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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/01/2026 has been entered.
Claims 18-19 are added. Claims 1,7-16, 18 amd 19 are pending and under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—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 or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 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 and 7-16 remain rejected and newly added claims 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention relates to treatment and prevention of cancer by administering agents that interfere with a protein complex that has a role in telomere lengthening. The claims are drawn to a method of treating or preventing cancer comprising administering one or more agents that inhibit ZSCAN4 and/or MRE11. The preamble is given weight and interpreted to read into the claims that a measurable reduction in the presence of cancerous cells.
The specification (Example 1) and Meltzer (2006. ZSCAN4: A Novel Regulator of Telomere Length in Cancer. Doctoral dissertation, University of Maryland. The UMB Digital Archive) supports an association of ZSCAN4 with cancer via telomerase extension. ZSCAN4 is positively associated with telomere elongation. Example 1 of the Specification supports that ZSCAN4 can lead to telomere extension in the absence of telomerase using telomerase-independent alternatives to telomere extension. Para 131 of the specification teaches coimmunoprecipitation experiments that show ZSCAN4 associates with MRE11 and RAD50. ZSCAN4 knockdown was also associated with a reduction in RAD50 and MRE11.As well, blocking MRE11 activity reduces ZSCAN4-mediated telomer elongation. ZSCAN4 depletion was shown to lead to telomere shortening and cell death. The specification shows that ZSCAN4 knockdown in cancer cells injected into mice have a reduced capacity for tumor formation.
Neither the Specification nor Meltzer teaches inhibition of ZSCAN4 or MRE11 to treat or prevent cancer. The most relevant experiment shows cells administered shRNA to knock down ZSCAN4 can be transplanted into mice and show a reduction in tumor formation compared to control cells not administered shRNA targeting ZSCAN4. At most, the Specification and Meltzer support a link between ZSCAN4 and cancer as there is no guidance with regard to how to treat or prevent cancer. The only relevant experiment that relates to cancer prevention is the knockdown of ZSCAN4 in cancer cells ex vivo that are exogenously introduced into mice and it is found that fewer tumors form. This fails to support treatment of an existing cancer in vivo and, because the experiment uses a cancerous cell line ex vivo it fails to support prevention of cancer in an individual. It merely supports that the cancerous cell fails to form tumors. While this points to ZSCAN4 as a potential therapeutic target, it fails to amount to treating or preventing cancer in an individual.
The Specification is silent with regard to how the skilled artisan would target and deliver shRNA to cancer cells. Because the Specification and Meltzer show that ZSCAN4 shRNA leads to cell death, specific targeting and dosing represent an undue amount of experimentation that would be required to carry out effective treatment. Zhong (Signal Transduction and Targeted Therapy (2021) 6:201, 48 pages) teaches, “The biggest characteristic of chemotherapy is the inability to distinguish between cancer cells and normal cells, resulting in significant toxicity and side effects.” Zhong teaches that there has been much progress with regard to targeting small molecule chemotherapeutics to cancer cells; however, doing so present other challenges such as low response rate and drug resistance. Zhong teaches that targeted anti-cancer drugs are only effective in a limited number of patients (see Discussion). Cimino-Reale (2016, Current Pharmaceutical Design, 22:6612-6624) teaches, in the case of G-quadruplex ligands that also target preventing telomere elongation in cancerous cells, that none of the many developed small molecule compounds has become a candidate for clinical development due to a lack of suitable pharmacological properties or occurrence of worrisome side-effects when tested in animals. The Specification also fails to teach the requisite effect on any type of cancer cell. Experimentation is only carried out using a transformed cancer cell line.
Charbe (Acta Pharmaceutica Sinica B 2020;10(11):2075e2109) teaches that RNAs have a high negative charge, can be destroyed by nucleases, are rapidly cleared by the kidney and are inefficiently delivered to cancer cells (see section 4). Charbe states,
The therapeutic success of siRNAs in cancer not only depends on its delivery to the tumor site, but for the highest clinical benefit, it must be administered systemically or orally. For systemic delivery of the siRNA, the foremost hurdle clinical scientists facing are: 1) getting siRNA delivered to the specific gene site without affecting the healthy cells, 2) maintaining the optimum level of siRNA at the site of action, 3) enhancing its efficiency by increasing cellular uptake, and 4) monitor efficiencies. One of the approaches to overcome these challenges is the development of novel delivery systems. (page 2082)
Charbe discusses some delivery systems that are under investigation for delivering small RNAs to cells in vivo. These include use of liposomes as delivery vectors, chemical modification of the RNA to enhance stability, positively charged polymers, micelles. Charbe teaches that due to off-site targeting, siRNA must be administered in low dose, which prevents its optimum use. And, an additional, critical non-intended side effect is innate immune system activation because of the immune motif in siRNA sequences (page 2099).
