DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 5-13, 15, 16, 19, 21, 23 and 31-38 are pending. Claim 23 is withdrawn as directed to non-elected subject matter.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/29/2025 has been entered.
This application claims priority to U.S. Provisional No. 62/771,869, filed on November 27, 2018, U.S. Provisional No. 62/796,959, filed on January 25, 2019, and U.S. Provisional No. 62/893,492, filed on August 29, 2019.
Information Disclosure Statement
An IDS filed 9/29/2025 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action. An initial indicates that the reference has been considered.
Response to Amendment
Applicants’ amendment is sufficient to overcome the objections to the claims.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-13, 15, 16, 19, 21, 23 and 31-38 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method of treating a USP6 negative Ewing Sarcoma and AML in a subject the method comprising intratumoral administration and/or administration at the site of the tumor of an mRNA encoding USP6, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This rejection is updated based upon new literature (see Syed et al, 2025).
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to a method of therapy for treating cancer in which the effect of administering a nucleic acid encoding USP6 in order to increase USP6 levels.
2) Scope of the invention. The scope of the invention is extremely broad in that the cancer targeted is any. However, as set forth below, universal cancer therapy has not proven possible.
3) Number of working examples and guidance. The specification establishes the mechanism of action of USP6 on Ewing Sarcoma cells in vitro. USP6 induced IFN mediated cell death in ES cells (Figure 3). The administration of USP6 in cell culture enhanced immune cell infiltration (figure 7) and survival in J:NU mice (ultimately nude mouse models) through NK cell activation. Cell survival in models with bladder cancer, cervical cancer, head and neck cancer, lung adenocarcinoma, ovarian cancer, pancreatic cancer and AML is claimed. However, only AML showed results consistent with applicants’ principle.
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Example 1 states that USP6 expression in neoplasms is far more restricted than initially believed and is limited to tumors of mesenchymal origin including Ewing Sarcoma (bridging ¶, page 23-24). USP6 was associate with an IFN response in human tumors and sensitized Ewing sarcoma to exogenous IFN. The proposed mechanism is the following:
It appears that there are two types of Ewing Sarcoma, one with high levels of USP6 and one without and those with high levels have a higher incidence of survival (see Example 2). This was also proposed for AML (Example 3).
(page 35) USP6 can dramatically enhance tumor cell’s response to interferons (IFNs), a potent anti-tumor cytokine. USP6 can induce the production of the anti-tumor cytokines CXCL9I, CXCL10, CCLS5, and TRAIL and IFN treatment leads to the synergistic increase in expression of these chemokines.
4) State of the Art. Applicants invention is directed to use of USP6 as an anti-tumor specific molecule. The election of mRNA will be the focus of this review. Huang et al reviews this art calling it “an emerging class of therapeutic agent”. This reference is post-filing and states
Challenges related to mRNA stability and immunogenicity, as well as in vivo delivery and the ability to cross multiple biological barriers, have been largely addressed by recent progress in mRNA engineering and delivery. In this Review, we present the latest advances and innovations in the growing field of mRNA nanomedicine, in the context of ongoing clinical translation and future directions to improve clinical efficacy.
Aside from use to produce an immune response to accessible viruses, clinical success has lagged. For example “clinical success requires expression in target cells or tissues in vivo (page 2273).
Upon local or systemic administration, mRNA can be rapidly degraded by the abundant nucleases in the extracellular space, removed by macrophage phagocytosis or cleared by renal filtration24,32,33 (Fig. 1b). In the meantime, mRNA is a large, very negatively charged, single-stranded polynucleotide that is difficult to pass through negatively charged cell membranes. In fact, only 0.01% of extravasated mRNAs from blood vessels can enter target cells2 , where most of the mRNAs are trapped in endosomes and degraded thereafter (Fig. 1c). Eventually, a fraction of the internalized mRNAs escape from endosomes and reach ribosomes for therapeutic protein translation.
As to the cancers taught, most of the results are in relation to Ewing Sarcoma. The disclosure is aware and teaches the obstacles encountered in developing therapies.
[[0077]] The key etiologic agent in Ewing sarcoma is a translocation product that fuses the EWS RNA-binding protein with an Ets family transcription factor, most commonly FLI1 (Cidre-Aranaz, et al. (2015) Front. Oncol., 5:162). Sustained EWS-FLI1 activity is required for transformation, and significant efforts have been aimed at identifying its critical targets. Multiple effectors that contribute to pathogenesis have been identified, both in cultured cells in vitro and in murine models. Furthermore, therapeutics have been developed against some of these effectors, including IGF, VEGF, and EWS-FLI1 itself (Gaspar, et al. (2015) J. Clin. Oncol., 33:3036-46; Toomey, et al. (2010) Oncogene 29:4504-16). However, their clinical efficacy has been limited, underscoring the need to identify novel targets and approaches for Ewing sarcoma treatment.
mRNA delivery like other cancer therapies appears best served by IT delivery (Li et al, Discussion).
Compared with systemic delivery, local administration requires much lower doses of drugs to prime local tumor specific immunity, resulting in a systemic and long-lasting antitumor response [39]. Local delivery of cancer immunotherapies may allow for the use of combinations of multiple therapies, while diminishing systemic exposure and off-target toxicities [39,40]
5) Unpredictability of the art. The method as claimed reads on an unpredictable art as shown by the state of the art. This is complicated by the broad breath of claims. First, the generic claim of cancer is not supported by the results. The disclosure states (page 8) that “Moreover, high USP6 expression is associated with dramatically increased survival in Ewing sarcoma, as well as other highly lethal cancers, including pancreatic ductal adenocarcinoma, bladder carcinoma, cervical carcinoma, and lung adenocarcinoma. Indeed, USP6 expression is highly restricted in normal tissues. However, elevated expression of USP6 occurs in several pediatric and adult cancers, including Ewing sarcoma. Approximately 25% of Ewing sarcoma patients were found to harbor elevated USP6 expression. Strikingly, Ewing sarcoma patients with high USP6 levels experienced dramatically increased event-free and overall survival when compared to those with low expression.” The results demonstrate a proof of principle but do not demonstrate that administration of USP6 mRNA will treat any cancer.
