DETAILED ACTIONNotice 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/11/25 has been entered.
Application Status
Claim 8 is pending. Claim 8 has been amended to exclude “malignant melanoma” from the therapeutic method. Amendments to claim 8 necessitate a new §103 rejection.
Examination of the merits commences on claim 8.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103 - New
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.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Lee of record (Lee, T., US20180030440A1) in view of Zhang (Zhang, Hong, et al. "Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma." Hepatology 67.6 (2018): 2271-2286) and Rae of record (Rae, James M., et al. The Prostate 66.8 (2006): 886-894.) and Tamura of record (Tamura, Kenji, et al. Cancer research 67.11 (2007): 5117-5125.) and Lee2 of record (Lee, Eugine, et al. Elife 8 (2019): e41913.).
Regarding claim 8, Lee teaches a method for treating cancers by administering a pharmaceutical composition comprising one or more miRNAs of miR-3670, miR-8078, and miR-4477a to the patient/subject in need of cancer treatment (claim 1 and [0043] and abstract), i.e. the composition for cancer treatment includes the combination of miR-3670, miR-4477a, and miR-8078. Lee teaches miR-3670 within that combination inhibits the expressions of the CBX4, NRAS, CASR, TXLNA, SNIP1, HNF1A, FZD4, TRIB1, ADMA19, and CKAP5 at the same time, while the miR-8078 inhibits the expressions of GREB1, HECTD3, and RIPK4, and the miR-4477a inhibits the expressions of STIL, KIF11, AKAP11, and FAM120A at the same time (FIG. 6). [0043]. Lee teaches for each of the selected genes, 3 kinds of siRNAs were also synthesized, and using the synthesized siRNAs, the experiment was performed in the same manner as described as utilizing the miRNA anti-cancer sequences [0074]. Lee also repeatedly discloses the well-known use of siRNAs as advantaged anti-cancer therapeutics [0003] and expands upon the utility of the siRNA through miRNA compositions [0005]. Regarding the specific cancers targeted, Lee teaches GREB1 is associated with the signaling pathways of tissues or tumors that respond to hormones, and is known to be overexpressed in various kinds of tumor cells to stimulate the growth of the cells [0049]. Lee further teaches the compositions of the invention delivered to a subject in need trigger apoptosis and targets various cancers including liver cancer as well as lung and breast cancer [0054].
Although these composition combinations are targeted to liver cancer, lung cancer, and breast cancer, among others, Lee does not describe the specific liver cancer to be hormone insensitive hepatocellular cancer such as hepatocellular carcinoma (HCC).
Zhang teaches the significant role of androgen receptor (AR) overexpression and AR as a gene target in hepatocellular carcinoma (abstract). Zhang teaches AR is overexpressed in the nucleus of approximately 37% of HCC tumors, where AR overexpression is significantly associated with advanced disease stage and poor survival (abstract). Zhang teaches AR overexpression in HCC cells markedly alters AR‐dependent transcriptome, stimulates oncogenic growth, and determines therapeutic response to enzalutamide, a hormone therapy AR antagonist (abstract). Zhang teaches androgen receptor (AR) is a member of the steroid hormone receptor superfamily where in response to stimulation by androgens such as testosterone, AR translocates into the nucleus where it binds to androgen response elements (AREs) and regulates cell growth and survival genes (pg 2272 col 1 para 2).
Tamura teaches AR overexpression is likely to play a central role of clinical hormone-refractory prostate cancers (HRPCs), where knockdown of these overexpressing genes by small interfering RNA results in drastic attenuation of prostate cancer cell viability (abstract). Tamura teaches hormone refractory prostate cancers associated with increased levels of AR expression, implicating that AR down-regulation by means of small interfering RNA (siRNA) or other methods should suppress tumor growth even in HRPCs (pg 5117 col 2 para 3). Tamura teaches androgen receptor (AR) signaling pathway plays a central role in prostate cancer development, and the prostate cancer growth is usually androgen-dependent at a relatively early stage but that patients eventually acquire androgen-independent and more aggressive phenotype that has been termed hormone-refractory prostate cancers (HRPCs) (pg 5117 col 2 para 2).
Rae teaches GREB1 is a critical regulator of hormone induced growth shared between breast and prostate cancer (pg 891 col 2 para 2). Rae applies GREB1 knockdown to prostate cancer and teaches that GREB1 is an androgen-regulated gene, it is expressed in hormone refractory prostate cancer (i.e. a type of hormone insensitive prostate cancer), and that suppression of GREB1 with siRNA blocks androgen-induced growth of prostate cancer cell lines (pg 893 col 2 para 2 and Fig. 4). Rae teaches Analysis of the 10 kb region 50 of the GREB1 transcriptional start site demonstrated that it contains multiple putative hormone response elements including those for the Androgen Receptor (AR) (pg 887 col 1 para 3). Rae further teaches it is likely that the key genes responsible for androgen-stimulated tumor cell proliferation to become constitutively upregulated in androgen-independent disease and presents attractive therapeutic targets for treatment (pg 887 col 1 para 2).
Lee2 teaches the significance of AR amplification as a clinically important drug resistance mechanism by tumors and that AR amplification detected in circulating tumor DNA or in circulating tumor cells (CTCs) is correlated with reduced clinical benefit from the next generation AR inhibitors abiraterone or enzalutamide (pg 1 para 2). Lee2 teaches GREB1 knockdown converted high AR output cells to a low AR output state and restored enzalutamide sensitivity in vivo (pg 2 para 5). Lee2 further teaches GREB1 mRNA levels are increased in primary prostate tumors that have high AR activity (pg 2 para 5). Collectively, these further data implicate GREB1 as an AR signal amplifier that contributes to cancer disease progression and antiandrogen resistance as well as AR signaling as a therapeutic target (pg 2 para 5).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have employed the anti-Greb1 microRNA and siRNA compositions of Lee where anti-Greb1 oligonucleotide combinations are administered to treat subjects with liver cancer, and applied those compositions specifically to the treatment of the type of liver of liver cancer claimed, hepatocellular cancer (hepatocellular carcinoma/HCC). It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Lee’s siRNA composition could inhibit expression of GREB1 because Lee and Rae demonstrate effective suppression of GREB1 to treat subjects with cancer. It would have been predictable that the GREB1 RNAi could effectively treat HCC liver cancer which expresses GREB1 and is insensitive to hormone treatment because; 1) Rae teaches diminishing AR amplification by GREB1 knockdown restores tumor sensitivity to hormone interfering treatment agents, 2)Tamura teaches AR expression inhibition as a treatment strategy specifically applicable to hormone refractory cancer, 3) Lee2 teaches GREB1 as an AR signal amplifier that contributes to cancer disease progression and antiandrogen resistance, and 4) Zhang teaches the significant role of androgen receptor (AR) overexpression in HCC and AR signaling specifically as a target in hepatocellular carcinoma. Therefore, the skilled artisan would have found it predictable that Lee’s anti-Greb1 ant-liver cancer compositions would be similarly effective against HCC. The skilled artisan would therefore be motivated to employ anti-GREB1 oligonucleotides as claimed to subjects with HCC in order to diminish AR expression to minimize tumor growth and restore sensitivity to hormone mediated anti-tumor agents for enhanced overall therapeutic efficacy.
Response to Arguments
Applicant’s arguments (Remarks pg 3) regarding “a malignant melanoma” are directed to a withdrawn §103 rejection related to treating malignant melanomas, therefore, the arguments are moot. Applicant’s amendments to remove malignant melanoma from the claim limitations necessitate a new §103 rejection.
Conclusion
All claims are rejected.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637