DETAILED ACTION
Status of the Claims
Claims 1 and 6-10 are pending in the instant application. Claims 2-5 have been canceled by Applicant with the response filed 08/28/2026. Claims 8-10 have been withdrawn based upon Restriction/Election as discussed below. Claims 1, 6 and 7 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant's election without traverse of Group I drawn to compositions of matter in the reply filed on 08/28/2026 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Claims 8-10 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/28/2026.
Priority
The instant Application is a Continuation of PCT/CN2021/138893 filed 12/16/2021.
The U.S. effective filing date has been determined to be 06/14/2024, the filing date of the instant application. Applicant's claim for a priority date of, 12/16/2021, the filing date of document PCT/CN2021/138893, is acknowledged, however no English translation of the said document has been provided such that the examiner can verify written description support therein. Accordingly, foreign priority to this document cannot be afforded at this time.
Information Disclosure Statement
The information disclosure statement submitted on 07/10/2025 was filed before the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6 and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1 is rejected as being indefinite because the claim recites “the EZH2 inhibitor is MF-438.” in line 7. However, the species MF-438 is an inhibitor of Stearoyl-coenzyme A desaturase 1 (SCD1) per the instant Specification (p. 4, lines 4-5 & 7). Appropriate clarification is required. Claims 6 and 7 both inherit the limitation of claim 1 which is considered indefinite, as discussed above, and are rejected for the same reasoning.
Claim 1 contains the trademark/trade names “GSK126” and “MF-438”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe EZH2 inhibitors and SCD1 inhibitors, respectively, and, accordingly, the identification/description is indefinite. Claims 6 and 7 both inherit the limitation of claim 1 which is considered indefinite, as discussed above, and are rejected for the same reasoning.
Claim Rejections - 35 USC § 103
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 factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over KNUTSON (US 2014/0128393 A1; published May, 2014) in view of BEN-DAVID (US 2015/0148359 A1; published May, 2015); Hirukawa et al. (“Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program,” 2018, NPG; Nature Communications, Vol. 9, No. 2547, pp. 1-15) and Zhao et al. (“Exogenous lipid promote the growth of breast cancer cells via CD36,” 2017, Oncology Reports, Vol. 38, pp. 2105-2115).
Applicants Claims
Applicant claims a pharmaceutical composition for enhancing an anti-tumor effect of an EZH2 inhibitor, comprising; an EZH2 inhibitor and an SCD1 inhibitor, wherein the SCD1 inhibitor enhances the anti tumor effect of the EZH2 inhibitor, the mass ratio of the EZH2 inhibitor to the SCD1 inhibitor is 10:10 to 10:4, the solid tumor is selected from melanoma or liver cancer, the EZH2 inhibitor is GSK-126 and the [SCD1] inhibitor is MF-438 (instant claim 1).
Claim interpretation: The claim limitations “for enhancing an anti-tumor effect of an EZH2 inhibitor” and “the solid tumor is selected from melanoma or liver cancer” are regarded as intended use limitations not limiting the claimed compositions of matter (see, e.g., MPEP §2111.02-II).
Determination of the scope
and content of the prior art (MPEP 2141.01)
KNUTSON teaches methods of treating cancer by administering an EZH2 inhibitor compound (title, abstract, see whole document), and particularly “by administering to a subject in need thereof a therapeutically effective amount of an EZH2 inhibitor, where the subject has a cancer selected from the group consisting of […] breast cancer […].” ([0004] & [0430] to [0432]). KNUTSON teaches that: “In some embodiments the EZH2 inhibitor is
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stereoisomers thereof or pharmaceutically acceptable salt or
solvate thereof.” ([0302])(instant claim 1, “the EZH2 inhibitor is GSK126”).
KNUTSON teaches “Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.” ([0432]). And teaches oral formulations: “Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose […].” ([0436], [0427])(instant claim 7). And further that: “The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.” ([0439])(instant claim 6).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of KNUTSON is that KNUTSON does not expressly teach including an SCD1 inhibitor with the EZH2 inhibitor (GSK126).
