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 .
Priority
This application filed on 04/26/2023 is a U.S. national stage of PCT/US2021/056545 filed on 10/26/2021, which claims the benefit of U.S. Provisional Patent Application No. 63/105,728, filed 10/26/2020 and.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 04/26/2023, 08/07/2025 and 06/15/2026, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
Election/Restriction
Applicant’s response filed on 10/30/2025 to Restriction/Election Requirement filed on 09/10/2025, is acknowledged. Applicant elected without traverse Group I drawn to a bifunctional compound and a pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound. Claims 1 and 50 read on the elected Group. Claims 51, 58-74 of Group II are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
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 final rejection. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/15/2026 has been entered.
Status of claims
Amendment and applicant argument submitted on 06/15/2026 have been received and have been carefully considered.
Claim 1 was amended, and claims 2-49 and 52-57 were previously cancelled. Claims 1, 50-51, and 58-74 are pending, claims 51 and 58-74 are withdrawn, and claims 1 and 50 are under consideration.
Claim interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. MPEP § 2111.01 (III). However, specific embodiments of the specification cannot be imported into the claims, particularly where the subject claim limitation is broader than the embodiment. MPEP § 2111.01(II).
Claim 50 recites “A pharmaceutical composition, comprising a therapeutically effective amount of the bifunctional compound …”. The instant specification defines the “therapeutically effective amount” as:
As used herein, the term, "therapeutically effective amount" refers to an amount of a bifunctional compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition including a bifunctional compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder characterized or mediated by aberrant protein activity. The term "therapeutically effective amount" thus includes the amount of a bifunctional compound of the invention or pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, or which simply kills or inhibits the growth of diseased (e.g., cancer) cells, or reduces the amount of aberrant proteins in diseased cells. [0105].
Thus, claim 50 “therapeutically effective amount” is interpreted consistent with the instant specification.
Rejection Maintained
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 and 50 remain rejected under 35 U.S.C. 103 as being unpatentable over Huang, H., et al. Cell Chemical Biology, Volume 25, Issue 1, 18 January 2018, Pages 88-99.e6, “Huang” cited in the IDS dated 04/26/2023).
Huang discloses TL12-186, a heterobifunctional degrader for FLT3 and BTK [Abstract, and page 25, Figure 1]:
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Huang’s compound TL12-186 differs from claim 1 compound SK-3-87 in the region highlighted with the dashed oval as depicted below:
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Huang’s linker includes 2 polyethylene glycol units, whereas claimed compound SK-3-87 includes 3 polyethylene glycol units. However, as provided in MPEP 2144.09, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
Compounds which are homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups, in instant case -O-CH2CH2) 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). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.).
Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979) (Claimed and prior art compounds were both directed to heterocyclic carbamoyloximino compounds having pesticidal activity. The only structural difference between the claimed and prior art compounds was that the ring structures of the claimed compounds had two carbon atoms between two sulfur atoms whereas the prior art ring structures had either one or three carbon atoms between two sulfur atoms. The court held that although the prior art compounds were not true homologs or isomers of the claimed compounds, the similarity between the chemical structures and properties is sufficiently close that one of ordinary skill in the art would have been motivated to make the claimed compounds in searching for new pesticides.).
The presumption of obviousness based on a reference disclosing structurally similar compounds may be overcome where there is evidence showing there is no reasonable expectation of similar properties in structurally similar compounds. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (appellant produced sufficient evidence to establish a substantial degree of unpredictability in the pertinent art area, and thereby rebutted the presumption that structurally similar compounds have similar properties); In re Schechter, 205 F.2d 185, 98 USPQ 144 (CCPA 1953).
