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 .
Status of claims
Pending claims 14-25 have been examined on the merits.
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 23-24 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating non-small cell lung (NSCLC), colorectal cancer (CRC), pancreatic cancer, and bladder cancer based on xenograft studies, does not reasonably provide enablement mesothelioma, endometrial cancer, ovarian cancer, bile duct cancer, gastric, cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, and neuroendocrine tumor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP 2164.0l(a), considers the
following factors:
Breadth of the Claims
Claim 23-24 directed to a method of treating a tumor in a patient in need thereof, wherein the tumor is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, mesothelioma, endometrial cancer, ovarian cancer, bladder cancer, bile duct cancer, gastric cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, and neuroendocrine tumor.
As such, the claim encompasses a variety of cancer types and is therefore exceedingly broad in scope.
Level of Skill in Art
The level of skill in the art is a clinician or a scientist with a PhD or MD.
State of the Prior Art
The specification demonstrates treatment for non-small cell lung cancer, colorectal cancer, pancreatic cancer, and bladder cancer with E7386+sotorasib; non-small cell lung cancer with E5786±adagrasib. However, KRAS inhibitors in one tumor type or experimental model does not establish that the same activity will extend across the full scope of cancers including multiple mesothelioma, endometrial cancer, ovarian cancer, bile duct cancer, gastric, cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, and neuroendocrine tumor. For example, Hong (page 1207) discloses phase 1 study of sotorasib in KRAS G12-C-mutated advanced solid tumors including NSCLC OR CRC. Hong (page 1207) discloses sotorasib produced a confirmed objective response (complete or partial response) of 32.2% in patients with NSCLC, however, only 7.1% in patients with colorectal cancer. Furthermore, limited responses were also observed in pancreatic, emdometrial, and appendical cancers, (page 1207 and 1215). Hong (page 1215) further added “the treatment outcome in patients with NSCLC or colorectal cancer similar to patients in our study is generally poor.”
In addition, Palma (page 7) discloses activity of a KRAS G12C inhibitor does not necessarily establish durable therapeutic activity, as acquired resistance mechanisms have been observed following treatment, particularly in patients with NSCLC and seven with CRC. This indicates that activity of KRAS inhibitors cannot be extrapolated across different types of tumors. As Palma (5) demonstrated that sostorasib and adagrasib were consistently evaluated in phase studies against NSCLC and CRC, and not against a broad genus of cancers as disclosed in the instant claims. Therefore, without supporting evidence, it would be improper to establish that clinical evidence from one tumor type can also be extended to other cancers.
Regarding the cell culture data, they are insufficient to serve as a model for treating tumor. For example, as evidence by Biointron (page 3-4) that in vitro testing is considered early-stage research that may show promising preclinical benefits; however, such data do not constitute proof that the therapy would be effective in vivo. Therefore, merely demonstrating inhibition in cell cultured does not demonstrate possession of a complete therapeutic method of treatment. This is because in vitro models do not always translate directly to in vivo outcome. Not to mention, the specification does not explain, in the absence of xenografts model, why should a POSITA expect the claimed combination in cell culture would be effective in treating gastric cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, mesothelioma, endometrial cancer, ovarian cancer, bladder cancer, bile duct cancer, and neuroendocrine. (see Hong et al., KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med 2020;383:1207-1217.
Palma, G., Khurshid, F., Lu, K. et al. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. npj Precis. Onc. 5, 98 (2021).
