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 .
Current Status of 18/569,519
This Office Action is responsive to the amended claims and Applicant remarks of 05/13/2026. Claims 54-83 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/EP2022/066504, filed 06/16/2022, which claims priority to GB patent application No. 2108572.5, filed 06/16/2021.
Response to Arguments
35 U.S.C. § 112(a)
Claim 82 has been amended to recite that the disorder for treatment is cancer. This amendment renders the previous rejection moot. The rejection is withdrawn.
35 U.S.C. § 103
Applicants allege that Bondke does not teach PPDA-001 as a CDK12 inhibitor. Applicants emphasize that the reference is directed to the development of CDK7 inhibitors. Applicants allege that CDK12 appears in a “laundry list” recitation of a broad CDK family and that there is no data that links PPDA-001 to CDK12 inhibition. Applicants further argue that the reference is focused on CDK7 inhibitors. Applicants point out that the inhibitory assays performed with PPDA-001 did not include CDK12. Applicants then contend that the artisan would not view PPDA-001 as a selective CDK12 inhibitor.
These arguments are not persuasive. The reference expressly teaches PPDA compounds, including PPDA-001, as CDK inhibitors and expressly identifies CDK12 among the CDKs whose function may be inhibited by the disclosed PPDA compounds. The absence of CDK12 specific assays does not negate the reference’s teaching that CDK12 inhibition is among the contemplated CDK-inhibitory uses of the disclosed compounds.
Applicants allege that Slabicki teaches that the phenyl-pyridyl moiety is only one component of a multiple component interface that forms the CDK12-CR8-DDB1 interface. Applicants cite the screening of other moieties of Figure 3 to support their position that the desired CDK12-DDB1 glue activity and subsequent degradation of cyclin K is only present in a very specific CR8-like configuration. Applicants allege that these characteristics therefore represent an unpredictable SAR, not a predictable design rule. Applicants further allege that there would have been no motivation to include the phenyl-pyridyl moiety into PPDA-001 because the pyrazolo[1,5-a]pyrimidine scaffold is distinct from the structure of CR8.
These arguments are not persuasive because they rely on modifications that are not the basis of the rejection. The rejection does not assert that the phenyl-pyridyl analog or arbitrary modification of the CR8 scaffold would necessarily retain molecular glue activity. Rather, the reference teaches that the CDK-bound CR8 compound presents a solvent exposed pyridyl group that induces formation of a CDK12-cycklin K-DDB1 complex and confers cyclin K degrader activity. The fact that altering this moiety affects the desired activity of the compound is precisely what would have led the artisan to choose this motif. The reference clearly provides a motivation to use this specific motif. Even if SAR is unpredictable, the reference itself identifies which motif is beneficial. Sensitive SAR does not undermine the motivation to select the specific successful motif taught by the reference. Applicants’ arguments regarding the alleged structural distinctions between PPDA-001 and CR8 are not persuasive because it focuses on atom-by-atom difference in the fused heterocyclic cores while ignoring the conserved CDK-inhibitor structure and substituent positions. Both compounds contain a fused nitrogen-bearing heterobicyclic core bearing an isopropyl group and amino-benzyl/aryl substituents on the six-membered ring. PPDA-001 also already contains an amino-benzyl group at the position corresponding to the phenyl-pyridyl moiety used in CR8, which is taught as being responsible for the CDK12/cyclin K glue activity. The modification follows directly from the prior art’s identified SAR.
Applicants contend that the substitution of iPr for CyPr is context dependent and often detrimental to affinity. They further allege that such substitutions are not predictable and that there is no teaching or suggestion that this substitution would retain PPDA-001’s affinity for CDK.
These arguments are not persuasive. The rejection does not assert that every iPr to CyPr substitution in every chemical context necessarily improves or retains activity. Rather, the substitution represents a conservative modification of a small hydrophobic moiety on a known CDK inhibitor. In this context, the replacement of iPr with CyPr represents routine bioisosteric lead-optimization modification expected to preserve broadly similar hydrophobic interactions and steric character while potentially tuning potency, conformation, or pharmacokinetic properties.
The assertion that these substitutions are context dependent does not negate the motivation to make the claimed compound. Medicinal chemistry optimization is often context dependent, but obviousness does not require certainty of success. Applicants have failed to show that the prior art teaches away from this replace or that the replacement would be expected to abolish the CDK binding of the core compound.
Applicants’ arguments of hindsight analysis are unpersuasive. The art teaches that PPDA-001 is a CDK inhibitor and expressly teaches CDK12 among the contemplated CDKs for inhibition. The art also teaches that the phenyl-pyridyl motif is essential to the glue degrader activity. Finally, the art recognizes cyclopropyl groups as common isosteres of isopropyl groups and would have been screened as part of routine isosteric modifications. In short, you have a known compound expressly taught to be a CDK inhibitor that expressly contemplates CDK12 inhibition, a known phenyl-pyridyl motif that is essential for complex formation of CDK12, and one of the most common bioisosteric replacements in medicinal chemistry. No hindsight is required to arrive at the instant invention.
