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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1 – 2, 5, 7, 9 – 11, 13, 18, 23, 30 – 31, 34, and 58) drawn to a compound having of Formula (I), or a pharmaceutically acceptable salt, ester, hydrate, or stereoisomer thereof: W-L-T wherein W, L, and T are defined in the reply filed on March 10th, 2026 is acknowledged. Moreover, applicant’s species election without traverse of compound 5 of structure
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and chemical name 2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione in the telephone interview on March 30th, 2026 is acknowledged.
Claims 43 – 44, 49, 51, and 53 – 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II (a method of treating or preventing a CDK-associated disease), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 10th, 2026.
Hence claims 1 – 2, 5, 7, 9 – 11, 13, 18, 23, 30 – 31, 34, and 58 are being examined on the merits herein.
Specification
The use of the term GraphPad (page 249 paragraph 00822), GraphPad Prism (page 248 paragraph 00819), and Cell Tier Glo (page 249 paragraph 00822), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 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.
Claims 1 – 2, 5, 7, 9 – 11, 13, 18, 23, 30 – 31, 34, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application US 2019/0248774 A1 to Pham et. al. (herein after Pham’774; cited on the IDS dated 10/13/2023) in view of US Patent Application Publication Number US 2015/0291562 A1 to Crew et. al. (herein after Crew’562).
Regarding claims 1 – 2, 5, 7, 9 – 11, 13, 18, 23, 30 – 31, 34, and 58, Pham’774 teach compounds that inhibit cyclin-dependent kinases (CDK) (page 1 paragraph 0002). Specifically, Pham’774 teach one embodiment wherein a compound of chemical structure (I-A)
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(page 8 paragraph 0096). More specifically, Pham’774 teach compound no. 510 of the structure
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(page 162 Table 1 row 2) wherein instant W = formula (Ia) (claim 1 and 7); a substituted carbon is C-F (claim 5); and instant Z =
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wherein instant Z2 =
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and instant Z3 =
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, that is a substituted carbonyl. Moreover, Pham’774 teach that compound no. 510 had an IC50 of 3 nM against CDK4 and 4 nM against CDK6 (claim 2); but, no inhibition against CDK1/B, CDK2/A, CDK2/E, CDK5/p25, CDK7/H, CSK9/K, FMS, nor PI3Kδ (page 406 Table 2 row 45). Additionally, Pham’774 teach that the compounds of this disclosure, which include compound 510, may be used in combination with other anti-cancer agents (claim 58) or immunotherapies (page 231 paragraph 0189).
Likewise, Pham’774 teach that the compounds of this disclosure, which include compound 510, may be administered to an individual as a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient (claim 31) (page 236 paragraph 0224). Moreover, Pham’774 teach that the compounds of this disclosure, which include compound 510, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral (claim 34) and transdermal (page 236 paragraph 0226). Furthermore, Pham’774 teach that the present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein (page 237 paragraph 0230).
However, Pham’774 fails to teach a compound wherein the L = L1-L2-L3 or linker portion
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(claims 11, 13, 18, and 23), and the T or E3-ligase binding linking group
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(claims 1, 9 – 10, and 30).
Nevertheless, Crew’562 teach bifunctional compounds which function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same (page 1 paragraph 0010). In particular, Crew’562 teach that the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein (page 1 paragraph 0010). Moreover, Crew’562 teach that an advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/ inhibition of targeted polypeptides from virtually any protein class or family (page 1 paragraph 0010).
Specifically, Crew’562 teach that the generic structure of the bifunctional compound is
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wherein PTM is a protein/polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety (claim 9) (page 2 paragraph 0014). Moreover, Crew’562 teach that PTM encompasses protein targets that are cyclin dependent kinases (CDKs) (page 19 paragraph 0125). Additionally, Crew’562 teach that the PTM, L, and CLM can be coupled directly or via one or more chemical linkers or a combination thereof (page 5 paragraph 0043). Furthermore, Crew’562 teach that the CLM can have the structure of
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(claims 9 – 10)(page 11 column 2 row 1) wherein Rn comprises 1-4 independent functional groups or atoms, and optionally, one of which is modified to be covalently joined to a PIM, a chemical linker group (L), a ULM, CLM ( or CLM') or combination thereof (page 7 paragraph 0074).
Additionally, Crew’562 teach that the linker group L is a group comprising one or more covalently connected structural units of A (e.g., -A1 . . . Aq-), wherein A1 is a group coupled to at least one of a ULM, a PIM, or a combination thereof (page 15 paragraph 0102). Furthermore, Crew’562 teach that A1 to Aq are, each independently, a bond, CRL1RL2, O and wherein RL1 = RL2 = H (page 15 paragraphs 0104). Thus given the choices available from the lists provided by Crew’562 and the relative skill of one of ordinary skill in the art, it would have been obvious to have a linker with the form PTM-CH2-CH2-O-CH2-CH2-CLM, or
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(claims 11, 13, 18, and 23) wherein instant L1 is absent and only either instant L2 or instant L3 are present and have the above linker structure. Moreover, Crew’562 teach that the bifunctional compounds of the disclosure can be formulated into pharmaceutical compositions comprising pharmaceutically acceptable carrier, additive or excipient (page 32 paragraph 0232) and can be administered by orally, topically, parenterally, intramuscularly, intravenously, sub-cutaneously, transdermally (page 32 paragraph 0232). Additionally, Crew’562 teach that various modifications or changes in light thereof will be suggested to persons skilled in the art and are included within the spirit and purview of this application and are considered within the scope of the appended claims (page 67 paragraph 0517). Moreover, Crew’562 teach that those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein (page 67 paragraph 0517). Additionally, Crew’562 teach about 35 example compounds with the PTM-L-CLM combinations that have been successfully synthesized (pages 68 – 75 Table 1) and capable of degrading their respective target proteins (pages 75 – 79 Table 1).
Therefore it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the compound no. 510 of Pham’774 in view of Crew’562, that is to chemically couple compound no. 510 to a linker and CLM to get the combined structure of
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. One of ordinary skill in the art would have been motivated to make this modification to create a compound that is selected for a protein target of interest and capable of degrading/ inhibiting the target protein. One or ordinary skill in the art would have had a reasonable expectation of success because about 35 example compounds with the PTM-L-CLM combinations that have been successfully synthesized and were shown to be capable of degrading their respective target proteins. Moreover, as taught by Crew’562 that those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention.
Conclusion
Claims 1 – 2, 5, 7, 9 – 11, 13, 18, 23, 30 – 31, 34, and 58 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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