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 18/705,770
This Office Action is responsive to the amended claims of 04/29/2024 and Applicant remarks of 07/13/2026. Claims 1-18, 20-23, and 25-26 are pending and have been examined on the merits.
Election/Restrictions
Applicants’ election without traverse of compound 28 as a species of Formula I in the reply filed on 07/13/2026 is acknowledged. An STN structure search of compound 28 was conducted and the elected species was free of the prior art. The search was extended beyond the specific scope of the elected species to encompass the generic scope of Q3 as recited in claim 1. No prior art was identified that discloses a compound satisfying the claimed combination of Q1, Q2, and Q3, including the broader alternatives encompassed by Q3. The extended search did not identify prior art that anticipates or renders obvious the instantly claimed genus.
Priority
The instant application is a national stage entry of PCT/EP2022/080318, filed 10/31/2022, which claims priority to EP21205991.9, filed 11/02/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/26/2024 and 07/27/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 18 is objected to because of the following informalities: The structures of claim 18 are of insufficient clarity and resolution such that the substituents depicted in the chemical structures cannot be read or identified with reasonable certainty. Applicant is advised to review the claim figures and provide legible structures that clearly identify all recited structural features. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-3 and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph due to lack of written description.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, claims 1-3 are drawn to a bifunctional compound of formula I. Claim 1 recites that Q1 is a ubiquitin ligase ligand. Claim 2 recites that Q2 is a E3 ubiquitin ligase ligand. Claim 3 recites that Q1 is a CRBN, VHL, or a different type of E3 ubiquitin ligase other than a CRBN or a VHL ligand. These claims define Q1 solely by its desired function as a ubiquitin ligase ligand rather than by any structural limitation.
Level of skill and knowledge in the art:
The state of the art is that an “E3 ubiquitin ligase ligand” does not constitute a closed or structurally defined class of compound. Belcher et al. teaches that only a relatively small number of the more than 600 E3 ligases encoded by the human genome have been exploited using small-molecule ligands and describes ongoing approaches for identifying additional E3 ligase recruiters. The identity and structural scope of compounds functioning as E3 ubiquitin ligase ligands therefore remains open-ended.
(2) Partial structure:
Applicants have provided general structures of Q1-I, Q1-II, Q1-VII, Q1-VIII for the CRBN ligand (pg. 13) and further provided explicit structures of Q1-I-1 through Q1-I-6, Q1-II-1 through Q1-II-7, and Q1-VII-1 through Q1-VII-3 (pgs. 14-17). Applicants have also provided a general structure of Q1-III for the VHL ligand (pg. 18) and further provided explicit structures of Q1-III-1 through Q1-III-5 (pg. 19). Applicants have provided structures of different, non-CRBN and non-VHL E3 ubiquitin ligase ligands of general formulas Q1-IV, Q1-V, Q1-XII, and Q1-XIII (pgs. 20-22) and further provide Q1-XII-1 and Q1-XIII-1 (pgs. 21 and 22). Complete structures of the heterobifunctional compounds comprising the above moieties of Q1 are disclosed in Table 1 for compounds 1-122 (pg. 267-293).
(3) Physical and/or chemical properties, (4) Functional characteristics and (5) Method of making the claimed invention:
Characterization data, including 1H NMR and LC-MS, are provided for compound 1-122 (pgs. 185-267) as well as methods of synthesis to afford the compounds.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that claims 1-3 are broad and generic, with respect to all possible compounds encompassed by the claims. The possible structural variations are limitless to any ubiquitin ligase ligand in the case of claim 1 and any E3 ubiquitin ligase ligand in the case of claims 2 and 3.
Although the claims may recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function and structure of the compounds beyond those compounds specifically disclosed in the examples in the specification. Moreover, the specification lack sufficient variety of species to reflect this variance in the genus. While having written description of Q1 as Q1-I, Q1-II, Q1-III, Q1-III, Q1-IV, Q1-V, Q1-VI, Q1-VII, Q1-VIII, Q1-XII, and Q1-XIII (of claim 4) and compounds identified in the specification tables and/or examples, the specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim 26 is rejected under 35 U.S.C. §112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 26 lacks written description as the claim recites “a ternary complex, comprising (i) a compound according to claim 1; (ii) a TEAD protein; and (iii) a ubiquitin ligase.” The specification states that “[a] compound of Formula I may form a ternary complex comprising (i) a compound of formula I; (ii) a TEAD protein; and (iii) a ubiquitin ligase” (pg. 99, lines 8-9). The specification also generally teaches that bifunctional degraders act through formation of a complex comprising a target protein, the degrader molecule and an E3 ubiquitin ligase (pg. 3, lines 20-22; pg. 4, lines 20-22). However, these general statements do not demonstrate possession of the presently claimed ternary complexes. The specification does not provide a working example or other experimental characterization demonstrating formation of a claimed ternary complex, nor does it provide representative species sufficient to support the breadth of the claimed genus. Thus, the disclosure does not reasonably convey possession of the claimed genus of ternary complexes, especially in view of the extreme breadth of the compounds encompassed by claim 1.