Claim Rejections - 35 USC § 103 (Maintained)
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 54-68, and 73-83 are rejected under 35 U.S.C. 103 as being unpatentable over Bondke (WO 2015/124941, found in IDS filed 10/22/2024) in view of Slabicki (Słabicki, Mikołaj, et al. "The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K." Nature 585.7824 (2020): 293-297, found in IDS filed 10/22/2024) and Bauer (Bauer, Matthias R., et al. "Put a ring on it: application of small aliphatic rings in medicinal chemistry." RSC Medicinal Chemistry 12.4 (2021): 448-471.).
Bondke teaches pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds and their use in the treatment of CDK mediated diseases. The reference teaches these compounds as compositions comprising the compound and a pharmaceutically acceptable carrier or diluent (claim 95); a method of preparing a composition comprising mixing the claimed compound and a pharmaceutically acceptable carrier or diluent (claim 96); a method of inhibiting CDK function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of the claimed compound (claim 97); a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of the claimed compound (claim 98); and teaches methods of treating a disorder comprising administering the claimed compounds to a subject in need thereof (pg. 10, lines 34-38), the disorders are specified on pg. 58 lines 21-26 and includes proliferative disorders and cancers. The treatment further comprises treatment with additional active ingredients including a Her2 blocker and chemotherapeutic agents (Abstract).
One disclosed compound is PPDA-001
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(pg. 44), which has the following substitutions according to the formula of instant claim 54: L7 is -CH2-; Ar1 is phenyl; X5 is -NH-; L5 is -CH2-; Cy5 is Cy5A, Cy5A is a C5 heterocycle that contains one nitrogen ring atom (6-membered heterocycle), the Cy5A ring is substituted with an -RCy5AC group which is -OH, Cy5 is (3R, 4R)-3-hydroxy-piperidin-4-yl group; R3 is an iso-propyl group. PPDA-001 differs from the instantly claimed compounds at positions R3 and Ar2. However, these substitutions are obvious modifications of PPDA-001.
Slabicki teaches that CR8
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is a CDK inhibitor and that CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation (Abstract). The reference goes on to empirically show that the phenylpyridine functionality that contains a 2-pyridyl group is essential for complex formation between DDB1 and CDK12 (Fig 3, pg. 296; CR8 phenylpyridine confers glue activity section pg. 296).
Bauer teaches that cyclopropane (CyPr) rings are the most ubiquitous small ring system in medicinal chemistry and is consistently the most frequently used small ring in patent literature due to its unique structure and physiochemical properties (pg. 449, right column second para.). The reference teaches that CyPr groups are extensively used in medicinal chemistry because they can increase potency, provide conformational stability, and improve pharmacokinetics and solubility of drug compounds (pg. 449, right column, second to last para.). CyPr groups are also frequently used as isosteres for small alkyl groups such as isopropyl. The reference then goes on to provide specific examples highlight the utility of the incorporation of CyPr groups into medicinal chemistry applications (see pg. 449-453).
The artisan would have experience in the design, synthesis, and evaluation of small-molecule CDK inhibitors for therapeutic use. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques used to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would also be familiar with previously reported CDK inhibitors. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
Bondke identifies PPDA-001 as a CDK12 inhibitor, the artisan would have been motivated to modify PPDA-001 to further optimize its activity and properties for the treatment of CDK12-associated disorders.
With respect to the substituents Ar1 and Ar2, Slabicki teaches that the 1,4-phenylene moiety at Ar1 connected to a pyridine-2-yl group at Ar2 is essential for the formation of the CDK12-DDB1 complex, which is implicated in ubiquitination and degradation pathways associated with CDK12 function. Based on this, the artisan would have been motivated to incorporate this moiety into their compound in order to more effectively modulate CDK12-mediated biological process. This represents a logical modification to the core molecule and constitutes routine optimization of a known CDK12 inhibitor.
Regarding the R3 group, Bauer teaches that CyPr groups are common isosteres of isopropyl groups in medicinal chemistry and are frequently employed to modulate physiochemical and ADME properties. Because PPDA-001 contains an isopropyl group, the artisan would have been motivated to substitute this group for a CyPr group as part of routine isosteric modification to improve or optimize the drug-like properties of the compound without significantly altering its CDK12 inhibitory activity.
Accordingly, the combination of references Slabicki and Bauer would have rendered the instantly claimed compounds obvious, as the proposed modifications represent predictable, routine changes made by the artisan to optimize a known CDK12 inhibitor for therapeutic use.
Conclusion
Claims 54-68 and 73-83 are rejected.
Claims 69-72 are objected to as being dependent upon a rejected base claim.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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