First, the proof of principle is much more limited than that demonstrated. The disclosure teaches that USP6 turns a cold tumor into a hot one that allows immunotherapies to reach their full potential (page 9). Hence, there is a secondary molecule affecting the tumor according to the disclosure and yet the claims are not so drawn. This is reiterated in Example 1 wherein the disclosure states that USP6 “might serve as a prognostic indicator for response of Ewing sarcoma to IFN treatment” (page 21).
Secondly, the mechanism of action that is cited is not necessarily shown in all of the cancer systems. even the specification contradicts this.
It is often incorrectly cited that USP6 is widely expressed in cancer cell lines. However, this erroneous conclusion is based on an early study in which Northern probes cross-reacted with the highly related, widely expressed USP32 gene (Nakamura, et al. (1992) Oncogene 7:733-41). Later reverse transcription-quantitative PCR (RT-qPCR) of primary tumors with USP6-specific primers indicated that its expression is far more restricted: high USP6 expression appears to occur predominantly in tumors of mesenchymal origin (Oliveira, et al. (2005) Oncogene 24:3419-26).
To this end, the results are shown in in vitro cell lines and mouse models comprising nude mice that are administered cells comprising USP6 under control of doxycycline. The results are supposed to demonstrate that high expression vs low expression of USP6 (presumably due to =/- dox treatment) show differential survival rates. Other than Ewing sarcoma and AML the differences are not detectable. Then there is the consideration of ability to reach the tumors. Time has shown that mouse models do not recapitulate therapy issues of humans due to size and biodifferences (Mak et al). Applicants own publication teaches (page 1625, col1),
A reasonable concern with xenograft models is that mouse NK cells have artifactually elevated cytolytic activity against xenografted human Ewing sarcoma cells because they lack “self” MHCI to suppress effector function (25, 29). Indeed, mouse LAKs are capable of killing control RD-ES and A673 cells (Fig. 2A; Supplementary Fig. S3C, see −dox samples).
Third the action of the molecule is said to follow administering USP6 protein to the cancer, tumor and/or TME. However, the mode of administration does not allow that. The generic means of delivery recited will not lead to such a level of USP6 that would even be close to high USP6 required given the obstacles described above. The disclosure states that USP6 increased level/activity is transient which avoids potential constitutive off-target expression in non-tumor tissue (page 10). Such a situation does not avoid off-tissue effects which in this case is apoptosis. Nor does it engender confidence that enough will be expressed to effect the tumor cell death.
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. As set forth above, the method as broadly stated lacks support in the art and the disclosure. The invention recites treatment of a broad group of cancers with a broad method. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the outcome from in vitro and nude mice models, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.”
Response to Arguments
Applicants have overcome issues of delivery. Applicants argue that USP6, contrary to the rejection, is capable of treatment as a solo agent. As well, with the newly limited scope, the use of USP6 as a monotherapy appears enabled. Applicants evince this with results from cell line data in which apoptosis was induced. Henrich et al provided with the response is also cited as teaching efficacy against ES and AML and “other tumors”.
Applicants attempts to claim a method of treating all cancers that forms tumors is especially suspect given the nascent state of the art of USP6. Henrich 2025 provided by applicants, states, which is in concert with much of the comments made throughout prosecution history (page 1803, col 2, ¶1),
A key benefit of intratumoral delivery is mitigation of problems associated with systemic administration, such as off-target side effects, poor pharmacokinetics, and hepatic clearance. In the current study, we demonstrate that the immune-igniting and antitumorigenic functions of USP6 can be conveyed by intratumoral administration of USP6 mRNA encapsulated in lipid nanoparticles (LNP) to achieve potent intracellular delivery, providing proof-of-concept for its potential as a novel immunotherapeutic for Ewing sarcoma as well as multiple other cancers.
Tumor therapy is etiological specific. It is associated with tumor promoter such as breast cancer and colon cancer to name a few (see Syed et al 2025, CDD press, Figure 4 and Table 1).
Applicants argue that the in vitro cell culture results demonstrate that USP6 can treat a number of tumors. Applicants also refer to Henrich which teaches that treatment is plausible for diverse malignancies. However, the art and the rejection have established that cell culture methods cannot recapitulate the complexity of in vivo results. The cell culture and to a great extent animal models provide proof of principle. However, when confronted with results that contradict or render unpredictable the ability to perform the method in humans, they cannot provide adequate demonstration that these obstacles are overcome. Henrich 2025 recognizes this and the need to have tumor specific therapies.
We speculate that USP6 mRNA may suppress tumorigenesis in different cancer types through distinct mechanisms that vary in relative reliance on direct vs. immune-mediated means, as well as the dominant responsible immune lineages/pathways.
In the case of the instant claims, the art is clear that USP6 has tumor promoting and tumor suppressing effects and the very cancers applicants claim are affected by USP6 as tumor promoted.
Conclusion
The art does not appear to teach use of USP6 for cancer therapy.
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/MARIA MARVICH/Primary Examiner, Art Unit 1631