Biointron: https://www.biointron.com/blog/in-vivo-vs-in-vitro-understanding-the-differences.html (Retrieved, 09/08/2026)
Predictability in the Art
Palma (abstract) and Hong (page 1207) teach that both sotorasib and adagrasib are promising KRAS G12C inhibitors, particularly against KRAS G12C- mutated NSCLC. Hong (page 1207 and 1215) discloses sotorasib has limited effect in other tumor types compared to NSCLC, which to suggest a lack of prediction that KRAS G12 inhibitors will exhibit the same level of therapeutic efficacy across different types of cancer. This is also supported by Palma (page 4-5, Table 1) disclosing that the clinical studies were discontinued once compounds JNJ-74699157 and LY3499446 entered phase I trials. Although Palma does not reveal the reason for discontinuing the studies, Synapse (page 2) discloses “Early molecules from Eli Lilly LY3499446 and Johnson & Johnson JNJ-74699157 had their clinical trials terminated due to toxicity.” Therefore, this suggests that promising preclinical and in vitro data cannot, by themselves, establish or predict either clinical efficacy or safety profile. Therefore, each tumor type must be evaluated separately in their respective models. In fact, the specification itself provides evidence in only four xenografts’ models: non-small cell lung cancer, colorectal cancer, pancreatic cancer, and bladder cancer with E7386+sotorasib; whereas E5786±adagrasib xenograft is limited only to the NCI-H358 NSCLC model. The disclosure does not establish that E7386 combination effect transfer from sotorasib to adagrasib across cancer types. Therefore, as supported by Palma and Hong, a positive result in selected sotorasib xenografts does not provide a reasonable expectation that the claimed combinations will be effective to treat the full scope of cancer genus.
(see Palma, G., Khurshid, F., Lu, K. et al. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. npj Precis. Onc. 5, 98 (2021).
Synapse: https://synapse.patsnap.com/blog/discussing-astrazeneca's-brain-penetrating-kras-inhibitor; retrieved 9/30/2026).
Working Examples
Example 1 begins on page 35 ([0072]). The study evaluates whether the presence of E7386 enhances the antiproliferative effect of sotorasib in NSCLC cancer cell line. The cells were cultured in RPMI-1640, seeded into 96-well plates, and allowed to grow for 24 hrs. The cells were then treated for 72 hours with sotorasib±E7386. Then, the cells were fixed and stained before measuring GI50. Conclusion: sotorasib+E7386 treatments significantly increased growth inhibition compared with sotorasib alone. See Table 1 and Figure 1.
Experiment 2 ([0076]) assesses antitumor effect of E7386 in the presence or absence sotorasib in an NSCLC xenograft. NCI-H353 cells were mixed with Matrigel /HBSS at 50:50 and implanted subcutaneously into nude mice. Seven days after implantation, mice received orally E7386 at 25 mg/kg alone or E7386+sostorasib, once daily for 14 days. Tumor volume was calculated, and results were reported as mean±SEM. Conclusion: E7386+sotorasib significantly suppressed tumor growth compared to control. See Table 2 and Figure 2.
Example 3 ([0082]) evaluates treatment of E7386±KRAS inhibitors on cell-growth inhibition. Human cancer cell lines were seeded into 96 well plates and cultured for one day. The cells were then treated for five days with KRAS inhibitor ± E7386. After five days, the cells were treated with CellTiter-Glo 3D reagent before luminescence was measured and reposted as GI50 values. Conclusion: greater growth inhibition was observed with E7386±KRAS inhibitor combination compared to KRAS inhibitor alone. See Table 3; Figure 3A-3F; and Table 4
Example 4 ([0087]) assesses the effect of E7386±KRAS inhibitor at suppressing tumor in xenograft models (KRAS G12C Mutation-Positive Human Colorectal Cancer Cell Line SW837, KRAS G12C Mutation-Positive Human Pancreatic Cancer Cell Line MIA PaCa-2, KRAS G12C Mutation-Positive Human Bladder Cancer Cell Line UM-UC-3, and KRAS G12C mutation12C mutation-Positive Human Non-Small Cell Lung NCI-H358. The cell lines were mixed with Matrigel /HBSS at 50:50 and implanted subcutaneously into six-week-old nude mice. The mice were administered with E7386±KRAS inhibitor until the day before the final day of the test period. Tumor diameters were measured by caliper twice weekly, and tumor volume were measured and reported as mean±SEM. Conclusion: administration of E7386 and sotorasib exhibited significant antitumor effect compared with each drug alone in the xenograft models. See Table 5, Table 6, Figure 4A to 4D.
Direction and Guidance
Given the unpredictability of the art and the lack of working examples, the specification does not provide sufficient guidance to enable a POSITA to make and use the full scope of claimed invention.
