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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/23/2025 has been entered.
Claims Status
Claims 1-4, 8, 9, 11, 12, 16, & 17 filed on 12/23/2025 are pending. Claims 5-7 are withdrawn from consideration as being drawn to a non-elected invention. The cancellation of claim 15 without prejudice in the response dated 12/23/2025 is acknowledged. Claims 1-4, 8, 9, 11, 12, 16, & 17 are currently under examination directed to the elected species of SEQ ID NO: 1, tissue, chemotherapy, and Sorafenib (see response dated 01/20/2025). All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112
Claims 1-4, 8, 9, 11, 12, 16, & 17 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.
Regarding amended claims 1 & 8, the recitation of “measuring a methylation level of a nucleic acid sequence consisting of SEQ ID NO: 1, a nucleic acid sequence consisting of SEQ ID NO: 2 or a combination thereof” in lines 4-6 of claim 1 and of lines 2-4 of claim 8 followed by the recitation of “determining that the biological sample originated from liver cancer when the methylation level is higher than that of a normal control sample” in lines 7-8 of claim 1 and of lines 5-6 of claim 8 is unclear. It is unclear if “determining the methylation level is higher” in step (c) of claim 1 and in step (b) in claim 8 comprises a methylation level of only one of SEQ ID NO: 1 or SEQ ID NO: 2 or requires the methylation level of the combination of SEQ ID NO: 1 and SEQ ID NO: 2 to determining that the biological sample originated from liver cancer.
Regarding claim 9, the recitation of “wherein the methylation level is a methylation level of CpG site of the nucleic acid sequence consisting of SEQ ID NO: 1 and the nucleic acid sequence consisting of SEQ ID NO: 2” in lines 1-3 of the claim is unclear as step (a) of claim 8, from which claim 9 depends from, requires measuring a methylation level of SEQ ID NO: 1, SEQ ID NO: 2, or a combination and further step (b) of claim 8 requires determining that the subject has liver cancer when the methylation level is higher than a control sample. Therefore, it is unclear if “the methylation level” requires just a higher methylation level in SEQ ID NO: 1 and SEQ ID NO: 2 or requires and active step of measuring a methylation level of SEQ ID NO: 1 and SEQ ID NO: 2 and then using these methylation levels to determine if the combined methylation levels are higher for determining if a sample has originated from a liver cancer sample.
Claims 2-4 are rejected due to their dependence on claim 1 and claims 11, 12, 16, & 17 are rejected due to their dependence on claim 8.
Claim Rejections - 35 USC § 103
Claim(s) 1-4, 8, 11, 12, 16, & 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jun (CN109609629A, April 2019), machine translation obtained from Science & Technical Information Center (STIC), in view of Ikeda (Ikeda et al.; Annals of Oncology, Vol. 27, pages 2090-2096, August 2016).
Regarding newly amended claims 1 & 2, Jun detection of liver cancer through analysis of abnormal methylation of the RNF135 gene through extracting genomic DNA from the biological sample (separating DNA from a biological sample), measuring the methylation state of a target gene of the RNF135 gene of SEQ ID NO: 2, in which SEQ ID NO: 2 of Jun comprises SEQ ID NO: 1 in the instant application from position 184 to 305 (measuring a methylation level of a nucleic acid sequence consisting of SEQ ID NO: 1), in which there are significant differences in the methylation status of RNF135 gene in liver cancer tissue and normal liver tissue as the RNF135 gene are methylated in liver cancer tissue and not methylated in normal liver tissue providing a method to detect liver cancer (determining that the biological sample has originated from liver cancer when the methylation level is higher than that of a normal control sample) (paragraph [0011] lines 1-10; paragraph [0012] lines 1-4; paragraph [0014] lines 1-2; paragraph [0041] line 1; paragraph [0042] lines 1-6; paragraph [0065] lines 1-8; paragraph [0069] lines 1-11).
Jun does not teach the method further comprising treating the subject.
