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 .
Election/Restrictions
Applicant’s election of Group I, (drawn to a cancer treatment method for treating a subject), in the reply filed on 11/12/2024 is acknowledged.
Claims 1-3, 6-9 and 21-30 are pending. Claims 10-20 (Group II and III) were cancelled and claims 21-30 are the newly added claims. Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). The restriction requirement is still deemed proper and is made Final.
Pending claims 1-3, 6-9 and 21-30 have been examined on the merits.
Claim Rejections - 35 USC § 112 (Enablement)
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 1-3, 6-9 and 21-30 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1, 21, and 27 teaches “wherein the therapeutically-effective amount yields a synergistic effect” (emphasis added). The specification fails to teach a person of ordinary skill in the art (POSITA) how to achieve such results across the full scope of the instant claim without undue experimentation. For example, the claim broadly encompasses a large genus of ‘a heteroarotinoid’ and ‘a CD4K/6 inhibitor’ at ‘a therapeutically effective dose’ would produce synergy. Despite this claim, the specification (Figures 50-57) discloses inconsistent dosing across treatment groups and also demonstrates variable outcomes, including additive and antagonistic effects. These, inconsistencies clearly do not reliably establish synergy at all concentration tested or treatment groups (Figure 50-51; Figures 53-57). The disclosure also fails to provide generalized guidance, dose-selection principles, or structure-activity relationship that would allow a POSITA to predict which combination or doses ranges with the claimed genus would yield synergy rather than mere additivity or antagonism. For example, specification (page 9, [0062], Figure 49-58) discloses (60mg/kg SHetA2: 100m/kg palbociclib, ratio 3:5) to demonstrate the combined treatment is effective at reducing tumor size in SiHa xenografts. However, the treatment does not match the doses or agents in the isobologram analysis, which clearly undermines comparability and the claimed of finding a true synergy.
Regarding ratios claims 9 and 30, the specification (page 35, [0114]; emphasis added) discloses:
PNG
media_image1.png
250
744
media_image1.png
Greyscale
Therefore, a POSITA would consider such statement to be speculative, open-ended ratios covering essentially the entire conceivable dose ratio, with no expectation of success. Given synergy is highly sensitive to dose ratio and concentration, thus a POSITA would conclude that the specification does not determine the exact operative boundaries of synergy as claimed. Therefore, the disclosure does not provide reliable guidance as to how to achieve synergism as claimed.
Regarding a cancer treatment, the specification fails to enable treatment across this vast and heterogenous genus diseases. The specification discloses, at most, limited experimental data in select cell lines and provides no guidance demonstrating that the claimed heteroarotinoid and CD4K/6 combinations are effective in treating the full range of cancers encompassed by the claim. Nor does the specification teach how to identify which cancers would respond to the claimed treatment without undue experimentation. Given the unpredictability of oncology therapy, efficacy in a limited subset of cancer models clearly does not enable treatment of all cancers.
Claim 2 and 28, Figure 49 (specification (page 9, [0062]) shows data for SHetA2 and palbiciclib combination, but the tumor size curves substantially overlap with the monotherapy groups, indicating no reliable evidence of enhanced benefit. Given the inconsistency data where only SHetA2 and abemaciclib, and ShetA2 and ON123300 combination demonstrate consistent effects, thus, these isolated results do not establish that ShetA2 with CDK4/6, or heteroarotinoids with CDK4/6 inhibitors are representative combinations of the claimed invention.
Consequently, as indicated above, the lack of enablement of the claimed subject matter at the time of filing, suggest that Applicant did not possess supporting data to the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
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.
Claims 1-3, 6-9 and 21-30 are rejected under 35 U.S.C. 103 as being unpatentable over Myers et al., Invest New Drugs. 2009 Aug;27(4):304-18, in view of Zhao et al., US 20180243306, Liu et al. Anti-Cancer Drugs - Nature, Synthesis and Cell, InTech, 7 Dec. 2016. Bellutti et al., Cancer Discov. 2018 Jul;8(7):884-897.
