DETAILED ACTION
This office action is in response to applicant’s filing dated March 16, 2026.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on November 10, 2025 has been entered.
Status of Claims
Claims 1 – 7, 10 – 13 and 16 – 20 are pending in the instant application. Acknowledgement is made of Applicant's amendment of claims 2 – 6, filed on March 16, 2026. Claims 13 and 16 – 20 remain withdrawn, as being drawn to an unelected invention or specie.
Claims under consideration in the instant office action are claims 1 – 7 and 10 – 12, as they relate to the elected species,
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(Compound AST-DT-218).
Preliminary Matters.
By Applicant’s request, Examiner acknowledges receipt of the certified copies of the priority documents retrieved by the U.S. Patent Office on February 9, 2025. Acknowledgment of receipt has been reflected in the Office Action Summary, related to the present Office action.
Priority
The present application was filed on October 15, 2024 and claims the benefits of priority of foreign application KR10-2023-0137434, filed October 16, 2023.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 7 and 10 – 12 are rejected under 35 U.S.C. 103 as being unpatentable over Bradner et al (WO 2017/007612 A1 hereinafter Bradner).
Instant claims are drawn to a compound of general formula 1:
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, where R1 is C2-C7 alkyl, cycloalkyl, aryl, aromatic or non-aromatic heterocyclyl; e.g. a compound of formula
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(compound AST-DT-218) and a pharmaceutical composition wherein said composition is administered via various routes (e.g. oral, intravenous or intradermal). The compound of Formula 1 functions as a molecular glue substance that binds to the Cereblon (CRBN).
Bradner teaches bifunctional compounds, which function to recruit targeted proteins to E3 Ubiquitin Ligase for degradation. Bifunctional molecules, taught by Bradner, have a following structure: Degron-Linker-Targeting Ligand,
where Degron is a small molecule binding to an E3 Ubiquitin Ligase (e.g., cereblon) (page 2, lines 29 – 32), where the Degron is a thalidomide or a derivative or analog thereof (page 18, line 14), having a structure:
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wherein
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is
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(page 44, table D4). Bradner further teaches that Degron, selected from Tables D, D1, D2, D3, and D4, is capable of targeting proteins for degradation (e.g., through a ubiquitination pathway), without being bound to a Targeting Ligand through a Linker, i.e., the Degron is capable of degrading one or more cellular proteins (e.g., IKZF1) after being administered to the cell (page 45, lines 2 – 8). Thus, Bradner teaches “Degron” as individual compounds, capable to degrade cell proteins, without being incorporated into PROTAC, and therefore, said compounds act as molecular glue, since compounds, taught by Bradner, are structurally similar to the instantly claimed compounds. MPEP 2112.01states: composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Although claimed compound AST-DT-218 and a compound
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where
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is
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, taught by Bradner, are not identical, their structures are very similar and differ only by -CH2- group, also both compounds known to have similar property of binding affinity to cereblon protein. MPEP 2144.09 states: Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). Bradner further teaches a pharmaceutical composition comprising above compounds for treatment of certain types of cancer, wherein said pharmaceutical composition is administered orally or intravenously (page 223, line 34).
Thus, since Bradner teaches compounds, thalidomide analogues, or more specifically pomalidomide derivatives, structurally similar to instantly claimed compounds and capable of binding to an E3 Ubiquitin Ligase (e.g., cereblon) which property can be utilized in treatment of cancer through targeted protein degradation mechanism, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to try to make various compounds of similar structure to a known compound (e.g. isomers or homologs) in search for a new drug with similar or better desired properties, to come to claimed compounds, with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues:
- The Office relies on Bradner, teaching bifunctional compounds that recruit targeted proteins to E3 Ubiquitin Ligase for degradation, which compounds require a tripartite structure: a "Degron-Linker-Targeting Ligand." The claimed compounds are molecular glues, not PROTACs. This is a critical distinction, as molecular glues are significantly smaller molecules and they have different pharmacological properties, membrane permeability etc., compared to PROTACs. Therefore, modifying a degron moiety utilized in Bradner's PROTAC structure to arrive at the claimed standalone molecular glue requires a complete shift in molecular design that is neither taught nor suggested by Bradner.