Ikeda teaches a method for treating hepatocellular carcinoma (HCC) through the combination of hepatic arterial infusion chemotherapy with cisplatin to Sorafenib (abstract background paragraph lines 1-3; pg. 2091 column 1 3rd full paragraph lines 1-16). In addition, Ikeda teaches this method of combined treatment for patients with HCC lead to a favorable overall survival outcome (pg. 2095 column 2 2nd full paragraph lines 1-4).
Jun and Ikeda are considered to be analogous to the claimed invention because they are all in the same field of analysis of liver cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the methylation level of SEQ ID NO: 2 comprising the RNF135 gene, in which SEQ ID NO: 2 of Jun comprises SEQ ID NO: 1 of the instant application from position 184 to 305, for liver cancer diagnosis taught in Jun to incorporate the treatment of the liver cancer patients with the combination of chemotherapy and Sorafenib as taught in Ikeda because Ikeda teaches that doing so could lead to a favorable survival outcome in the HCC (liver cancer) patients.
Regarding claim 3, Jun teaches measuring methylation status of SEQ ID NO: 2 comprising the RNF135 gene in biological samples comprising tissue biopsies/paraffin-embedded tissues (the biological sample is tissue) (paragraph [0066] lines 1-4).
Regarding claim 4, Jun teaches measuring the methylation status of SEQ ID NO: 2 comprising the RNF135 gene in liver cancer biological samples comprises PCR, methylation-specific PCR, real time methylation specific PCR, etc. (paragraph [0092] lines 1-10).
Regarding newly amended claims 8, Jun detection of liver cancer through analysis of abnormal methylation of the RNF135 gene through extracting genomic DNA from the biological sample, measuring the methylation state of a target gene of the RNF135 gene of SEQ ID NO: 2, in which SEQ ID NO: 2 of Jun comprises SEQ ID NO: 1 in the instant application from position 184 to 305 (measuring a methylation level of a nucleic acid sequence consisting of SEQ ID NO: 1), in which there are significant differences in the methylation status of RNF135 gene in liver cancer tissue and normal liver tissue as the RNF135 gene are methylated in liver cancer tissue and not methylated in normal liver tissue providing a method to detect liver cancer (determining that the biological sample has originated from liver cancer when the methylation level is higher than that of a normal control sample) (paragraph [0011] lines 1-10; paragraph [0012] lines 1-4; paragraph [0014] lines 1-2; paragraph [0041] line 1; paragraph [0042] lines 1-6; paragraph [0065] lines 1-8; paragraph [0069] lines 1-11).
Jun does not teach the method further comprising treating the subject.
Ikeda teaches a method for treating hepatocellular carcinoma (HCC) through the combination of hepatic arterial infusion chemotherapy with cisplatin to Sorafenib (abstract background paragraph lines 1-3; pg. 2091 column 1 3rd full paragraph lines 1-16). In addition, Ikeda teaches this method of combined treatment for patients with HCC lead to a favorable overall survival outcome (pg. 2095 column 2 2nd full paragraph lines 1-4).
Jun and Ikeda are considered to be analogous to the claimed invention because they are all in the same field of analysis of liver cancer samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of measuring the methylation level of SEQ ID NO: 2 comprising the RNF135 gene, in which SEQ ID NO: 2 of Jun comprises SEQ ID NO: 1 of the instant application from position 184 to 305, for liver cancer diagnosis taught in Jun to incorporate the treatment of the liver cancer patients with the combination of chemotherapy and Sorafenib as taught in Ikeda because Ikeda teaches that doing so could lead to a favorable survival outcome in the HCC (liver cancer) patients.
Regarding claim 11, Jun teaches analyzing the methylation status of SEQ ID NO: 2 comprising the RNF135 gene compared to a control sample of normal liver tissue (the normal control sample is from a non-cancer subject) (paragraph [0069] lines 1-7; paragraph [0121] lines 1-3).
Regarding claim 12, Jun teaches analyzing the methylation status of SEQ ID NO: 2 comprising the RNF135 gene compared to a control sample of normal liver tissue from patients with liver disease or healthy individuals (control sample is a sample other than liver sample from a liver cancer patient, i.e. is a liver sample from a non-liver cancer patient) (paragraph [0069] lines 1-7; paragraph [0121] lines 1-3).
