DETAILED ACTION
Status of Application
The amendments and response filed 23 February 2026 are acknowledged and have been considered in their entireties. Claims 1-9, 11-12 and 14-20 remain pending and subject to examination on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 17 March 2026 has been considered by the examiner. See initialed and signed PTO/SB/08.
Withdrawal of Previous Objections/Rejections
The objection to claim 6 is withdrawn in view of the amendment to the claim to insert “gene” in the second line.
The rejection of claims 2, 4 and 5 under 35 U.S.C. 112(b) is withdrawn in view of the amendment to claim 1 to remove reference to “anti-cancer therapeutic gene” and instead to refer to “cancer therapeutic gene” instead.
The rejection of claim 5 under 35 U.S.C. 112(b) for lack of antecedent basis for reciting “agent-sensitizing gene” is withdrawn in view of the amendment to make claim 5 depend from claim 4, rather than claim 1.
The rejection of claim(s) 11-12 and 14-19 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lee et al. (US 2020/0270612 – cited previous PTO-892) is withdrawn in view of the amendments to require the expression vector to comprise the trans-splicing ribozyme of claim 1.
New Objection
Claim 12 is objected to because of the following informalities: the claim can be improved with respect to grammar by replacing “ribozyme gene” with “trans-splicing ribozyme”. Appropriate correction is required.
Maintained Rejection
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.
Claim(s) 1-7, 11-12 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 2020/0270612 – cited on previous PTO-892) in view of Shin et al. (Molecular Therapy, 2013 – cited on IDS 08/27/2024).
Lee et al. teach: “A cancer-specific trans-splicing ribozyme and a use thereof are disclosed. The trans-splicing ribozyme does not act on normal tissue, but is specifically expressed in cancer tissue. Therefore, it is very safe and has excellent expression efficiency at the post-transcription level, and thus can be effectively used in treatment of cancer” (See Abstract). They specifically teach that the effective and safe trans-splicing ribozyme construct for cancer treatment comprises: a nucleic acid construct, comprising, in this order from 5′ end to 3′ end: (i) a cytomegalovirus (CMV) promoter;
(ii) a ribozyme-desired gene expression cassette, which includes (a) a sequence encoding a trans-splicing ribozyme targeting a cancer-specific gene and (b) a target gene connected to a 3′ exon of the ribozyme-encoding sequence,
wherein the nucleic acid construct has a splicing donor/splicing acceptor sequence (SD/SA sequence) connected to the 5′ end of the ribozyme-desired gene expression cassette, and a Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) connected to the 3′ end of the ribozyme-desired gene expression cassette; and
(iii) a nucleic acid sequence recognizing microRNA-122 (miR-122), which is connected to the 3′ end of the WPRE. (Claim 1). The desired gene is an anti-cancer therapeutic gene selected from one or more selected from the group consisting of a drug-sensitizing gene, a proapoptotic gene, a cytostatic gene, a cytotoxic gene, a tumor suppressor gene, an antigenic gene, a cytokine gene and an anti-angiogenic gene, and most preferably, a drug-sensitizing gene (See claims 5-6 and paragraph 0116). It is further taught one or more anti-cancer therapeutic genes may be used individually or in combination (paragraph 0117) and that the drug sensitizing gene is a HSVtk gene (See claim 7).
At paragraph 0122, it is taught the tumor suppressor gene according to an embodiment of the invention refers to a nucleotide sequence which may be expressed in target cells to suppress a tumor phenotype or induce cell death. As a representative example, the tumor suppressor gene may be a tumor necrosis factor-α (TNF-α) gene, a p53 gene, an APC gene, a DPC-4/Smad4 gene, a BRCA-1 gene, a BRCA-2 gene, a WT-1 gene, a retinoblastoma gene, an MMAC-1 gene, an adenomatous polyposis coil protein, a deleted colon carcinoma (DCC) gene, an MMSC-2 gene, an NF-1 gene, a nasopharyngeal tumor suppressor gene located on chromosome 3p21.3, an MTS1 gene, a CDK4 gene, an NF-1 gene, an NF-2 gene, a VHL gene or a programmed death-1 (sPD-1) gene.
The preferred construct is presented in Figure 1 and reproduced below:
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In Experimental Examples 1 and 6, the anticancer efficacy/treatment of this construct is demonstrated in vitro in cancer cells (liver, glioblastoma cell line, colon cancer cell line, melanoma cell line, cervical cancer cell line, lung cancer cell line, osteosarcoma cell line, breast cancer cell line and bile duct cancer cell line); and in Experimental Example 2 and Comparative Example 1, confirmation of in vivo anticancer effects are demonstrated in animal models after systemic administration or intratumor injection. Claims 13 and 18-19 teach pharmaceutical formulations and suitable routes of administration for said formulations.
Lee et al., however, while suggesting “one or more anti-cancer therapeutic genes” can be utilized in their cancer treating trans-splicing ribozyme construct, they do not experimentally teach utilizing more than one gene such as a tumor suppressor gene of soluble sPD-1 (e.g. immune checkpoint inhibitor) in their cancer-specific trans-splicing ribozyme, nor the motivation to make to make this specific selection.
Shin et al. teach utilization of an adenovirus that comprises a herpes simplex virus thymidase kinase gene (HSVtk) gene under the regulation of a trans-splicing ribozyme targeting human telomerase reverse transcriptase (hTERT-TR) demonstrated significant antitumor activity. In addition, when this was coupled with the co-expression of another antitumor gene, namely, a gene expressing soluble PD1 (sPD1) in the form of a sPD1-Ig fusion, that this significantly increased the antitumor effect compared to just when just HSVtk was present in the adenovirus: “Regression of murine tumors was markedly enhanced when sPD1-Ig was incorporated into the adenovirus as compared with a single-module adenovirus expressing only HSVtk.” – See Abstract.
