in order to determine whether the subject has HCC based on differential expression. The steps of determining miRNA expression level and determining differential expressions of miRNA via comparison with a reference appear to encompass any/all methods of observing the presence of the correlation at a high level of generality and is data gathering necessary to achieve diagnosis. Therefore, these steps recited at high-level of generality, merely observe natural laws and constitute abstract ideas.
The diagnosis aspect does not integrate the judicial exception into a practical application nor render the claim patent-eligible. The courts have repeatedly held that diagnostic claims based on naturally occurring correlations, without additional elements that impose meaningful limits on the judicial exception, are ineligible under 35 U.S.C. 101. See Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 927 F.3d 1333, 1352 (Fed. Cir. 2019) (en banc) (Moore, J., dissenting) (expressing that the current interpretation of Section 101 eliminated diagnostic testing as patentable subject matter). Diagnostic testing claims fail because the step across the claims involves the mental step of reading the results and comparing them to a known relationship, or otherwise observing a natural law. See id. at 1336 (Lourie, J., concurring) (acknowledging that the only consistent interpretation of Supreme Court decisions resolving issues of patentable subject matter requires invalidating patents for diagnostic tests that merely observe natural laws); Roche Molecular Sys., Inc. v. CEPHEID, 905 F.3d 1363, 1372 (Fed. Cir. 2018) (explaining that observation of the relationship between the sample and known phenomena does not involve an inventive concept).
Claim 1 further recites a treatment step: "treating the subject diagnosed with HCC."
The treatment step has been considered but does not render the claim patent-eligible under 35 U.S.C. 101 for two reasons.
First, the administering step is contingent and not required by every embodiment of the claimed invention.
Claim 1 recites "determine whether the subject has HCC … treating the subject diagnosed with HCC," which, is a contingent limitation that does not limit the scope of the claimed method.
MPEP §2111.04 states: "The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met."
Here, the treating step is only applicable to the scenario when the subject is diagnosed with HCC, it is therefore formulated as contingent language not essential to the operation of the claimed method, as it does not require an action upon every practice of the claim. For instance, in the scenario which the subject is not diagnosed as having HCC, the treating step is not performed.
Because this administering step is not required by every embodiment of the claimed invention, and is only applicable in certain situations, it does not sufficiently transform the judicial exception into a practical application.
Second, even if the administering step is required, it fails to transform the claimed method into patent-eligible subject matter because it does not recite a treatment that is sufficiently particular.
MPEP 2106.04(d)(2) states the following regarding consideration for particular treatment in Step 2A Prong Two:
"In order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. "
"The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s)."
Here, claim 1 only broadly recites "treating the subject diagnosed with HCC," without specifically identifying any treatment that goes beyond merely applying the exception in a generic manner.
Thus, this treating step does not integrate the observed natural correlation of claim 1 into a practical application.
Step 2B- Whether a Claim Amounts to Significantly More: No.
According to MPEP§ 2106.05, The second part of the Alice/Mayo test is often referred to as a search for an inventive concept. Alice Corp. Pty. Ltd. v. CLS Bank Int'l, 573 U.S. 208, 217, 110 USPQ2d 1976, 1981 (2014) (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). An “inventive concept” is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
In this instant case, the claims, when considered as a whole, do not recite any inventive concept with additional elements that amount to significantly more than the judicial exception.
The claims do not recite any additional elements beyond observing the judicial exception.
As recognized by the courts, determining the marker expression level through molecular biology techniques such as PCR amplification and sequencing, represents well-understood, routine, conventional activity in the life science arts. See University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014).
The dependent claims 2-5 do not recite additional elements that amount to significantly more than the judicial exception, as they either further describe the judicial exception or represent mere general linkage of the judicial exception to the additional elements in the claims (MPEP § 2106.05(h)).
In conclusion, the claims 1-5 are not patent eligible under 35 U.S.C. 101 3.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over
Qu (US20180163274A1- Circulating microrna as a marker for hepatocellular carcinoma; published 2018-06-14), in view of
Huang (Huang et al., Microarray analysis of microRNA expression in hepatocellular carcinoma and non-tumorous tissues without viral hepatitis. J Gastroenterol Hepatol. 2008 Jan;23(1):87-94. doi: 10.1111/j.1440-1746.2007.05223.x. PMID: 18171346);
Burwinkel (US20180245159A1- Biomarker panel for the detection of cancer; published 2018-08-30), as evidenced by
Wang(US20140220043A1 - Gene signature for predicting prognosis of patients with solid tumors; published 2014-08-07).
A) Qu teaches methods for diagnosing and treating liver cancer by determine differentially expressed microRNA in bodily fluid (e.g. saliva) compared to a reference (Abstract; [0007] [0022]).
