DETAILED ACTION
This action is in response to Applicant’s submission dated January 8, 2024, in which Applicant amended the specification and claims 20 and 22, and canceled claim 21.
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 .
Information Disclosure Statement
The references contained in the IDS dated May 5, 2025 and January 8, 2024 are made of record.
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 non-obviousness.
Claims 1-13, 17-20, and 22-23 are rejected under 35 U.S.C. § 103 as being unpatentable over Brand, et al., Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML in view of Bradner, US 2020/0339704.
Determining the scope and contents of the prior art.
Brand, et al. discloses a bifunctional compound having an analogous structure represented by Formula I, wherein the targeting ligand binds CDK6 and the linker comprises a polyethylene glycol chain (abstract; p. 301, Figure IC; p. 302, Figure 2B).
Bradner teaches a potent degrader wherein the degron of figure 1 is attached to a target moiety via a linker (para [0608]; [0787]-[0788]; p. 80, Table 29, Compound 1-57).
Brand does not disclose the specific degron of formula I.
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand and Bradner to design a bifunctional compound of formula 1 because both Brand and Bradner disclose structurally similar degrons that can be linked to a target molecule, which can have increased selectivity to degrade the CDK6 kinase (Brand, p. 302, column 2, paragraph 1; p. 305, column 1, paragraph 1).
As to claim 2, Brand, et al. discloses a bifunctional compound of claim 1 having a structure analogous to formula Ia (p. 301, Figure IC).
Brand does not disclose the specific degron of formula Ia.
Bradner teaches a potent degrader wherein the degron of formula Ia is attached to a target moiety via a linker (para [0608]; [0787]-[0788]; p. 80, Table 29, Compound 1-57).
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand and Bradner to design a bifunctional compound of formula 1a because both Brand and Bradner disclose structurally similar degrons that can be linked to a target molecule, which can have increased selectivity to degrade the CDK6 kinase (Brand, p. 302, column 2, paragraph 1; p. 305, column 1, paragraph 1).
As to claims 3-4, Brand, et al. discloses a bifunctional compound of claim 1 wherein the linker comprises an alkylene chain interrupted by at least one oxygen (p. 301, Figure IC).
As to claim 5, Brand, et al. discloses a bifunctional compound of claim 1 wherein the linker comprises a 1-6 alkylene units (p. 301, Figure IC).
As to claim 6, Brand, et al. discloses a bifunctional compound of claim 1 wherein the linker comprises and polyethylene glycol chain (p. 301, Figure IC).
As to claim 7, Brand, et al. discloses a bifunctional compound of claim 6 wherein the linker terminates at one terminus with at least one oxygen (p. 301, Figure IC).
As to claim 8, Brand, et al. discloses a bifunctional compound of claim 1 wherein the linker comprises 3 ethylene glycol units (p. 301, Figure IC).
As to claim 9, Brand, et al. discloses a bifunctional compound of claim 1 wherein the linker is of the last structure of claim 9 (p. 301, Figure IC).
As to claims 10-11, Bradner discloses the bifunctional compound of claim 1 wherein the linker is attached to the phenyl ring in the metal or para positions (para [0787]-[0788]; “R10”).
As to claim 12, Brand, et al. discloses a bifunctional compound of claim 1, that is analogous to compound Ia-3 of claim 12 (p. 301, Figure IC).
Brand does not disclose the degron on the right side of the compound Ia-3.
Bradner teaches the degron of compound Ia-3 (p. 80, Table 29, Figure 1C), linked to the linker-target moiety of a bifunctional compound via a polyethylene glycol linker (para [0787]-[0788]; “R10”).
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand and Bradner to design a bifunctional compound of formula 1a-3 because both Brand and Bradner disclose structurally similar degrons that can be linked to a target molecule, which can have increased selectivity to degrade the CDK6 kinase (Brand, p. 302, column 2, paragraph 1; p. 305, column 1, paragraph 1).
As to claim 13, Bradner discloses a pharmaceutical composition comprising a therapeutically effective amount of bifunctional compound of claim 1 and a pharmaceutically acceptable carrier (paragraph [0310]).
As to claim 17, Brand discloses a method of treating a disease or disorder that is characterized by aberrant activity by CDK6 (abstract; p. 300, column 2, paragraph 2; p. 302, column 2, paragraph 1 “Leukemia”).
