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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/03/2026 has been entered.
Election/Restrictions
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 Status
Claims 1-4, 6, 44-47, 49-52, 55-60, 62, 67 and 69 are pending.
Claims 44-47, 49-52, 55-60, 62, 67 and 69 are withdrawn, drawn to nonelected inventions.
Claims 1-4 and 6 are currently under examination.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “a.”, “b.”, “c.”, “d.”, “e.”, “f.”, and “g.”. The periods should be removed and can be replaced with single or double parentheses, e.g., “a)” or “(a)”.
MPEP 608.01(m) Form of Claims [R-10.2019] states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, (37 CFR 1.75(i).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 1-4 and 6 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 (c) recites the broad recitation “or a fragment or variant thereof”, and the claim also recites “SEQ ID NOs: 1 or 2”, which is the narrower statement of the range/limitation. Claim 1 (d) recites the broad recitation “or a fragment or variant thereof”, and the claim also recites “SEQ ID NOs: 3 or 4”, which is the narrower statement of the range/limitation. Claim 1 (e) recites the broad recitation “or a fragment or variant thereof”, and the claim also recites “SEQ ID NOs: 5 or 6”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. It is noted that the metes and bounds of limitation “variant thereof” cannot be determined regarding the length of a given SEQ ID NO and the identity of nucleotide at a given position of a given SEQ ID NO recited in claim 1. Claims 2-4 and 6 depend on claim 1.
Claim 1 is indefinite over the limitation “unannotated small non-coding RNA" (ln 1 and ln 19) based on the unclear metes and bounds meant by the term “unannotated”. The phrase " unannotated” typically indicates a subject/object/region, etc. with no previously known characterization. The metes and bounds of the term “unannotated” were not defined in the specification because it is not clear if identical, complementary or similar sequences or findings in regard to the region would be considered as an unannotated or annotated or if “unannotated” indicates there was absolutely no information or similar sequences previously known. Claims 2-4 and 6 depend on claim 1.
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) in view of Michele Cargill (“Cargill”; Patent App. Pub. US 20070054278 A1, March 8, 2007).
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) and “The disclosure generally relates to a method of diagnosing a subject with a benign, pre-malignant, or malignant hyperproliferative cell comprising: detecting the presence, absence, and/or quantity of at least one non-coding RNA or functional fragment thereof in a sample” (Para. 131). 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… for example, amplification-based methods” (Para. 69). Note, that the MPEP states "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, it would be obvious to one of ordinary skill in the art to detect more than two non-coding RNA sequences, such as cluster of three small non-coding RNAs. 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). The “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”. Goodarzi teaches “previously unknown small RNAs were discovered and annotated” (Para. 152), thus it would be obvious to the ordinary skilled artisan that small non-coding RNAs does not exclude unannotated small non-coding RNA. Goodarzi also teaches that “the approaches and concepts presented here are generalizable and can be applied across several cancers. Taken together, these findings open the possibility that further examination of the cancer-specific RNA landscape and investigation into oncRNAs may yield alternative therapeutic and diagnostic methods across many cancer types” (Para. 165). Thus, Goodarzi suggests 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.
However, Goodarzi does not explicitly teach the limitations of SEQ ID No. 2, 4 or 6.
Cargill discloses “… In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.” (Abstract).
Regarding claim 1, Cargill teaches a method wherein “methods of detecting these polymorphisms in a test sample, methods of determining the risk of an individual of having or developing an enzyme-mediated disorder” (Para. 75). “enzyme-mediated disorder” reads on hepatocellular carcinoma. Cargill teaches a method wherein “the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences” (Para. 85). “non-coding exonic sequences” read on small unannotated RNA. Cargill teaches a method wherein “Probes and primers, may be designed to hybridize to either strand” (Para. 77). Cargill teaches a method wherein “isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product” (Para.177). “nucleic acids” reads on small unannotated non-coding RNAs. Cargill teaches the following SNP-containing nucleic acid sequences that align to SEQ ID No: 2, 4 or 6 with 86-100% similarity:
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Thus, Goodarzi and Cargill suggest a method according to the limitations of claim 1, wherein the primer sequence comprises the nucleotide sequence of SEQ ID NOs: 1 or 2 or a fragment or variant thereof or the nucleotide sequence complementary to SEQ ID NOs: 1 or 2; wherein the primer sequence comprises the nucleotide sequence of SEQ ID NOs: 3 or 4 or a fragment or variant thereof or the nucleotide sequence complementary to SEQ ID NOs: 3 or 4; and wherein the primer sequence comprises the nucleotide sequence of SEQ ID NOs: 5 or 6 or a fragment or variant thereof or the nucleotide sequence complementary to SEQ ID NOs: 5 or 6.