Regarding claims 1-3, 6-8, 21-29 Myers (abstract; page 307-308) teaches a method of treating cancer using an effective amount of SHetA2 with dose-responsive apoptosis in Caki-1 renal cancer Xenografts (20, 40 and 60 mg/kg/day) and ovarian cancer cell line (2, 4, 6, 8 and 10 μM), as an example. Myers (abstract, page 308 and 313-314) teaches that SHetA2 treatment decreased cell proliferation and particularly, treated Caki-1 renal cancer Xenografts resulted to about 40% reduction in tumor size, which was associated with decreased tumor vascularization.
This is supported by Liu (page 71; page 86) teaches SHetA2 exhibited no evidence of toxicity in animal models including dogs, and SHetA2 is now in Phase-0 clinical trial for ovarian cancer chemoprevention. Liu (page 86, Table 5) teaches SHetA2’s pharmacokinetic studies and explains that the studies reveal SHetA2’s oral bioavailability at 20 mg/kg and 60 mg/kg. Liu (page 68) also teaches SHetA2 disrupts mortalin-p53 binding, leading to apoptosis in cancer cells. As evidence by the specification (page 2- 3) discloses that SHetA2 disrupts mortalin/p53 complexes in ovarian cancer cells.
The combined teachings of Myers and Liu, however, do not teach synergistic effect in combination with CDK4/L6 compound.
Zhao (page 3, [0048]; page 12 and 13) teaches combining CDK4/6 inhibitor, e.g., ribociclib, palbociclib and abemaciclib, with another anticancer agent, such as HSP90 inhibitor or ganetespib, would lead to a synergistic therapeutic effect. For example, Zhao (page 12, [0152]-[0153]) teaches palbociclib combined with ganetespib synergistically suppresses cancer cell viability and tumor growth compared to either agent alone. Zhao (page 10, [0123]-[0125]) also teaches the dose of CDK4/6 can be about 0.1 mg/kg to about 100 mg/kg by weight. Therefore, it would have been obvious to a POSITA to infer from Zhao’s teachings that combining a CDK4/6 inhibitor with a second therapeutic agent, such as SHetA2, would produce a synergistic anti-tumor effect, leading to a decreased in tumor size or growth. This inference is further supported by Liu’s teachings, as mentioned above, SHetA2 disrupts p53 pathway via mortalin, while it is also known in the art that CDK6 antagonizes p53-induced responses during tumorigenesis, as supported by Bellutti (page 1-5 and 9).
Therefore, it would also have been obvious to a POSITA to combine the teachings of Myers, Liu, Zhao, and Bellutti to explore a dual-targeting strategy, such as pairing a heteroarotinoid (SHetA2) with a CDK4/6 (palbociclib) inhibitor, with a reasonable expectation of success to arrive at the claimed invention. This is because the combined references teach that these compounds are effective against cancer and can affect a shared p53 pathway, known for its major in tumorigenesis, which would further motivate a POSITA to expect enhanced or synergistic therapeutic activity when combined these compounds together.
In addition, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” See MPEP 2144.06.
Furthermore, it would have been obvious to a POSITA, prior to the effective filing date of the instantly claimed invention, to modify the teachings Myers and Zhao, in view of Liu and Bellutti to administer a combination of a CDK4/6 and SHetA2 conjointly, either sequentially or simultaneously, to enhance their therapeutic efficacy to treat cancer, and arrive at the claimed invention. Also, a POSITA would have been motivated to so because optimization of two compounds either sequentially or simultaneously would improve dose tolerance, treatment adherence, side effects, delaying drug resistance, and would achieve therapeutic efficacy.
Regarding claim 9 and 30, the combined teachings of Myers, Liu, Zhao, and Bellutti do not explicitly teach the recited ratio in the instant claim.
However, the cited prior art teaches the combined use of SHetA2 and a CDK4/6 inhibitor and also teaches dose ranges that overlap with those cited in the instant claim. While, the combined prior art does not explicitly disclose the specific ratio range claimed, a POSITA would understand that the compounds and their dosing ranges are well known in the art. Therefore, through routine optimization, a POSITA would have determined a ratio that minimizes toxicity and improves the compounds therapeutic benefit. Moreover, a POSITA would have been motivated to explore various ratios to achieve optimal therapeutic effects and arrive at the claimed invention.
In addition, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP 2144.05.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622