A prima facie case of obviousness based on structural similarity is rebuttable by proof that the claimed compounds possess unexpectedly advantageous or superior properties. In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (affidavit evidence which showed that claimed triethylated compounds possessed anti-inflammatory activity whereas prior art trimethylated compounds did not was sufficient to overcome obviousness rejection based on the homologous relationship between the prior art and claimed compounds); In re Wiechert, 370 F.2d 927, 152 USPQ 247 (CCPA 1967) (a 7-fold improvement of activity over the prior art held sufficient to rebut prima facie obviousness based on close structural similarity). However, a claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences, in fact, in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc).
In the instant case, and in view of MPEP 2144.09, the claimed compound and prior art compounds are: homologs, because as stated in the 103 Rejection above, the linker only differs by successive addition of the same chemical group, e.g., by -O-CH2CH2- groups. Please note that the MPEP stated that “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious “; The claimed compound and the prior art compound have very close structural similarities and very similar properties as the claimed compounds and prior art compounds have similar utilities, kinase degrader; and Applicant does not provide evidences of unexpectedly advantageous or superior properties of the claimed compounds over the prior art compounds.
Therefore, Huang’s compound TL12-186 renders instant claim 1 obvious.
With regard to claim 50, Huang teaches that TL12-186 displays potent binding to CRBN (IC50 = 12 nM), [page 5, 1st para., Figure 1]. Huang teaches a composition of compound TL12-186 is DMSO. [Page 14, 1st para.].
Response to Arguments
Applicant argues:
The PROTAC art, as attested to by Huang itself, remains empirical and unpredictable (even more than two decades since the inception of PROTACs) -- it readily concedes that there is sizeable gap between concept/design and reality/success. Huang repeatedly emphasizes the unpredictability and uncertainty with respect to the effect of making structural changes, particularly in connection with linker length and constitution. Several reports described the importance of varying all three components of degrader molecules, namely the warhead, the linker, and the E3 ligase ligand, to optimize degradation efficiency (Bondeson et al., 2015; Lai et al., 2016; Zengerle et al., 2015). Changes in the chemical composition may affect cellular uptake and stability, two key factors that affect the efficacy of bivalent degraders. Different warheads and linker lengths also affect orientation in which the target and the E3 ligase can be brought into proximity, which may affect ubiquitination efficacy. We used the available FLT3-AC220 crystal structure (PDB: 4XUF) to inform the site for installing a PEG linker, and 9 degraders with variable linker types and lengths were explored (Figures 4C and S3A). Unexpectedly, we observed that AC220 treatment in MOLM-14 cells led to a significant increase in FLT3 levels (Figures 4D and 4E), an effect that we postulate to occur via disruption of the control over FLT3 endocytosis and degradation. While several degraders demonstrated no effects on FLT3 degradation, likely due to suboptimal linker attachments and lengths, TL13-117 and TL13-149 caused FLT3 degradation to the endogenous levels or slightly below (Figures 4D, 4E, S3B and S3C).
Applicant found that compound TL12-186 is a relatively promiscuous degrader - it caused degradation of 60 kinases, See, Table 1 on page 93. This result would not have been expected by persons skilled in the art. Donovan et al., "Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development," Cell, 2020, 183:1714-1731 (copy submitted herewith) assessed the importance of subtle linker differences around the TL12-186 degrader, and concluded as follows: Analysis of the data revealed that the number of kinase targets decreased with increasing linker length-PEG1 (25), PEG2 (23), and PEG3 (18) (Figure 6C; Table S10). This is surprising because multiple studies have reported that longer linkers can be more productive at forming ternary complexes and inducing degradation than their shorter counterparts.