BEN-DAVID teaches selective inhibitors of undifferentiated cells (title), “as well as pharmaceutical compositions comprising a compound of any of Formulas I-VI,” (abstract, see whole document). BEN-DAVID teaches that: “According to some embodiments of the invention, the undifferentiated cells comprise undifferentiated cancer cells.” ([0065]). And that: “According to some embodiments of the invention, the composition is identified for use in treating a proliferative disease or disorder associated with proliferation of undifferentiated cells.” ([0066]). And further that: “ According to some embodiments of the invention, the proliferative disease or disorder is selected from the group consisting of a teratoma, an undifferentiated cancer, a leukemia, a brain cancer, a breast cancer, a colon cancer, an ovarian cancer, a pancreatic cancer, a prostate cancer, a melanoma, a liver cancer, a lung cancer, a head and neck cancer, a mesenchymal cancer and a multiple myeloma.” ([0067]).
BEN-DAVID teaches that: “Stearoyl-CoA desaturase (SCD) is an enzyme which catalyzes production of oleic acid by desaturation of stearic acid. Two isoforms, SCDl and SCD5, have been reported in humans.” ([0009]). And that: “Inhibition of SCDl has been reported to induce endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in some human cancer cell lines, leading to apoptosis of these cells, and has been suggested as a potential target for cancer therapy […].” ([0010]).
BEN-DAVID teaches that: “According to further embodiments of the any of the methods, uses and compositions presented herein, the compounds of the present invention can be combined with other active ingredients which are commonly used to treat a condition described herein (e.g., a proliferative disease or disorder associated with proliferation of undifferentiated cells).” ([0286]).
BEN-DAVID teaches that: According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of an SCD inhibitor and a pharmaceutically acceptable carrier.” ([0292]). And that: “Exemplary SCDl inhibitors include […] MF-438 (2-methyl-5-[6-[4-[2-(trifluoromethyl)phenoxy ]piperidin-1-yl]pyridazin-3-yl]-1, 3,4-thiadiazole ), […].” ([0294], p. 13, col. 2, chemical structure of MF-438). And that: “As used herein, the phrase "therapeutically effective amount" describes an amount of the compound being administered which will relieve to some extent one or more of the symptoms of the condition being treated.” ([0186]).
BEN-DAVID teaches that: “The pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. Administration may be done orally, […].” ([0279]). And that: “Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, caplets, capsules or tablets.” ([0281]).
Hirukawa et al. teaches targeting EZH2 in breast cancer (see whole document). Hirukawa et al. teaches that: “With respect to breast cancer, Ezh2 levels are observed to be elevated and increased expression has been associated with poor survival.” (p. 2, col. 1, 2nd paragraph, lines 1-3). And that: “Given that the behaviour of Ezh2 is context-dependent, in this study we investigated the role of Ezh2 specifically in Luminal B breast cancer. To this end, we employed a transgenic mouse model to examine the effects of Ezh2 ablation at each stage of tumorigenesis from early hyperplastic lesions to invasive metastatic disease. This work led to the identification of a Luminal B specific anti-metastatic transcriptional program centred on the master transcriptional regulator FOXC1, which is silenced in these tumours in an Ezh2-dependent manner. Notably, pharmacological inhibitors targeting Ezh2 de-repressed FOXC1 and reactivated this anti-metastatic program in both murine and human preclinical models, resulting in a dramatic reduction in both the size and number of metastatic lesions. This is significant because the vast majority of breast cancer-associated morbidity and mortality are due to distant metastasis. Thus, our finding have important implications for the treatment of Luminal B breast cancer, where a paucity of options for targeted therapy has significantly hindered progress in improving patient outcomes.” (p. 2, col. 1, 3rd paragraph).
Hirukawa et al. teaches that: “In light of our genetic studies indicating that loss of Ezh2 impairs metastasis, we wished to explore the clinical relevance of these observations further and establish whether they were directly related to the methyltransferase activity of Ezh2. Several pharmacological inhibitors developed to target PRC2 activity have already shown clinical response in early phase trials in
leukaemia. To test the hypothesis that Ezh2 is a druggable anti-metastatic target, we treated immune-competent mouse models reflective of different clinical situations with the Ezh2 methyltransferase inhibitor GSK-126.” (p. 2, col. 2, 3rd paragraph).
Hirukawa et al. teaches that: “Taken together, these data provide compelling evidence that pharmacological intervention targeting the EZH2-dependent repression of a FOXC1-driven transcriptional program can hinder the metastatic properties of human Luminal B breast cancer (Fig. 8).” (p. 9, col. 2, last paragraph). And that: “In summary, this work establishes an oncogenic function for EZH2 in the development of Luminal B breast cancer and particularly in the metastatic phase of the disease. We have further established the potential of using FOXC1 as a prognostic biomarker in specific breast cancer subtypes and identified a pharmacological means to suppress metastatic progression in a subtype of breast cancer for which there is unmet clinical need.” (p. 12, col. 1, 2nd paragraph).