Therefore it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to further incorporate a sPD-1-Ig gene (e.g. an immune checkpoint inhibitor) into the trans-splicing ribozyme construct of Lee et al. because (a) Lee et al. suggest one or more anti-cancer genes can be expressed in said construct, (b) they do suggest sPD-1 as one potential anti-cancer/tumor suppressor genes, and (c) Shin et al. demonstrate that when both HSVtk and sPD-1-Ig genes are expressed in the transplicing ribozyme construct that this significantly enhances tumor regression. This would be motivation in and of itself for one skilled in the art. One skilled in the art would have a more than reasonable expectation of success in including a sPD-1-Ig tumor regression gene (e.g. immune checkpoint inhibitor) in the construct of Lee et al. and that it would equally have significantly better tumor regression than the construct with only HSVtk because both Shin et al. and Lee et al. utilize the same trans-splicing ribozyme and both utilize the anti-cancer gene HSVtk. The addition of sPD-1-Ig into the construct of Lee et al. would reasonably demonstrate the same expected better antitumor activity as demonstrated by the co-expression of the two in Shin et al.
Applicant’s Remarks and Examiner’s Rebuttal:
Applicant’s traverse the rejection of record for claim(s) 1-7, 11-12 and 14-20 rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 2020/0270612 – cited herein) in view of Shin et al. (Molecular Therapy, 2013 – cited on IDS 08/27/2024).
In the Remarks, pp. 8-12, Applicant’s re-emphasize what is described in the specification and that the trans-splicing ribozyme of the invention (RZ-001+) comprising a cancer therapeutic gene in combination with an immune check point inhibitor demonstrates superior results in reducing tumor size, having reduced liver toxicity, and anticancer activity as compared to a trans-splicing ribozyme that comprise only a therapeutic cancer gene and no immune check point inhibitor (alone or in combination with Atezolizumab), which can could not be predicted by the cited references.
In this respect, Applicant’s proceed to detail the differences of the claimed invention as compared to Lee, alone. It is asserted Lee does not teach or suggest two or more cancer therapeutic genes operably linked to a 3' exon of the ribozyme for enhancing anticancer efficacy. Furthermore, the "tumor suppressor gene" that Lee identifies as a possible target gene does not aim to activate the immune system, nor does Lee suggest an immune checkpoint inhibitor gene as a cancer therapeutic gene.
The Examiner acknowledges these points. However, Lee does suggest utilizing one or more cancer therapeutic genes and specifically do suggest that one of them may be a programmed death-1 (sPD-1) gene. While not specifically stated as an “immune check point inhibitor”, it is still nonetheless is exactly that. With regard to the tumor suppression gene that Lee identifies as possible cancer target genes and the assertion that the tumor suppression gene does not aim to activate the immune system, there is nothing in the claims require such a limitation. It appears Applicant’s are reading limitations from their own specification into the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Finally, Applicant’s assert that in order to solve the technical challenge of "improving anticancer therapeutic efficacy and reducing side effects through the use of an immune checkpoint inhibitor," which is neither suggested nor implied in Lee, the ribozyme of the present claims comprises an "immune checkpoint inhibitor gene" and a "cancer therapeutic gene distinguishable therefrom," neither of which is disclosed or suggested in Lee. This results in significantly superior anticancer effects and simultaneously a reduction in liver toxicity compared to Lee. This is acknowledged, however, is not convincing because Applicant’s the asserted improvement is not required in the claims and even if they were, the reasons for combining the cited references need not be identical to Applicant’s – See MPEP 2144(IV). In this regard, Applicant’s have not addressed the combined teachings of Lee and Shin, together.
Applicant’s subsequently turn to the differences of the claims versus Shin, alone. It is asserted: “Shin discloses a trans-splicing ribozyme targeting cancer-specific genes, which includes a cancer therapeutic gene in the 3' exon region. Specifically, Shin presents a single vector expressing a ribozyme (Rz) targeting the cancer-specific gene TERT, the cancer therapeutic gene HSVtK, and the immune checkpoint inhibitor sPD-1. However, in said vector, the expressions of Rz-HSVtK and sPD-1 are regulated by different promoters, whereas in the present claims both the cancer therapeutic gene and the immune checkpoint inhibitor gene are expressed under a single promoter. In other words, in Shin, the sPD-1 gene is not linked to the RZ-HSVtK gene and is regulated by the EFla promoter. Therefore, the expression of the sPD-1 gene occurs independently of intracellular TERT expression. Additionally, the EF 1a promoter is a ubiquitous promoter that induces sPD-1 expression in all cell types.”
However, again, Applicant’s are arguing features which simply are not in the claims. With the exception of claim 12, the claims do not even recite or require a promoter. And in claim 12, given the claim is open and comprising, additional promoters are permissible. In addition, the rejection is not based upon Shin alone. Rather, the rejection is based upon combination of Lee and Shin. 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).
Here, the combination of Lee, who do teach a trans-splicing ribozyme under the control of a single CMV promoter, with the teachings of Shin who teach exactly why you would want to add an immune check point inhibitor of sPD-1g into Lee because Shin noted: “Regression of murine tumors was markedly enhanced when sPD1-Ig was incorporated to the construct”. Given the Lee already suggests that one or more cancer therapeutic genes such as PD-1 can be added to their construct, these combined teachings provide the motivation and expectation of success in making the claimed combination.
For these reasons, the rejection is maintained.
Conclusion
No claim is allowed. Claims 8 and 9 are objected to and claims 1-7, 11-12 and 14-20 are rejected.
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.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656 26 March 2026