Regarding claim 16, Jun teaches measuring methylation status of SEQ ID NO: 2 comprising the RNF135 gene in biological samples comprising tissue biopsies/paraffin-embedded tissues (the biological sample is tissue) (paragraph [0066] lines 1-4).
Regarding newly added claim 17, Jun teaches measuring the methylation status of SEQ ID NO: 2 comprising the RNF135 gene in liver cancer biological samples comprises PCR, methylation-specific PCR, real time methylation specific PCR, etc. (paragraph [0092] lines 1-10).
Response to Arguments
Applicant’s arguments, see pages 7-10 of the response filed on 12/23/2025 and paragraphs 6-11 of the Declaration Under 37 C.F.R. §1.132 filed on 12/23/2025, with respect to the rejection(s) of claim(s) 1-4, 8, 9, 12, 16, & 17 under 35 U.S.C. 103 of Wu (Wu et al.; World Journal of Hepatology, Vol. 8, pages 301-306, February 2016), as cited in the IDS dated 05/14/2024, as evidenced by GenBank Accession Number AK226030 (July 2006), in view of Ikeda (Ikeda et al.; Annals of Oncology, Vol. 27, pages 2090-2096, August 2016) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Jun (CN109609629A, April 2019), machine translation obtained from Science & Technical Information Center (STIC), in view of Ikeda (Ikeda et al.; Annals of Oncology, Vol. 27, pages 2090-2096, August 2016), as discussed further above.
Allowable Subject Matter
The following claim is free of the prior art and would be allowable:
A method of treating liver cancer in a subject comprising
(a) measuring the methylation level of CpG sites of the nucleic acid sequence consisting of SEQ ID NO: 1 and the nucleic acid sequence consisting of SEQ ID NO:2 in a biological sample from the subject;
(b) determining that said measured methylation level is higher than the methylation level of CpG sites of the nucleic acid sequence consisting of SEQ ID NO: 1 and the nucleic acid sequence consisting of SEQ ID NO:2 in a normal control sample;
(c) diagnosing the subject of (b) as having liver cancer; and
(d) administering to the diagnosed subject an effective amount of a therapeutic agent, chemotherapy, radiation therapy, surgical intervention, or a combination thereof,
wherein the therapeutic agent comprises Afatinib, AK105, Anlotinib, Apatinib, Atezolizumab, Avelumab, axitinib, Bevacizumab, bosutinib, BSC, Cabozantinib,Cabozantinib-S-Malate, Camrelizumab, canertinib, carboplatin, capecitabine, celecoxib, CC-122, CF102, crizotinib, dasatinib, docetaxel, Donafenib, Dovitinib, doxorubicin, Durvalumab, EKB-569, entrectinib, epirubicin, erlotinib, etoposide, everolimus, FGF401, FOLFOX 4, fostamatinib, Galunisertib, qefitinib, qemcitabine, 1B1305, ibrutinib, imatinib,INC280, Infiqratinib, Ipilimumab, irinotecan, lapatinib, leflunomide, Lenvatinib, LY2875358, Mesylate, mitomycin c, MSC2156119J, neratinib, nilotinib, Nintedanib, Nivolumab, oxaliplatin, Palbociclib, Panobinostat, pazopanib, PDR001, Pembrolizumab, Pemiqatinib, Pexavec, Phosphate, Ramucirumab, Reqorafenib, ruxolitinib, semaxinib, selumetinib,SGO-110,SHR-1210,Sintilimab,Sorafenib,SU6656,sunitinib, spartalizumab, sutent, TACE, Tasquinimod, Temozolomide, Temsirolimus, Tislelizumab, Tivantinib, Tosylate, toripalimab, Tremelimumab, vandetanib, vatalanib, XL888, Y90, or a combination thereof.
Conclusion
Claims 1-4, 8, 9, 11, 12, 16, & 17 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682