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 1-17 have been examined on the merits.
Objection
Claims 1 and 3 are objected to, because of their reliance on the cited Table 1 and thus, the instant claims fail to clearly define the full scope of the claimed invention.
Applicant is reminded that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. MPEP 2173.05(s).
Claims 2 and 4 are also objected to because the compound identifier “FSEN-3” is not clearly associated with a corresponding chemical structure. The name/identifier are structure are presented separately, rendering the relationship between the two ambiguous. The claims should be amended to clearly associate the compound name and identifier with its corresponding structure.
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 3-17 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 3 encompasses methods of treating a broad genus of cancers, including but not limited to lung cancer, liver cancer, glial cancer, bone cancer, connective tissue cancer, pancreatic cancer, neuroblastoma, colorectal cancer, astrocytoma, adenocarcinoma, breast cancer, brain cancer, liver cancer, kidney cancer, skin cancer, or intestinal cancer, as disclosed in claim 16. The specification (page 27, [0065]) discloses evaluation of the claimed compounds using limited number of human cancer cell lines, including models for lung, liver, breast, glial, bone, connective tissue, and skin cancer. However, the specification does not provide representative cancer models or descriptive support for several claimed cancers such as, pancreatic, neuroblastoma, colorectal, kidney, and intestinal cancer. Therefore, the disclosed cell lines are not representative of the full claimed genus. Moreover, the specification provides no data or scientific rationale demonstrating that inhibition of FSP1 in the tested cell lines is predictive of therapeutic efficacy across the untested cancers, particularly in view of the biological heterogeneity of the recited malignancies and the differing dependence of individual cancers on the FSP1/ferroptosis pathway. This is supported by Wilding (page 2382) discloses the following:
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Furthermore, the disclosed compounds also exhibit substantially different inhibitory potencies (e.g., 90.1 to 39200 nM) across the tested cell lines, and the specification does not explain how these differences correlate with therapeutic efficacy or provide guidance for determining whether the claimed methods would be effective across the full scope of the recited cancers. Therefore, the specification does not reasonably convey to a person of ordinary skill in the art (POSITA) was in possession of methods for treating the breadth of the claims. (Wilding JL, Bodmer WF. Cancer cell lines for drug discovery and development. Cancer Res. 2014 May 1;74(9):2377-84.)
Claims 6 and 15 recite “radiation, photodynamic therapy.” Although the specification (page 17, [0026]) discloses that FSP1 inhibition is “likely” to sensitize cancer cells to radiotherapy and photodynamic therapy. This disclosure is predictive and is not accompanied by representative experimental data demonstrating that the claimed FSP1 inhibitors function as radiosensitizers or photosensitizers. The specification does not identify which of the numerous compounds encompassed by Table A possess such activity, nor does the specification provides working examples of combination treatment, including the timing or sequence of administration, radiation treatment parameters (e.g., dose or fractionation), photodynamic therapy conditions, or other guidance demonstrating possession of the claimed combination methods. Therefore, a POSITA would reasonably recognize that Applicant was not in possession of the full scope of administering the claimed compounds in combination with radiation or photodynamic at the time of filing.
Claim 12 recites “a ferroptosis-resistant cancer or a GPX4-inhibitor-resistant cancer.” The specification discloses experiments using GPX4 knockout (GPX4KO) cell lines, in which the GPX4 gene has been genetically deleted, thereby creating a genetically modified cell model. The specification also demonstrates that FSP1 inhibition sensitizes cells to GPX4 inhibitors, such as RSL3 and ML162. However, the specification does not disclose or characterize any GPX4 inhibitor-resistant cancer cell models. A GPX4 knockout model is distinct from GPX4- inhibitor-resistant cancer model, as the former represents a genetic modification of the GPX4 gene whereas the latter represents a pharmaceutical drug-resistance phenotype. However, while the specification describes ferroptosis-resistant cancer cell models, however the specification does not provide representative examples, or descriptive support demonstrating possession of methods for treating GPX4-inhibitor-resistant cancers. The specification does not identify any cancer model as resistant to GPX4 inhibitors or demonstrate that the claimed FSP1 inhibitors are effective in cancers exhibiting resistant to GPX4 inhibitor therapy. Therefore, the specification does not reasonably convey to a POSITA that Applicant was in possession of the full scope of the claimed invention.