Wong (Molecular Therapy Vol. 31 No 11 November 2023, 3127-3145) discusses 5 years post-filing, the difficulties associated with viral delivery of small interfering RNAs (shRNAs are a type of small interfering RNA). Wong teaches one of the largest obstacles to siRNA in clinical application is the effective in vivo delivery for potent gene knockdown. Wong states, “…a competent delivery strategy should encompass the following qualities: (1) the ability to safeguard the RNAi effector in extracellular space; (2) the ability to seamlessly penetrate the cellular membrane; and (3) the ability to release the RNAi effector into the cytoplasm when appropriate” (page 3128, left col). Wong teaches that despite recent successes with use of viral vectors for in vivo delivery, the in vivo application of retroviral-based RNAi delivery so far has been largely limited to local administration (i.e., treatment of neurological disease) or ex vivo approaches (i.e., HSC programming) owing to safety and efficacy limitations associated with systemic delivery (page 3131, right column). Wong teaches that lentiviruses don’t have any natural tumor tropisms, integrating viruses can offer long-term expression at the risk oof oncogenesis and non-integrating viruses, such as AdV, have a limitation due to host immune response that results in lowered expression (page 3132). AAV vectors are reported to have shown pre-clinical promise for delivery of RNAi therapies but notably, Wong states,
One of the main challenges with AAV-based cancer gene therapy is improving the AAV-specific transduction of cancer cells. Efficient targeting of cells and tissues beyond the liver remains a challenge for both AdV- and AAV-based RNAi delivery. Systemic administration of AdV and AAV vectors often results in liver retention, thus representing a key barrier when other organs are the intended targets. (page 3133)
Therefore, in light of the guidance in the specification regarding the effect of ZSCAN4 inhibition on all cell types, and the lack of working examples regarding treatment of cancer in vivo, as well as the state of the art with regard to the effectiveness of targeted chemotherapeutics, and the complexities of in vivo RNA delivery, it would require undue experimentation for the skilled artisan to carry out the invention as claimed.
Applicant’s remarks have been fully considered but are not found persuasive. Applicant asserts that it would not be undue burden to design shRNA expression constructs, package them into viral vectors, assess their knockdown efficiency and validate antitumor effects. In response, the claims do not recite that the shRNA is packaged in a viral vector. However, viral delivery of small interfering RNAs such as shRNAs was unpredictable as supported by Wong (above). While some experimentation can be needed, the art supported unpredictabilities with regard to RNA delivery in vivo renders the experimentation to be other than routine and amounts to being undue. The guidance in the Specification supports delivery of RNA to cancer cells in vitro, then transplant of those cells into an animal for assessment of tumor development. Delivery of an shRNA using a viral vector would require use of a gene promoter that expresses an appropriate level of shRNA in appropriate cells. This is not a consideration in inv itro or ex vivo delivery of shRNA to cells, directly.
Applicant has provided the Zalzman Declaration, dated 04/01/2026. THe declaration supports the presence of ZSCAN4 in a variety of cancers and that it has a role in cancer cell proliferation and survival. Inhibition of ZSCAN4 shRNA sequences result in a progressive loss of proliferative capacity and cellular senescence. The declaration provides a mechanistic explanation of how SCAN4 works at the telomeres and again supports that ZSCAN4 dep[letion decreases tumor survival. Figure 6 of the decalartion suppression of tumor growth in cells having reduced ZSCAN4 expression. In response, this fails to address the issue at hand. THe cells with suppressed ZSCAN4 are cancer cells from an in vitro cell line that were delivered shRNA the reduces ZSCAN4 protein in the cells. THe cells are then grafted into a mouse. This does not address the issue of how to deliver the shRNA in vivo such that it is either delivered or expressed at an effective level in the appropriate cells.
Applicant again notes that reduxing ZSCAN4 activity using the disclosed inhibitory agents is sufficient to suppress tumor cell growth and viability in a variety of cancer cells and that the claims are limited to cancer types where ZSCAN4 is upregulated. This, again, is not persuasive as the guidance provided fails to address the art-accepted complexities in small interfering RNA delivery in vivo.
As previously set forth, support for inhibition of ZSCAN4 correlating to tumor inhibition is at most an ex vivo model where tumor cells are treated with ZSCAN4 shRNA to inhibit ZSCAN4 protein production and the cells are observed to have shorter telomeres, and as a result, lesser tumor formation when implanted into mice. This fails to correlate to in vivo treatment of cancer where the cancer cells are in vivo to a subject. For experimentation to not be undue, the skilled artisan would have to be able to envision the parameters that could lead to treatment of cancer with a reasonable expectation of success. These experiments do not correlate to in vivo treatment of cancer with any level of understanding of delivery and dosage and whether it would be successful given, at the very least, the teachings of Charbe and Wong. Applicant has not addressed the art-accepted need to target delivery to cancer cells and prevent delivery to non-cancer cells in a subject. The extensive and varied list of generic delivery systems in previously submitted Exhibit 2 do not address these concerns. Furthermore, less growth of transplanted, transformed tumor cells fails to support that even a targeted knockdown of ZSCAN4 in cancer cells in vivo, would result in a treatment effect of in vivo cancer. The specification, and the post-filing art, have not approached the art-accepted difficulties of formulations and dosages to treat cancers.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632