DETAILED ACTION
The claim amendment was filed.
Applicant’s election without traverse of Group I, claims 1-4 and 6, drawn to a method of detecting three, small unannotated non- coding RNAs specific for hepatocellular carcinoma in a subject and species SEQ ID No: 2, 4 and 6, in the reply filed on 10/07/2025 is acknowledged.
Claims 44-47, 49-52, 55-60, 62, 67 and 69 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/07/2025.
Applicant’s arguments regarding previous rejection(s) of claim(s) 1-4 and 6 under 35 U.S.C. 103 have been fully considered and are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final are maintained and revised as documented below on Pg. 2-10, in light of applicants arguments on Pg. 7-11.
Claims 1-4 and 6 in the claim set filed on 02/05/2026 are currently under examination.
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.
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 1-2, 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Goodarzi et al. (“Goodarzi”; Patent App. Pub. WO 2019094780 A2, May 16, 2019).
Goodarzi discloses “The present disclosure relates generally to detection of non-coding RNAS molecules in a sample or diagnosis of subject based upon detection or quantification of non-coding nucleic acid sequences in a sample, specifically to identify and use of molecular biomarkers for cancer including breast cancer.” (Abstract).
Regarding claim 1, Goodarzi teaches a method comprising “sample" refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample... Such a "processed sample" may comprise, for example nucleic acids … extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification … isolation and/or purification of certain components, etc.” (Para. 50). Goodarzi teaches a method comprising “any of the methods of the disclosure comprise the step of isolating total RNA from a sample or cell or exosome or microvesicle” (Para. 68). Goodarzi teaches a method comprising “primers are used to detect … small non-coding RNAs” (Para. 95) and “using synthetic oligonucleotide” (Para. 158). Goodarzi teaches a method comprising “quantification of at least two small non-coding RNAs of interest in one reaction volume by using more than one pair of primers and/or more than one probe” (Para.76). Goodarzi teaches a method comprising “small non-coding RNA can be detected and quantified from a sample (including fractions thereof), such as samples of isolated RNA by various methods known for mRNA, including, for example, amplification-based methods” (Para.69). Goodarzi teaches a method comprising “detecting a hyperproliferative cell in a subject comprising detecting the absence, presence or quantity of non-coding nucleic acid in a serum or plasma sample” (Para. 6) and “hyperproliferative disease is a cancer of ... liver” (Para. 33). “detecting a hyperproliferative cell in a subject comprising detecting the absence, presence or quantity of non-coding nucleic acid in a serum or plasma sample” (Para. 6) and “hyperproliferative disease is a cancer of ... liver” (Para. 33).” reads on “ determining the presence of amplification products, wherein the presence of amplification products indicates the presence of small unannotated non-coding RNAs specific for hepatocellular carcinoma in the sample”. “small non-coding RNAs” reads on unannotated small non-coding RNAs, as it does not exclude it. Thus, Goodarzi teaches a method of detecting three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject, comprising: a. isolating exosomes from a sample from the subject; b. extracting RNA from the exosomes; c. contacting RNA from the exosomes with at least one primer which is a synthetic nucleic acid; d. further contacting RNA from the exosomes with at least one primer which is a synthetic nucleic acid; e. further contacting RNA from the exosomes with at least one primer which is a synthetic nucleic acid; f. subjecting the RNA and the primers to amplification conditions; and g. determining the presence of amplification products, wherein the presence of amplification products indicates the presence of small unannotated non-coding RNAs specific for hepatocellular carcinoma in the sample.
The teachings of Goodarzi are documented above in the rejection of claim 1 under 35 U.S.C. 103. Claims 2, 4 and 6 depend on claim 1.
Regarding claim 2, Goodarzi teaches a method wherein “small non-coding RNA biomarkers, alone or in combination, can be used to provide a measure of the relative risk that a subject has or does not have cancer” (Para. 56). Thus, Goodarzi teaches a method wherein the subject is at risk for hepatocellular carcinoma.