Zhao et al. teaches that: “Cancer cells present sustained de novo fatty acid
(FA) synthesis with increased production of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). This change in FA metabolism is associated with overexpression of stearoyl-CoA desaturase 1 (SCD1), which catalyses the transformation of SFAs into MUFAs (e.g., oleic acid). In this study, we provide new evidence that SCD1 inhibition leads to the anti-proliferation effect of breast cancer cells through induction of apoptosis, cell cycle arrest and migration prevention. However, the antitumor effect of the SCD1 inhibitor can be reversed by exogenous oleic acid. We hypothesize that, in addition to de novo synthesis, cancer cells may uptake exogenous FAs actively. CD36, also known as FA translocase (FAT), that functions as a transmembrane protein and mediates the uptake of FAs, is observed to be highly expressed in breast cancer tissues. Furthermore, the anti-proliferation effect caused by the SCD1 inhibitor can not be reversed by exogenous oleic acid supplementation in CD36 knockdown breast cancer cells. Our study revealed that the lipid metabolism of breast cancer is regulated not only by de novo lipogenesis but also by the availability of lipids outside cancer cells. Consistent with FA synthesis, FA uptake and transport will be another important target pathway for anticancer therapy, and the FA channel protein CD36 may provide a promising therapeutic target. Lipogenesis combined with FA transport will be a new orientation for antitumor therapy.” (abstract, see whole document).
Zhao et al. teaches that: “SCD1 inhibition results in a serum dependent decrease of cell proliferation in MCF-7 cells. MF-438 is a small molecule that specifically inhibits SCD1 enzymatic activity. To determine the effects of MF-438 on proliferation, MCF-7 cells were treated with MF-438 from 100 nmol/l to 100 µmol/l and the cell viability was assessed after 48 h. MF-438 revealed a significant dose-dependent proliferation inhibition in MCF-7 cells. Fig. 1A shows concentration response curves of MCF-7 cells treated in 10 or 2% FBS conditions.” (p. 2107, col. 2, last paragraph). And that: “In summary, SCD1 may control the overall rate of lipid synthesis and then affect cell proliferation in breast cancer cells. SCD1 may be a promising molecular target for cancer therapy. Consistent with FA synthesis, FA uptake and transport may be another important target pathway for anticancer therapy. Our study suggests that there was a synergistic cytostatic effect when both pathways were blocked simultaneously. Selective inhibition of key enzymes in endogenous lipogenesis, such as SCD1, combined with an exogenous FA uptake channel protein, such as CD36, may be a potential chemotherapeutic strategy for breast cancer. Although, our investigations reveal a synergistic antitumor response in breast cancer cells to SCD1 inhibition paired with CD36 depletion, the exact mechanism of this synergistic effect is not well defined, and further studies must be conducted in some other cell lines.” (p. 2114, col. 1, last paragraph).
Regarding the claim limitation “the mass ratio of the EZH2 inhibitor to the SCD1 inhibitor is 10:10-10:4”, the prior art clearly teaches treating cancer with both the EZH2 inhibitor GSK126 and the SCD1 inhibitor MF-438 in therapeutically effective amounts, therefore it would have been prima facie obvious to optimize the combination for the same (MPEP §2144.05(II)).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a pharmaceutical formulation comprising the EZH2 inhibitor GSK126, as suggested by KNUTSON, for the treatment of breast cancer, as suggested by KNUTSON and Hirukawa et al., and further to combine formulation with the SCD1 inhibitor MF-438, as suggested by BEN-DAVID and Zhao et al. for the treatment of breast cancer.
One skilled in the art would have been motivated to combine GSK126 and MF-438 in a pharmaceutical formulation because it is generally considered to be prima facie obvious to combine compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a composition that is to be used for an identical purpose. The motivation for combining them flows from their having been used individually in the prior art, and from the being recognized in the prior art as useful for the same purpose. As shown by the recited teachings, instant claims are no more than the combination of conventional components of pharmaceutical formulations for the treatment of cancer, and particularly breast cancer. It therefore follows that the instant claims define prima facie obvious subject matter. Cf. In re Kerkhoven, 626 F.2d 848, 205 USPQ 1069 (CCPA 1980).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 1, 6 and 7 are pending and have been examined on the merits. Claims 1, 6 and 7 are rejected under 35 U.S.C. 112(b) and claims 1, 6 and 7 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