Regarding claim 1, Qu teaches a method for diagnosing or prognosticating hepatocellular carcinoma (HCC) in a subject (Abstract, “methods for the diagnosis, or management of liver diseases, e.g., hepatocellular carcinoma, using profiles of the miRNAs determined from cellular or acellular body fluids”), comprising
determining, in an isolated sample of saliva, the expression level of at least one microRNA (miRNA) ([0007], determining, in an body fluid sample (e.g., cellular or acellular body fluid) from the subject, the level of one or more miRNAs; [0022] lines 1-4, body fluid sample includes saliva);
determining whether the miRNA in the saliva sample is differentially expressed as compared to as compared to a reference saliva sample ([0007] “diagnosing the subject as having hepatocellular carcinoma when a difference in the level of the one or more miRNAs compared to a reference level indicates hepatocellular carcinoma in the subject.”),
wherein the differential expression of miRNA is an upregulation or a downregulation of miRNA expression, in order to determine whether the subject has HCC ([0007]; [0016]), and
treating the subject diagnosed with HCC ([0010] apply anti-cancer therapy to a patient diagnosed as having hepatocellular carcinoma.).
Although Qu does not explicitly teach detecting at least one of the specific microRNA markers recited in the claim, this feature would have been obvious because hsa-mir-30d and hsa-mir-148b were known markers in the art for hepatocellular carcinoma (HCC), as supported by Huang and Burwinkel.
Huang teaches that hsa-miR-30d is differentially expressed in HCC samples (Figure 2; Table 3). A skilled artisan would have understood that the hsa-miR-30d nomenclature encompasses both mature forms, 3p and 5p, as evidenced by Burwinkel.
Burwinkel teaches that "a reference to a specific miRNA by its number (e.g. miR-652) equally refers to the -3p and -5p sequence (miR-652-3p and miR-652-5p)." ([0062]).
Burwinkel also teaches methods of diagnosing cancer, including HCC (Abstract; [0170]-[0173]), by determining at least one microRNA marker, such as hsa-mir-148b-3p ([0170] "
determining the presence, of at least one miRNA marker selected from the group consisting of … miR-148b"; [0062] "miRNAs are those of miRNAs of human origin"), which is also recited in the claim.
Accordingly, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it prima facie obvious to substitute the microRNA marker used in the method of Qu with other known alternative microRNA markers for detecting HCC, such as hsa-miR-30d-5p (disclosed in Huang) or hsa-mir-148b-3p (disclosed in Burwinkel). Because these microRNAs serve the same function as liver cancer biomarkers, the modification represents the principle of KSR for a simple substitution of one known element for another to obtain predictable results, see MPEP 2141.
There would have been a reasonable expectation of success because methods for detecting these microRNAs are known in the art, and modifying a microRNA detection assay to detect alternative known microRNAs would have been well within the knowledge and skill of the person of ordinary skill in the art.
B) Regarding claim 2, Qu teaches the reference sample is a comparable sample from chronic liver disease patients. A skilled artisan would readily understand chronic liver disease encompasses cirrhosis, as evidenced by Wang, which provides definition for cirrhosis as a chronic liver disease ([0105] “Cirrhosis: A chronic progressive disease of the liver characterized by the replacement of healthy cells with scar tissue.”) .
Regarding claims 3-5, as discussed above for claim 1, the combined teaching of Qu, Huang and Burwinkel teaches detecting differential expression of hsa-miR-30d-5p.
Subject Matter Not Taught/Suggested in Prior Art
Claim 6 and its dependent claims 7-8 are objected to as being dependent upon a rejected base claim 5/4/3/1, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following subject matter is not taught or suggested in the prior art:
Regarding claim 6, the prior art fails to teach or suggest all the claimed limitations.
Specifically, although microRNA sequencing is known in the art (see Burwinkel (US20180245159A1) in [0070]; see also Wojcicka(Wojcicka, A. et al. Next generation sequencing reveals microRNA isoforms in liver cirrhosis and hepatocellular carcinoma. Int J Biochem Cell Biol 53, 208–217, doi.org/10.1016/j.biocel.2014.05.020 (2014)) in Abstract; see also Hayes(Hayes, C.N.; Chayama, K. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma. Int. J. Mol. Sci. 2016, 17, 280.; doi.org/10.3390/ijms17030280) at page 4, "Measurement of Serum MicroRNAs"; page 5, "Baseline MicroRNA Expression in the Liver"), no prior art teaches or suggests analyzing the specific set of 8 miRNAs using the read-count formula as required by claim 6.
Conclusion
Claims 1 and 6-8 are objected to; claims 1-5 are rejected. No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681
1 Claims 11-23 are withdrawn as being drawn to non-elected species E-F.
2 Claims 9-10 are withdrawn as being drawn to non-elected species H and I.
3 It is noted that claim 6 and its dependent claims are excluded from the rejection under 35 U.S.C. 101. Claim 6 recites a combination of steps including obtaining normalized miRNA read counts by small RNA-seq and subsequently analyzing the normalized read counts using a specific formula.
This combination of elements, i.e., a specific assay approach and a specific data analysis step, is not considered well-understood, routine, and conventional in the art.
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