Brand does not disclose treating a disorder that is characterized by aberrant activity of Helios and the administration to a subject of a therapeutically effective amount of the bifunctional compound of claim 1. Bradner discloses a method of treating a disease or disorder that is characterized by aberrant activity of Helios (paragraph [0006]; [0076]; [0125]; “IK2F2 polypeptide is degraded by the degrader on p. 20, Table 29, Compound 1-57”; to treat leukemia (paragraph [0395]), comprising administering to a subject in need thereof a therapeutically effective amount of the bifunctional compound of claim 1 (paragraph [0006]; [0332]; [0787]; [0788]; p. 20, Table 29, Compound 1-57).
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand and Bradner to design through routine experimentation, a bifunctional compound treating a disease or disorder that is characterized by aberrant activity of CDK6 and Helios, because both Brand and Bradner disclose structurally similar degrons that can be linked to a target molecule, which can have increased selectivity to degrade the CDK6 kinase (Brand, p. 302, column 2, paragraph 1; p. 305, column 1, paragraph 1).
As to claims 18-20, Bradner discloses the method of claim 17 wherein the disease is cancer characterized by a solid tumor, wherein the cancer is selected from ovarian cancer (paragraph [0394]).
As to claims 21-22, Bradner discloses the method of claim 17 wherein the cancer is a hematological cancer that is selected from leukemia (paragraph [0395]).
As to claim 23, Brand discloses a method of reducing CDK6 in a cell in vitro comprising contacting the cell with a bifunctional compound of claim 1 (p. 303, Figure 3C, “BSJ”; p. 301, Figure 1C”).
Brand does not disclose the method of reducing Helios in a cell.
Bradner teaches a method of reducing levels of Helios (“IKZF2”) in a cell in vivo (paragraph [0006]; [0076]; [0125]; “IKZF2 polypeptide is degraded by the degrader on p. 20, Table 29, Compound 1-57”; to treat leukemia (paragraph [0395]) or in vitro (paragraph [0342]) comprising contacting the cell with a bifunctional compound of claim 1 (paragraph [0006]; [0787]-[0788]; p. 20, Table 29, Compound 1-57).
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand and Bradner to design a bifunctional compound capable of reducing the levels of CDK4 and/or CDK6, and Helios in a cell, either in vitro or in vivo, through routine experimentation, because both Brand and Bradner disclose structurally similar degrons that can be linked to a target molecule, which can have increased selectivity to degrade the CDK6 kinase (Brand, p. 302, column 2, paragraph 1; p. 305, column 1, paragraph 1).
Claims 14-16 are rejected under 35 U.S.C. § 103 as being unpatentable over Brand, et al., Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML in view of Bradner, US 2020/0339704 and in further view of WO 2017/185023.
As to claims 14-16, Bradner discloses a pharmaceutical composition comprising a therapeutically effective amount of bifunctional compound of claim 1 and a pharmaceutically acceptable carrier (paragraph [0310]).
Bradner does not disclose the dosage form as being a solid, tablet, capsule, or liquid.
WO 2017/185023 teaches a bifunctional compound of claim 1 comprising a target ligand that is a kinase inhibitor linked to a degrader (p. 2, lines 16-26) within a pharmaceutical composition with an excipient (p. 2, line 20 to p. 4, line 2; p. 45, lines 27-30) that can be the form of solid, liquid or tablet (p. 62, lines 15-31).
It would have been obvious to one of ordinary skill in the art when the invention was made to combine the teachings of Brand, Bradner, and WO 2017/185023 to design a solid, tablet, capsule, or liquid pharmaceutical composition comprising a compound of claim 1 because Brand, Bradner, and WO 2017/185023 each disclose similar bifunctional molecules as that of formula I with therapeutic utility.
In the absence of any substantiated unexpected property of the claimed bifunctional compound of formula 1a, then non-obviousness cannot be acknowledged for the claimed subject matter and subject matter referring thereto.
Conclusion
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ERICH A LEESER whose telephone number is (571) 272-9932. The Examiner can normally be reached Monday through Friday from 10-6 PST, M-F. PST.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Mr. James Alstrum-Acevedo can be reached at (571) 272-5548. The fax number for the organization where this application is assigned is 571-273-8300.
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/ERICH A LEESER/Primary Examiner, Art Unit 1622
United States Patent and Trademark Office
Tel. No.: (571) 272-9932