- The presumption that homologs or position isomers possess similar properties is rebuttable and does not apply when the prior art itself demonstrates unpredictability. Bradner explicitly demonstrates that mere structural isomerism in target- degrading compounds results in exponentially divergent efficacy, a person of ordinary skill in the art would not have a reasonable expectation that the structurally similar compounds with a difference of a -CH2- group would yield predictable similar properties.
- To further rebut the Office's position and provide the requested factual evidence, Applicant submits the accompanying Declaration under 37 C.F.R. § 1.132 executed by Dr. Jungwan Hong ("the Hong Declaration"). Dr. Hong conducted a Parallel Artificial Membrane Permeability Assay for the BBB (PAMPA-BBB) to directly compare the in vitro permeability of a representative compound of the claimed compound (AST-DT-218 (AST-035A)) against AST-25-015, which corresponds to the structurally analogous compound lacking the methyl group (DT4 in Bradner). The results show that AST-035A, a representative embodiment of the claimed compound achieved a mean relative permeability of 41.2%, whereas Bradner's analog AST-25-015 achieved a mean relative permeability of only 16.8%. Therefore, the claimed compound exhibits an approximately 2.5-fold higher relative permeability than the prior art analog, which is a profoundly unexpected improvement that cannot be dismissed as routine optimization.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: although Bradner teaches PROTACs, having a structure Degron-Linker-Targeting Ligand, each of the three necessary PROTAC fragments are usually selected from known small molecules, protein inhibitors and varieties of possible known in the art linkers. Since Degron in the molecules taught by Bradner, is the moiety that is intended to bind cereblon, the structure is chosen from known discrete compounds having a structure of e.g. thalidomide analogs. Moreover Bradner explicitly points out that the Degron, selected from Tables D, D1, D2, D3, and D4, is capable of targeting proteins for degradation (e.g., through a ubiquitination pathway), without being bound to a Targeting Ligand through a Linker, i.e., Bradner teaches “Degron” as individual compounds, capable to degrade cell proteins, without being incorporated into PROTAC, and therefore acting as molecular glues. The chemical structure of one of the exemplary compound shown in Table D4 in Bradner’s reference is a closest homolog of the instantly claimed compound AST-DT-218 (see the rejection section above). According to MPEP 2144.09, homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are presumably possess similar properties. To rebut established prima facie case of obviousness, Applicant should present sufficient factual evidence (see MPEP 2142).
Examiner acknowledges the submitted by Applicant Declaration under 37 C.F.R. § 1.132 of Dr. Jungwan Hong. The Declaration has been considered by Examiner but is not found persuasive, because experimental results, illustrated in Figure 1 of Declaration, do not prove that compound AST-035A (chiral agent) exhibits higher relative permeability than the prior art analog of Bradner AST-25-015. While the mean relative permeability of compound AST-035A is twofold higher than that of compound AST-25-015, the substantially overlapping standard deviations (41.2 ± 29.8 for compound AST-035A) indicate that this difference is not statistically significant. Thus, essential overlap in SD ranges of measured relative permeability suggests no superiority of compound AST-035A over the compound AST-25-015.
Examiner notes: since the structure of compound AST-25-015 is nowhere to be found, Examiner assumed, according to Applicant’s description, that the compound AST-25-015 is a closest homolog of instantly claimed compound AST-DT-218, lacking a chiral center and having a structure equivalent to compound taught by Bradner (see the structures in the rejection section).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 1 – 7 and 10 – 12 as obvious over teachings of Bradner is maintained.
Conclusion
Claims 1 – 7 and 10 – 12 are rejected. No claim is allowed.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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