Claim 7-11 and 15, broadly recite combinations of the claimed FSP1 inhibitor with large functional genera of ferroptosis-inducing agents, including GPX4 inhibitors, system xc- inhibitors, glutathione synthesis inhibitors, endoperoxides. However, the specification provides experimental data for only a limited of species namely RSL3 and ML162 (GPX4 inhibitors) and FINO2 and dihydroartemisinin (DHA) (endoperoxides), as an example. The specification lacks experimental evidence showing combinatorial activity between FSP1 inhibitors and the claimed species, including DPI series, JKE series, FIN56, ML210, artemether, arteether, artesunate, artelininic acid, artesunate, artelinate, artemisone, 3-artesanilide, artefenomel, Altretamine, NSC144988, Withaferin, buthionine sulfoximine, cyst(e)inase, erastin, erastin2, imidazole ketone erastin, piperazine erastin, DPl2, RSL5, glutamate, sulfasalazine, or sorafenib. In other words, although the specification discusses the mechanisms of RSL3, ML162, FINO2, and DHA, however, the specification does not disclose that the remaining claimed inhibitors function similar in combination with the claimed FSP1 inhibitor. Importantly, the deficiency in the specification is further reinforced by the unpredictability nature of ferroptosis biology. For example, Stockwell (page 365-371) discloses the compounds of claim 8-11 comprise structurally and mechanistically diverse
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classes of ferroptosis-modulating agent possessing different selectivity, potency, and pharmacological property, such that multiple probes are recommended to validate biological conclusions. For instance, Stockwell (page 365, 371) discloses that sorafenib inhibit system xc- but also induces necrotic cell death at higher concentrations, possess multiple target kinase activity, and exhibits anti-necroptotic activity, requiring careful interpretation of its biological effects. Sulfasalazine have very low potency and poor metabolic stability in vivo, limiting its utility as an experimental probe, while DPI2 and RSL5 are reported only as potential XC- inhibitors whose proposed mechanism has not been directly confirmed. Moreover, the claimed GP4X inhibitors encompass multiple structurally distinct classes including chloroacetamide, chloromethyltriazine, nitroisoxazole, furoxan and steroidal lactone, many of which are described as less well characterized than RSL3 or ML162 (Stockwell, page 366-368). Additionally, Stockwell (page 371) also discloses that ferroptosis signaling is highly context-dependent and that the biological responses to ferroptosis-modulating agents varies depending on cell type, genetic background, and physiological condition. Therefore, a POSITA would not reasonably infer those experimental results obtained with RSL3, ML162, FINO2, and DHA establish that the numerous structurally and mechanistically distinct inhibitors recited in the instant claims would therefore provide the claimed therapeutic benefit when combined with the claimed FSP1 inhibitor. Therefore, a POSITA would also reasonably conclude that that Applicant was not in possession of the full scope of the claimed combination at the time of filing. (Stockwell, Brent R., and Xuejun Jiang. “The Chemistry and Biology of Ferroptosis.” Cell Chemical Biology, vol. 27, no. 4, Apr. 2020, pp. 365–75.)
Subject Matter Free of the Art of Record
The subject matter of claims 1 and 3 are free of the art of record, and all claims that directly or indirectly depend on claim 1 and 3. The closest prior art is Chemical Abstracts Registry Number (RN: 862808-07-9; RN: 1115544-48-3; RN: 1158537-83-7; RN: 1223842-51-0) “RN”. While RN discloses compounds structurally comparable to the claimed compound (e.g., Table 1), however, RN does not disclose or suggest their use as FSP1 inhibitors or for treating cancer. Particularly, RN contains no teachings that the disclosed compounds inhibit FSP1, induce ferroptosis, or possess antitumor activity. Therefore, it would not have been reasonable for a POSITA to administer the RN’s compounds for the claimed methods of inhibiting FSP1 or treating cancer. This is because the claimed compounds were obtained through a high-throughput chemical library screen using an in vitro FSP1 activity assay, which identified small-molecule inhibitors of FSP1.Claims 1-17 are not allowable until the 112 rejection and objection are overcome.
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).
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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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