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 .
Applicant’s reply dated 09/19/2025 has been received. Claims 1-3 and 7-17 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.
The rejection of claims 1-3 and 7-17 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of the amendment to claim 1, limiting the inhibitors to specific shRNA sequences.
Claims 1-3 and 7-17 remain 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 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 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.
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, 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 argues that two different cancer cell lines led to more than 98% tumor cell growth inhibition in a xenograft mouse model. Applicant argues that the tumors grow much smaller and it is reasonable that a skilled artisan could administer the shRNA to an individual with tumors and determine the resultant size of the tumors. Applicant also asserts that it would not be undue burden to identify the therapy parameters for administration and extrapolate that to humans.
While there is no functional effect recited in the claims, the term “treating cancer” in the preamble is given patentable weight and thus, the vast array of potential delivery systems and inhibitors encompassed would need to capable of treating cancer. The Specification has only shown delivery of shRNAs to cancer cells ex vivo. Applicant fails to address the art that supports the state of the art with regard to delivery and treatment of cancer in vivo. 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. Applicant merely argues that it wouldn’t require undue experimentation to determine how to administer the shRNA. 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. 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. The instant invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that, "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may be workable." The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement." (See Genentech inc v. Novo NordiskA/S 42 USPQ2d 1001, at 1005). The claimed methods of treatment constitute such a "germ of an idea."
Conclusion
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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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632