DETAILED ACTION
Claims 1-25 are pending in the instant application.
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 .
Priority
The instant application claims priority to 371 of PCT/US2021/048372 filed 08/31/2021 which claims benefit of 63/075,758 filed 09/08/2020.
Information Disclosure Statement
The information disclosure statement (IDS) is in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement was considered by the examiner. Please see attached initialed Forms 1449.
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 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.
Claim Interpretation
Cytotoxic receptor binding small-molecule is defined as any molecule having a molecular weight of less than 1 kDa that binds to MCT-1 and results in cytotoxicity upon entering a cell ([0055]) of instant specification.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Geschwind (WO 2015/108933 A1) and Su et al. (Transport of haloacids across biological membranes, Biochimica et Biophysica Acta, 2016), further evidenced by Swaminathan et al. (Cyclodextrin-based nanosponges encapsulating camptothecin: Physicochemical characterization, stability, and cytotoxicity, European Journal of Pharmaceutics and Biopharmaceutics, 2010).
Geschwind discloses compositions comprising cyclodextrin encapsulating a selective ATP inhibitor (Abstract). The present invention is based in part on the discovery that encapsulating selective inhibitors of ATP production, such as 3-halopyruvates (3-BrPA) within cyclodextrins stabilizes the alkylating agent in vivo by protecting the halogen moiety away from aqueous and nucleophilic environments that would deactivate the compound and provides a steady release of the compound necessary to maintain a reasonable half-life of the compound in vivo (pg 3, lines 1-7). Geschwind discloses that 3-bromopyruvate is a highly potent small-molecular inhibitor of the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and is the only available anti-glycolytic drug candidate that is able to enter cancer cells selectively through the monocarboxylate transporter 1 (MCT1) (pg 45, lines 25-30). In one embodiment, at least one alpha-D-glucopyranoside unit of the cyclodextrin has at least one hydroxyl chemical group replaced with an ionizable chemical group; at least one alpha-D-glucopyranoside unit is selected from the group consisting of C2, C3, and C6 hydroxyl chemical groups. In another embodiment the at least one alpha-D-glucopyranoside unit of the cyclodextrin is selected from the group consisting of two, three, four, five, six, seven, eight, and all alpha-D-glucopyranoside unit of the cyclodextrin (pg 3). The pharmaceutical agent within the composition is 3-halopyruvate (Claim 16).
Su teaches that MCT1 is a transporter for antitumor agent 3-bromopyruvic acid. Phylogenetic analysis of haloacid transporters and other monocarboxylate transporters reveals their evolutionary relationship (Abstract). Su teaches that haloacids are halogenated derivatives of carboxylic acids with hydrogen atom(s) replaced by halogen atom(s) like fluorine, chlorine, bromine or iodine (pg 3061); 3-bromopyruvic acid (3-BrPA) and dichloroacetate (DCA) have been investigated as potential antitumor drugs (pg 3062, right col). 3-BrPA caused cell deaths in cultured hepatoma cells and completely eradicated advanced glycolytic cancers, confirming its role as antitumor agent both in vitro and vivo. Intra-arterial delivered 3-BrPA significantly reduced cancer cells in liver-implanted rabbit tumors, and systematically delivered 3-BrPA suppressed metastatic tumors arise in the lungs. DCA induced apoptosis and inhibited proliferation and tumor growth without apparent toxicity (pg 3062, right col). One of ordinary skill in the art would immediately envisage that other haloacids could have antitumor activities as taught by Su (See Fig. 1 of various haloacids).
Geschwind discloses cyclodextrin encapsulating halopyruvate. Su discloses antitumor activities of haloacids. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to create a composition comprising cyclodextrin encapsulating an antitumor agent such as a cytotoxic receptor binding small molecule. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claims 2-4, alpha-D-glucopyranoside unit of the cyclodextrin is discussed above.
Regarding claim 5, Geschwind teaches that the ionizable chemical group is same at all replaced positions (claim 6).
Regarding claim 6, Geschwind teaches that the ionizable chemical group is weakly basic functional group or a weakly acidic functional group (claim 7).
Regarding claim 7, Geschwind discloses that the functional groups are selected from amino, ethylene diamino, dimethyl ethylene diamino, dimethyl anilino, and others (claim 10).
Regarding claim 8, Geschwind discloses that the composition is a liquid or solid pharmaceutical formulation (claim 12)
Regarding claim 9, Geshwind discloses that the cyclodextrin can be chemically modified according to the characteristics of the desired therapeutic agent and parameters for efficient, high-concentration loading (pg 12, lines 21-22). One of ordinary skill in the art would routinely experiment with various cyclodextrins for this purpose.
Regarding claim 10, cytotoxic receptor binding small-molecule is discussed above.
Regarding claim 11, Geschwind discloses that the pharmaceutical compositions can be formulated for various administrations such as systemic absorption (pg 18, lines 15-20).
Regarding claim 12, Geschwind discloses that the compositions can be assembled into kids for use in treating or preventing a disease, such as cancer (pg 38, lines 5-7).
Regarding claim 13, Geschwind discloses that the composition can be used to treat a subject with cancer (Claim 21).
Regarding claims 14-15, Geschwind discloses that the composition is administered systemically, as well as intravenously, intraperitoneally, subcutaneously, and intramuscularly (claims 22-23).
Regarding claim 16, Geschwind discloses that the subject is treated with at least one additional anti-cancer therapy (claim 24).
Regarding claim 17, Geschwind discloses that 3-BrPA is a highly potent small-molecular inhibitor which is only available anti-glycolytic drug candidate that is able to enter cancer cells selectively through the monocarboxylate transporter 1 (MCT1) (pg 45, lines 25-29). One of ordinary skill in the art would immediately envisage that MCT1 would be needed to enter cancer cells.
Regarding claims 18-19, Geschwind discloses that the cancer is a solid tumor, liver cancer, pancreatic cancer, lung cancer and/or breast cancer (claims 26-27).
Regarding claim 20, one of ordinary skill in the art would routinely experiment and treat for various types of cancers including triple negative breast cancer.
Regarding claims 21-22, Geschwind discloses the subject being a human (claims 29-30).
Regarding claims 23-25, Geschwind discloses that the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans. The dosage of any supplement, or alternatively of any components therein, lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity (pg 37, lines 24-30). Furthermore, Geschwind discloses that by protecting the stability of the selective ATP production inhibitor, it is meant that the selective ATP production inhibitor/cyclodextrin complex makes the selective ATP production inhibitor molecule more stable as seen by photo stability, shelf life stability, thermal stability, stability against intramolecular cyclization, stability to acid hydrolysis, stability against general degradation, and the like, as compared to the stability of a selective ATP production inhibitor molecule that is not in a complex with cyclodextrin (pg 12, lines 15-20). One of ordinary skill in the art would be motivated to assess the stability of a composition comprising cyclodextrin by using a method well-known. And it would have been obvious to do so in this case as well. As further evidenced by Swaminathan, Swaminathan discloses cyclodextrin-based nanosponges encapsulating camptothecin (abstract). Swaminathan discloses that determination of the in vitro release kinetics, the stability and the cytotoxicity of a cyclodextrin/camptothecin formulation is routinely practiced (pg 198, left col, 4th paragraph).
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615