Examiner response:
Applicant's arguments have been fully considered but they are not persuasive. Applicant major argument is directed to the assertion that proteolysis targeting chimeras (PROTACs) chemistry and bioactivity is unpredictable. Applicant added quotations from Huang and other cited references to support unpredictability of PROTAC degradation activity, see Remarks at pages 2-6. Applicant stated: “the critical parameters that influence PROTAC pharmacological profiles, include the choice of E3 ligase, the nature and length of the linker, and the dynamics of the ternary complex formation as well as the targeting ligand. The selection of the E3 ligase ligand is a crucial step in the design of PROTACs, … The choice of E3 ligase and its corresponding ligand impacts the efficacy, selectivity, and safety of PROTACs... Given these considerations, the development of PROTACs often involves extensive screening and optimization processes to identify the most suitable E3 ligase ligands (pages 29-30). The PROTAC discovery approach is still primarily empirical and requires significant, costly, and time-consuming working in synthetic and medicinal chemistry and maintaining favorable pharmacokinetic properties can be challenging”. However, the generic teachings from Huang or the cited art is not sufficient to overcome the rejection for the following reasons:
The outstanding 103 rejection over Huang is based on structure similarity between Huang’s TL12-186 and the claimed compound SK-3-87, which shares the warhead, the ligand and the linker, and only differs in that the linker of SK-3-87 contains an addition PEG group. Applicant does not argue the similarity (or the difference) between the prior art compound and the claimed compound. Nevertheless, Applicant argues the chemistry of PROTACs, the unpredictability, the challenging synthetic steps, the cost, etc. Applicant does not provide factual evidence of how these factor applied when the prior art compound is homologous with the claimed compound and prima facie obviousness due to the similarity is established. As provided in MPEP 2145, If a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. See, e.g., In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). Rebuttal evidence and arguments can be presented in the specification, In re Soni, 54 F.3d 746, 750, 34 USPQ2d 1684, 1687 (Fed. Cir. 1995), by counsel, In re Chu, 66 F.3d 292, 299, 36 USPQ2d 1089, 1094-95 (Fed. Cir. 1995), or by way of an affidavit or declaration under 37 CFR 1.132, e.g., Soni, 54 F.3d at 750, 34 USPQ2d at 1687; In re Piasecki, 745 F.2d 1468, 1474, 223 USPQ 785, 789-90 (Fed. Cir. 1984). However, arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicant does not provide comparison between Huang’s TL12-186 and the claimed compound SK-3-87 to support the unexpected effect of the claimed compounds or the effect of the asserted factor or unpredictability of the PROTAC art. As provided in MPEP 716 (b)(III) “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971).
Applicant stated that “the number of kinase targets decreased with increasing linker length-PEG1 (25), PEG2 (23), and PEG3 (18) (Figure 6C; Table S10). This is surprising because multiple studies have reported that longer linkers can be more productive”, however, the Applicant does not explain how this “surprising finding” is related to the current rejection over Huang as Applicant does not show if the warhead and ligand are similar/different. Moreover, the statement that longer linkers can be more productive” is not reflecting the current Huang’s compound/claimed compound because while Applicant provide more than two PEG groups, Huang’s TL12-186 and the claimed compound SK-3-87 only differ by one PEG group.
Furthermore, this Applicant statement is not clear: “Applicant found that compound TL12-186 is a relatively promiscuous degrader - it caused degradation of 60 kinases, See, Table 1 on page 93. This result would not have been expected by persons skilled in the art”, because TL12-186 is Huang’s compound that share structure similarity and utility with the claimed compound SK-3-87. Table 1 on page 93 includes SK-3-87. Even, if we consider that Applicant mistakenly refers to TL12-186 instead of SK-3-87, Table 1 does not show unexpected finding nor degradation of 60 kinases.
While Applicant has provided various data to support the challenges and unpredictability concerning PROTAC, it still stands that Huang’s compound and the prior art compound have very close structural similarities and very similar properties as the claimed compounds and prior art compounds have similar utilities, kinase degrader; and Applicant does not provide evidences of unexpectedly advantageous or superior properties of the claimed compounds over the prior art compounds, see MPEP 2144.09. Therefore, Applicant’s arguments and provided evidences are insufficient to overcome the rejection.
Conclusion
Claims 1 and 50 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MANAHIL MIRGHANI ALI ABDALHAMEED whose telephone number is (571)272-1242. The examiner can normally be reached M-F 7:30 am - 5:00 pm.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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