Regarding claim 4, Goodarzi teaches a method wherein “obtained from essentially any source, including cells, tissues, and fluids throughout the body” (Para. 63) and “bodily fluids… e.g., a blood sample or a lymph sample, or from another bodily fluid such as urine or saliva… bodily fluid, for example, blood, fractions thereof, serum, plasma, urine, saliva, tears, sweat, semen, vaginal secretions, lymph, bronchial secretions, CSF, whole blood, etc.” (Para. 64). Thus, Goodarzi teaches a method herein the sample is selected from the group consisting of blood, serum, plasma, bone marrow, pleural fluid, peritoneal fluid, cerebrospinal fluid, urine, saliva, amniotic fluid, ascites, broncho-alveolar lavage fluid, synovial fluid, breast milk, sweat, tears, joint fluid, and bronchial washes.
Regarding claim 6, Goodarzi teaches a method wherein “the sample is a fractionated human serum sample comprising exosomes” (Para. 5).”fractionated” reads on separation by ultra centrifugation. Thus, Goodarzi teaches a method wherein the exosomes are purified from the sample by a method selected from the group selected from ultracentrifugation, use of VN96 peptide, and use of a polymer which precipitates the exosome from the sample.
Therefore, the invention as recited in claims 1-2, 4 and 6 is prima facie obvious over the prior art Goodarzi et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to detect three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject according to the limitations of the instant application claims 1-2, 4 and 6 based on Goodarzi et al. (Patent App. Pub. No. WO 2019094780 A2). Although Goodarzi does not teach primer sequences comprising the nucleotide sequence of SEQ ID No:2, 4 or 6, one of ordinary skill in the art would have had a reasonable expectation of success given that the target chromosomal locations were known. "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." (MPEP 2144.05). Thus, synthetic oligonucleotide to the locations would be obvious to generate to detect the small non-coding RNAs.
Response to Arguments
Applicant’s arguments regarding previous rejection(s) of claim(s) 1-2, 4 and 6 under 35 U.S.C. 103 have been fully considered and are not persuasive. The 35 U.S.C. 103 rejections documented in the previously mailed non-final are maintained and revised as documented above on Pg. 2-7, in light of applicants arguments on Pg. 7-10. To clarify some instances argued in the response filed 02/05/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “Goodarzi does not teach, suggest or motivate a person of skill in the art to arrive at the claim method of detecting three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject.” (Pg. 8)
Response: In response, the examiner notes that as recited in the revised rejection above on Pg. 3-4, Goodarzi teaches a method comprising “sample" refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample... Such a "processed sample" may comprise, for example nucleic acids … extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification … isolation and/or purification of certain components, etc.” (Para. 50). Goodarzi teaches a method comprising “any of the methods of the disclosure comprise the step of isolating total RNA from a sample or cell or exosome or microvesicle” (Para. 68). Goodarzi teaches a method comprising “primers are used to detect … small non-coding RNAs” (Para. 95) and “using synthetic oligonucleotide” (Para. 158). Goodarzi teaches a method comprising “quantification of at least two small non-coding RNAs of interest in one reaction volume by using more than one pair of primers and/or more than one probe” (Para.76). Goodarzi teaches a method comprising “small non-coding RNA can be detected and quantified from a sample (including fractions thereof), such as samples of isolated RNA by various methods known for mRNA, including, for example, amplification-based methods” (Para.69). Goodarzi teaches a method comprising “detecting a hyperproliferative cell in a subject comprising detecting the absence, presence or quantity of non-coding nucleic acid in a serum or plasma sample” (Para. 6) and “hyperproliferative disease is a cancer of ... liver” (Para. 33). “detecting a hyperproliferative cell in a subject comprising detecting the absence, presence or quantity of non-coding nucleic acid in a serum or plasma sample” (Para. 6) and “hyperproliferative disease is a cancer of ... liver” (Para. 33).” reads on “ determining the presence of amplification products, wherein the presence of amplification products indicates the presence of small unannotated non-coding RNAs specific for hepatocellular carcinoma in the sample”. “small non-coding RNAs” reads on unannotated small non-coding RNAs, as it does not exclude it. Thus, Goodarzi does teach, suggest or motivate a person of skill in the art to arrive at the claim method of detecting three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject.
Applicants’ argument: “Goodarzi refers to liver cancer once in its 93-page disclosure in a laundry list of over 70 other cancers and does not ever specifically refer to hepatocellular carcinoma.” (Pg. 8)
Response: In response to applicant' s argument that “Goodarzi refers to liver cancer once in its 93-page disclosure in a laundry list of over 70 other cancers and does not ever specifically refer to hepatocellular carcinoma”, the argument is unpersuasive because liver cancer reads on hepatocellular carcinoma, thus it would be obvious to the ordinary artisan to arrive at hepatocellular carcinoma.