Quantity of Experimentation
Considering the lack of working examples, the unpredictability nature of the art, and the breadth of the claims, the amount of experimentation required to determine whether the claimed compounds are clinically effective across the claimed cancer indications, including mesothelioma, endometrial cancer, ovarian cancer, bile duct cancer, gastric, cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, and neuroendocrine tumor; would be significantly great. This amount of experimentation would require starting at proof-of-concept including preclinical models and meaningful patient endpoint for each type of cancer, dose schedule, route administration, safety, tolerability and pharmacokinetics. This amounts to invention, not development; and therefore, represents undue experimentation.
Thus, while being enabling to treat NSCLC, CRC, pancreatic cancer, and bladder cancer, however, the instant specification does not reasonably provide enablement for a method for the treatment of mesothelioma, endometrial cancer, ovarian cancer, bile duct cancer, gastric, cancer, breast cancer, small cell lung cancer, testis cancer, small intestine cancer, appendix cancer, and neuroendocrine tumor.
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 non-obviousness.
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 14-25 are rejected under 35 U.S.C. 103 as being unpatentable over Ozawa et al. WO 2021/086909 (IDS, 11/14/2024), Jeong et al., NPJ Precis Oncol. 2018 Feb 20;2(1):5 (IDS, 11/14/2024), Mirati: “https://ir.zailaboratory.com/news-releases/news-release-details/mirati-therapeutics-presents-positive-clinical-data-0/” Retrieved, 09/08/2026), and Amodio et. al.,” Cancer Discovery, vol. 10, no. 8, Aug. 2020, pp. 1129–39.
Regarding claims 14-25, Ozawa (page 4-5) teaches a method of treating cancer or tumor by administering to the individual a combination therapy comprises PD-1 antagonist and E7386 or a pharmaceutically acceptable salt thereof. Ozawa (page 4-5) discloses cancer may be a solid tumor, such as a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, a bladder cancer, a breast cancer, a non-small cell lung cancer (NSCLC), an endometrial cancer. Ozawa (page 1 and 4) discloses E7386, Wnt/β-catenin signaling pathway inhibitor, to be “(6S,9aS)-N-benzyl-8-({ 6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl }methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide” or a pharmaceutically acceptable salt thereof, comparable to the claimed compound:
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Ozawa (page 29) teaches PD-1 antagonist and E7386 in a combination therapy disclosed herein may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order. Ozawa, however, does not explicitly teach a combined therapy comprising E7386 and RAS inhibitor including sotorasib or adagrasib.
Jeong (page 1) teaches that both Wnt/β-catenin signaling and RAS pathway are involved in cancer/tumorigenesis, particularly notably colorectal cancer (CRC). Jeong (page 1 and 7-8) also discloses inhibition of both β-catenin and RAS, especially by degradation, could be a new ideal strategy for development of anti-cancer drugs for CRC. Therefore, a person of ordinary skill in the art (POSITA) would have been motivated to combine a known Wnt/β-catenin inhibitor such as E7386 with a RAS inhibitor, because Jeong’s teachings explicitly proposed simultaneous inhibition of β-catenin and RAS as a new ideal of anticancer strategy. Moreover, Mirati (page 1-2) further teaches that adagrasib, a selective KRAS G12C inhibitor, was being evaluated in combination with other anticancer therapies in patients with KRA G12C-mutated colorectal cancer. Mitra (page 1-2) discloses that adagrasib was well tolerated and showed meaningful clinical effectiveness in treating patients with KRAS G12C-mutated colorectal cancer. Mirati (page 1-2) also demonstrates that adagrasib monotherapy was effective, but combination with cetuximab produced even greater response and disease control. Furthermore, Amodio (page 1129 and 1134-1134) discloses patient-derived xenografts (PDX) from 2 patients with KRAS G12C-mutant colorectal cancer treated with a combination of AMG510 (sotorasib) and cetuximab was highly effective at shrinking tumors in the treat animals.
Therefore, a POSITA seeking to treat a tumor involving Wnt/β-catenin signaling and RAS/KRAS signaling would have been motivated to combine to modify Ozawa’s teachings in view of Jeong, Mirati and Amodio to combine a known Wnt/β-catenin inhibitor, E7386, with a known KRAS inhibitor such as adagrasib or sotorasib to arrive at the claimed invention. In addition, the combined therapy would have been predictable application of know agents already known in the art to be effective against tumorigenesis and apply such combination either simultaneously or at different time.
Conclusion
No claims are allowed.
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).
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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.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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