Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
This Office Action is in reply to Applicants’ correspondence of 08/19/2024.
Applicants’ 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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
Response to Amendment
The amendment filed 08/11/2025 regarding the Office Action mailed 05/21/2025 is acknowledged.
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Summary
Claims 1-29 were previously cancelled.
Claims 30, 31, and 35-37 have been amended.
Claims 30-44 are currently pending.
Information Disclosure Statement
The objection to the information disclosure statement (IDS) submitted on 08/22/2022 for containing many entries with no journal article title is withdrawn and the references are being considered by the examiner.
Withdrawn Objection to the Specification
The objection to the disclosure as set forth on page 2 of the Office Action of 05/21/2025 is withdrawn in light of the amendment to the specification provided by the applicant in the reply of 08/11/2025, which is entered.
Withdrawn Claim Objections
The objection to claims 30, 35, and 36, as set forth on page 3 of the Office Action of 05/21/2025 is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections
The rejection of claim 37 under 112(b) as being indefinite is withdrawn in view of applicant’s amendment to the claims.
The rejection of claims 30-44 under 35 U.S.C. 101 as being directed to non-statutory subject matter is withdrawn upon further consideration.
Claim Rejections - 35 USC § 103- MAINTAINED
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 30-32 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over
Yamamoto et al (2009; NPL A70 on IDS dated 08/22/2022) in view of Gramantieri et al (2007; NPL A16 on IDS dated 08/22/2022).
Regarding claim 30, Yamamoto teaches a method of detecting miRNA in a serum sample from cancer patients, including HCC patients (e.g., Yamamoto et al., page 535, left column, para 2; page 530, right column, last para; page 531, left column, para 1), and collecting samples prior to and following cancer treatment (e.g., Yamamoto et al., page 531, left column, para 2), reading on the limitations “A method comprising: (a) detecting a level of miRNA in a serum sample from a human subject diagnosed as having hepatocellular carcinoma (HCC), wherein the serum sample is obtained from the subject prior to administration of an anti-cancer therapy” and “wherein the serum sample is obtained from the subject at a time point following to administration of the anti-cancer therapy” of the instantly rejected claim 30. Yamamoto teaches detecting miRNA by reverse transcription qPCR using detectably labeled probes (e.g., Yamamoto et al., page 530, right column, last para; page 531, right column, first para), reading on the limitations “performing real-time reverse transcription polymerase chain reaction (RT- PCR) on the serum sample” and “using a detectably labeled probe specific for each miRNA assayed” of the instantly rejected claim 30. Yamamoto teaches the normalization of target miRNA expression levels against U6 controls (e.g., Yamamoto et al., page 531, left column, para 1; figs 3-4) reading on the limitation “and a control Ct value for U6 small RNA” of the instantly rejected claim 30. Yamamoto teaches the comparison of miRNA levels in pre-treatment and post treatment samples in HCC patients (e.g., Yamamoto et al., page 531, left column, para 2; abstract), reading on the limitation “comparing the delta Ct value of (a)(ii) to the delta Ct value of (b)(ii)” of the instantly rejected claim 30.
Yamamoto does not teach the detection of mi-RNA 199a, nor the use of delta Ct
calculations, but these were known in the art and were taught by Gramantieri.
Gramantieri teaches the detection of miR-199a in patients with HCC (Gramantieri et al., title; table 2; page 6097, left column, para 2) reading on the limitation “detecting a level of miR-199a miRNA in a serum sample from a human subject diagnosed as having hepatocellular carcinoma (HCC)” of the instantly rejected claim 30. Gramantieri et al teaches the use of delta Ct values for miRNA expression levels, including the subtraction of Ct value of U6 from the target miRNA Ct value (e.g., Gramantieri et al., page 6093, right column, para 2), reading on the limitations “calculating a delta Ct value by subtracting the U6 control Ct value from the miR-199a Ct value” of the instantly rejected claim 30.
It would have been obvious before the effective filing date of the claimed invention for a person having ordinary skill in the art to have performed the method for detecting miRNA in serum from a patient diagnosed with HCC via reverse transcription qPCR, and comparing the expression levels before and after treatment for cancer of Yamamoto with the delta Ct data analysis and specific miR-199a miRNA target of Gramantieri. The skilled artisan would have been motivated to use the method and teachings of an additional cited study of Gramantieri that found that miR-199a was differently expressed in HCC patients (e.g., Gramantieri et al., page 6097, left column, para 2). The study was found to help define cancer-associated miRNA-deregulated pathways involved in liver disease, which could contribute to identifying potential therapeutic targets (e.g., Gramantieri et al., page 6098, right column, para 2). Thus, the addition of the method of Gramantieri to the method of Yamamoto would have been a simple combination of known methods to yield predicable results.