Goodarzi and Cargill are both considered to be analogous to the claimed invention because they are in the same field of detecting non-coding RNAs as biomarkers for disease. 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 suggested by Goodarzi to incorporate the primer sequences comprising the nucleotide sequences of SEQ ID NOs: 2, 4, and 6 or a fragment or variant thereof or the nucleotide sequence complementary to SEQ ID NOs: 2, 4, and 6 or a fragment or variant thereof as taught by Cargill and provide a method according to the limitations of claim 1. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claim 1. Doing so would allow for detection of polymorphisms in a test sample and determination of the risk of an individual of having or developing an enzyme-mediated disorder, such as hepatocellular carcinoma.
The teachings of Goodarzi and Cargill 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 and Cargill suggest 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 and Cargill suggest 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 and Cargill suggest 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.
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 but do not apply to the new grounds of rejection. To clarify some instances argued in the response filed 06/03/2026 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.. Goodarzi does not teach or suggest the surprising finding that a three signature small RNA cluster (''3-smRC signature'') from exosomes (i.e., a cluster comprising the three, small unannotated non-coding RNAs specific for hepatocellular carcinoma) can detect and are diagnostic for hepatocellular carcinoma..” (Pg. 10)
Response: In response, the examiner notes that as recited in the final office action mailed on 03/03/2026 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) and “The disclosure generally relates to a method of diagnosing a subject with a benign, pre-malignant, or malignant hyperproliferative cell comprising: detecting the presence, absence, and/or quantity of at least one non-coding RNA or functional fragment thereof in a sample” (Para. 131). 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… for example, amplification-based methods” (Para. 69). Note, that the MPEP states "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, it would be obvious to one of ordinary skill in the art to detect more than two non-coding RNA sequences, such as cluster of three small non-coding RNAs. 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). The “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”. Goodarzi teaches “previously unknown small RNAs were discovered and annotated” (Para. 152), thus it would be obvious to the ordinary skilled artisan that small non-coding RNAs does not exclude unannotated small non-coding RNA. Goodarzi also teaches that “the approaches and concepts presented here are generalizable and can be applied across several cancers. Taken together, these findings open the possibility that further examination of the cancer-specific RNA landscape and investigation into oncRNAs may yield alternative therapeutic and diagnostic methods across many cancer types” (Para. 165).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.
Claim 3 is 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 Michele Cargill (“Cargill”; Patent App. Pub. US 20070054278 A1, March 8, 2007) as applied to claim 1, and further 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 and Cargill 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 and Cargill do 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, Cargill and Shen suggest 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.
Goodarzi, Cargill and Shen are considered to be analogous to the claimed invention because they are in the same field of detecting RNAs as biomarkers for disease. 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 suggested by Goodarzi and Cargill to incorporate a subject suffering from HCC and cirrhosis of the liver, hepatitis C virus infection or hepatitis B virus infection as suggested 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) 3 under 35 U.S.C. 103 have been fully considered but do not apply to the new grounds of rejection. To clarify some instances argued in the response filed 06/03/2026 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.” (Pg. 10)
Response: 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 Non-Final Office Action.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's
disclosure:
Patent App. Pub. No: US 20040181048 A1, Nov. 16, 2004
(matched entry(shown below)) Claim 1 SEQ ID No: 2, 4, and 6.
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Patent App. Pub. No:US20070083334A1, May 31, 2006
(matched entry (shown below); Para. 260; Para. 592) Claim 1 SEQ ID No: 2, 4, and 6.
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Patent App. Pub. No: US 20050228172 A9, Oct. 13, 2005
(matched entry (shown below)) Claim 1 SEQ ID No: 2, 4, and 6.
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No claims are in condition for allowance.
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