Claims 20, 21, and 25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for degrading TEAD 1 in NCI-H226 and SK-HEP1 cells using certain compounds identified in Table 4a, does not reasonably provide enablement for the treatment or prevention of any disease or condition mediated by TEAD activity comprising any compound of claim 1, nor does it provide a method of degrading a TEAD protein with any compound of formula I. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method of treating or preventing any disease or condition mediated by TEAD activity comprising administering an effective amount of any compound of formula I. The claims are also drawn to a method of degrading TEAD protein comprising contacting the TEAD protein with a compound of formula I. Thus, the claims taken together with the specification imply that the administration of an effective amount of any compound of formula I, including those not expressly disclosed in the application, is capable not only of treating any form of disease or condition meditated by TEAD activity but is also able to prevent these same conditions. The diseases and conditions recited in claim 21 encompass a variety of distinct cancers having distinct pathologies and etiologies, as well as non-neoplastic conditions including cardiovascular diseases and fibrosis. As written, claim 25 taken together with the specification implies that contacting any TEAD protein with any compound of formula I facilitates the degradation of the TEAD protein. Thus, the scope of the claims is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that target protein binding alone is not predictive of PROTAC-mediated degradation. Bondeson et al. demonstrated that PROTACs capable of binding more than 100 kinases degraded only a small subset of the bound targets and further teaches that degradation is dependent on the protein-protein interactions and the stability of the ternary complex (see Summary pg. 78; Discussion, right col., second para, pg. 83; left col., fourth para, pg. 84; Significance, pg. 85). Smith et al. further demonstrated that variation of linker connectivity and length using the same warhead and VHL recruiting ligand result in different degradation of p38a and p38d (Abstract, pg. 1; pg. 3, left col., first para). Smith et al. reiterate that protein-protein interactions that occur between the target protein and the recruited E3 ligase and high affinity ternary complexes between these two moieties determine the efficacy of the desired protein degradation (Abstract, pg. 1; pg. 5, left col. first para.). Smith further teaches that ternary complex formation is necessary for targeted protein degradation but does not necessarily result in degradation (pg. 10, left col., second para.). Donovan et al. teaches that starting from the highest potency binder is an ineffective method for discovering active compounds that facilitate targeted protein degradation (Abstract, pg. 1714).
The references discussed above demonstrate that neither the binding affinity of a target-binding warhead nor formation of a ternary complex is, by itself, sufficient to establish successful targeted protein degradation. Accordingly, PROTAC-mediated degradation is highly unpredictable and generally requires empirical evaluation to determine whether a particular compound will produce the desired degradation activity.
Even when a particular PROTAC is shown to degrade the desired target protein, this degradation does not by itself establish that the compound will be effective in the treatment of a disease associated with that target protein. The response of targeted therapy depends on the biological context of the particular disease being treated and the targeted pathway. Dagogo-Jack et al. teaches that cancer is a dynamic disease and that tumors are heterogenous mixtures of cells with differing levels of sensitivity to treatment, posing a significant challenge to treatment (Abstract, pg. 81). Kaneda et al. further highlights this unpredictability specifically for TEAD modulation. Kaneda et al. teaches that K-975 strongly inhibited YAP1/TAZ-TEAD signaling but exhibited substantially greater antiproliferative activity in NF2-noexpressing malignant pleural mesothelioma cells than in NF2-expressing cells of the same cancer type (Abstract, pg. 1). The limited examples of the instant disclosure merely show that some of the compound of the genus of formula I are capable of reducing TEAD 1 protein levels in only SK-HEP1 and NCI-h226 cells. These limited examples do not provide a reasonable basis for predicting the therapeutic efficacy across the broad spectrum of diseases encompassed by the instant claims.
(5) The relative skill of those in the art:
The relative skill of those in the art is high. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the synthesis, development, and biological evaluation of PROTACs for the targeted degradation of proteins.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for (1) determining whether compounds 1-6, 11, and 13 interact with TEAD 1, TEAD 2, TEAD 3, and TEAD 4 proteins based on changes in thermal stability (Table 2, pg. 295); (2) determining direct binding affinity of compounds 1-6, 9, 14, 16, and 36 to the TEAD 1 YAP-binding domain; (3) determining whether certain exemplary compounds reduce/degrade cellular TEAD 1 protein levels in SK-HEP1 and NCI-H226 cells (Table 4 and 4a, pg. 298). The specification further proves a Western blot assay confirming reduction of cellular TEAD 1 protein levels in NCI-H226 cells following treatment with compound 4(pgs. 302-303). The working examples disclosed above provide guidance for identifying compounds that interact with TEAD proteins, binding to TEAD 1, and reducing TEAD 1 protein levels for the specifically tested cellular systems with the tested compounds.
However, the specification does not provide sufficient guidance to enable the treatment of the full scope of disease and disorders mediated by TEAD activity using the full genus of compounds of formula I. The specification does not disclose any disease models demonstrating that compounds across the claimed genus are capable of treating the TEAD-mediated diseases and disorders encompassed by the claims, nor does it provide guidance or direction supporting prevention of such conditions. Further, the specification does not establish that compounds throughout the scope of formula I can degrade a TEAD protein upon contact with the protein.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the lack of a reliable correlation between target protein binding affinity and successful target protein degradation and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The phrase “having 2-25 C atoms” renders the scope of Q2 indefinite because the term “having” is not defined in the specification and does not clearly indicate whether the recited carbon atom limitation is open or closed. It is therefore unclear whether Q2 is limited to groups containing a total of 2-25 carbon atoms or whether additional carbon atoms may be present beyond the recited range. Accordingly, the metes and bounds of the limitation cannot be determined with reasonable certainty.
Claim 1 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of variables Q2 and Q3 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives encompassed by Q2 and Q3 do not belong to a recognized class and do not share a substantial structural feature common to all members of the respective groups. Rather each variable encompasses numerous structurally unrelated moieties having substantially different cores, ring systems, atomic compositions, and connectivities. Accordingly, Q2 and Q3 lack the structural commonality required for a proper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Conclusion
Claims 1-3, 20-21, 25, and 26 are rejected.
Claims 4-18 and 23 are objected to for being dependent upon a rejected base claim.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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