Regarding claim 31, Yamamoto et al teaches a method of detecting the level of miR-16 miRNA in the serum samples collected before and after treatment for HCC (e.g., Yamamoto et al., page 531, left column, para 3; page 531, left column, para 2).
Regarding claim 32, Yamamoto et al and Gramantieri et al teach a method where the level of miR-16 miRNA in the serum sample of taken before and/or after surgery (e.g., Yamamoto et al., page 531, left column, para 2-3) is detected by performing real-time reverse transcription polymerase chain reaction (RT-PCR) (e.g., Yamamoto et al., page 531, left column, para 3) on the serum sample to measure a Ct value for miR-16 miRNA and a control Ct value for U6 small RNA (e.g., Yamamoto et al., page 531, left column, para 1), wherein the Ct value is measured using a detectably labeled probe specific for each miRNA assayed (e.g., Yamamoto et al., page 531, left column, para 3); and (ii) calculating a delta Ct value by subtracting the U6 control Ct value from the target miRNA Ct value (e.g., Gramantieri et al., page 6093, right column, para 2).
Regarding claim 44, Yamamoto et al teaches a method wherein anti-cancer therapy for HCC is surgery (e.g., Yamamoto et al., page 531, left column, para 2).
The rejection of claims 33-40 under 35 U.S.C. 103 as being unpatentable over Yamamoto et al (2009; NPL A70 on IDS dated 08/22/2022) in view of Gramantieri et al (2007; NPL A16 on IDS dated 08/22/2022) in further view of Zhou et al (2006) and Perkins et al (2003) is maintained.
The rejection of claim 41 under 35 U.S.C. 103 as being unpatentable over Yamamoto et al (2009; NPL A70 on IDS dated 08/22/2022) in view of Gramantieri et al (2007; NPL A16 on IDS dated 08/22/2022) and Zhou et al (2006), in further view of Ertle et al (2009) is maintained.
The rejection of claims 42 and 43 under 35 U.S.C. 103 as being unpatentable over Yamamoto et al (2009; NPL A70 on IDS dated 08/22/2022) in view of Gramantieri et al (2007; NPL A16 on IDS dated 08/22/2022) and Zhou et al (2006), in further view of Antonov et al (2005) is maintained.
Response to Arguments
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Applicant’s arguments filed 8/11/25 have been fully considered but they are not persuasive.
Applicant Argument:
Applicant argues that Yamamoto and Gramantieri do not teach or suggest that miR-199a is present in plasma and that the teachings of Gramantieri Ct values of U6 are not used to generate a miR-199a delta Ct.
Response to Argument:
For the reasons discussed above, the combination of the teachings of Yamamoto (detecting miRNA in serum via reverse transcription qPCR) and Gramantieri (measuring miRNA expression levels) would suggest that miR-199a could also be present in serum, ultimately motivating a skilled artisan within the art to detect a level of miR-199a in a hepatocellular carcinoma serum sample.
Applicant has traversed claims 33-43 that depend upon the combination of Yamamoto and Gramantieri. For the reasons discussed above, the rejection under U.S.C. 35 103 is maintained.
Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 30-44 is/are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-15 of prior U.S. Patent No. 11421283. This is a statutory double patenting rejection.
The instantly rejected claims 30-32 and 37 are identical in scope to reference claims 1-3 and 8, with the order of target miRNA being switched between the independent and dependent claims, and newly amended change in claim dependency, but with no changes to the steps or scope.
Newly Rejected claim 37 recites “wherein the level of miR-199a, AFP, and DCP, and the percentage of AFP-L3 are detected…”, while reference claim 8 recites “wherein the level of miR-16, AFP, and DCP, and the percentage of AFP-L3 are detected…” and is otherwise identical in language to the instantly rejected claim.
Regarding claims 33-36 and 38-44, the language of the instant claims is identical to that of reference claims 4-7 and 9-15, aside from claim numbering.
Response to Arguments
Applicant Argument:
Applicant has traversed the Statutory Double Patenting rejection of claims 30-36 and 38-44 as claiming the same invention as that of claims 1-7 and 9-15 of prior U.S. Patent No. 11,421,283. Claim 31 has been amended to depend on claim 37. Applicant argues that claim 30 recites a method of detecting levels of miR-199a and none of the claims of ‘283 recite such method, rather a method of detecting levels of miR-16.
Response to Argument:
Claim 31 recites “further comprising detecting the level of miR-16 miRNA…”, while reference claim 2 recites “further comprising detecting the level of miR-199a…” and is otherwise identical in language to the instantly rejected claim. The amended change in dependency of claim 31 to depend on newly rejected claim 37 does not change the full scope of the invention as a whole as both claimed inventions are a combination of detecting the same hepatocellular carcinoma markers.
Conclusion
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/AVANDA E. HARVEY-BUTLER/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
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