Applicants’ argument: “a person of skill in the art would understand that genomic "dark matter" refers to RNA that does not code proteins and do not correspond to annotated genes (i.e., genes whose location, structure, and basic function have been identified and recorded in a reference genome database). A person of skill in the art would understand that unannotated genes refer to genes that have not been assigned specific functions or annotations and lack sufficient evidence to be formally classified as genes” (Pg. 8)
Response: Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. Furthermore, small non-coding RNAs read on unannotated small non-coding RNAs, as it does not exclude it.
Applicants’ argument: “the rejection appears to be based on nothing more than improper hindsight reconstruction. The M.P.E.P. specifically states that "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant's disclosure, such a reconstruction is proper" (emphasis added). M.P.E.P. § 2145(X)(A) (citing In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971); see also M.P.E.P. § 2142 ("The tendency to resort to 'hindsight' based upon applicant's disclosure is often difficult to avoid due to the very nature of the examination process. However, impermissible hindsight must be avoided.")” (Pg. 10)
Response: In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Furthermore, as supported by the revised rejection above, the conclusion of obviousness is not hindsight reasoning, as the claimed matter is made obvious over Goodarzi et al, as discussed in the response above.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Goodarzi et al. (“Goodarzi”; Patent App. Pub. WO 2019094780 A2, May 16, 2019) in view of Shen et al. (“Shen”; (2017). The role of exosomes in hepatitis, liver cirrhosis and hepatocellular carcinoma. Journal of cellular and molecular medicine, 21(5), 986–992.).
The teachings of Goodarzi are documented above in the rejection of claims 1-2, 4 and 6 under 35 U.S.C. 103. Claim 3 depends on claim 1. Goodarzi does not explicitly teach the limitations of claim 3.
Shen discloses “Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome‐mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome‐mediated biological processes.” (Abstract).
Regarding claim 3, Shen teaches a method wherein “Hepatocellular carcinoma is the most common primary liver cancer. Approximately, 80% of HCC cases are associated with chronic HBV or HCV infection and liver cirrhosis” (Para.). Thus, Goodarzi and Shen teaches a method wherein the subject is suffering from cirrhosis of the liver, hepatitis C virus infection, hepatitis B virus infection, non-alcoholic fatty liver disease or combinations thereof.
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detecting three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject as taught by Goodarzi to incorporate a subject suffering from HCC and cirrhosis of the liver, hepatitis C virus infection or hepatitis B virus infection as taught by Shen and provide a method for detecting small noncoding RNA wherein the subject is suffering from cirrhosis of the liver, hepatitis C virus infection, hepatitis B virus infection, non-alcoholic fatty liver disease. Doing so would allow for detection of HCC even in the presence of another liver disease.
Response to Arguments
Applicant’s arguments regarding previous rejection(s) of claim(s) 1 and 3 under 35 U.S.C. 103 have been fully considered and are not persuasive. To clarify some instances argued in the response filed 02/05/2026 see responses to the argument made by Applicant below:
Applicants’ argument: “Shen does not teach, suggest or motivate a person of skill in the art to arrive at the claim method of detecting three, small unannotated non-coding RNAs specific for hepatocellular carcinoma in a subject. Instead, Shen is a review that describes the role of exosomes in hepatitis, liver cirrhosis and hepatocellular carcinoma. Shen is silent on any discussion regarding unannotated non-coding RNAs, let alone the specific small unannotated non-coding RNAs as recited in the instant claims. Indeed, contrary to the Examiner's assertions on pages 6-7 of the Office Action, Shen does not provide a method of detecting small noncoding RNA wherein the subject is suffering from cirrhosis of the liver. At best, Shen teaches that exosomes contain various microRNAs, mRNAs and proteins and can play a role in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. A person of skill in the art would not readily arrive to the claimed methods in view of Goodarzi alone or in view of Shen.” (Pg. 10-11)
Response: Arguments against Goodarzi on Pg. 10-11 are not persuasive as discussed in the response above. Furthermore, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion of Response to Arguments
In view of the amendments, new grounds of rejections and above responses to arguments are documented in this Final Office Action. No claims are in condition for allowance.
Conclusion
THIS ACTION IS MADE FINAL. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (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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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682