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 .
Status of the Claims
Claims 1-25 are currently pending.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/GB2022/053005, filed on November 28 2022, which claims priority to, and the benefits of GB.2117225.9 filed on November 29 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/22/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
On page 24, line 53, the specification recites “A₂, A₃ or A₄,”, A₃ is not part of the base formula.
On page 24, lines 59, the specification recites “A₁, A₂ or A₄ are all CH”, “or” suggests that only one of A₁, A₂ or A₄ maybe selected, while “are all CH” requires all three to be CH.
Appropriate correction is required.
Claim Objections
Claim 4-25 are objected to because of the following informalities:
Claims 4-25 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims 4-25 are not been further treated on the merits.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
Written Description
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 are rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 1 broadly recites a compound of Formula I having multiple variable positions, including R², R⁴, R⁶, A₁, A₂, A₄, R¹¹, R¹², R¹⁴, L, and Q. Claim 1 further broadly recites L as a linker and Q as an E3 ubiquitin ligase-binding moiety. Claims 2–3 further limit the compound of claim 1, but do not cure the breadth of the Formula I genus recited in claim 1.
The specification states that methodology for synthesizing Formula I compounds will vary depending on the nature of R², R⁴, R⁶, A₁, A₂, A₄, L, Q, and related substituents, and that one or more of those groups may be further reacted to provide alternative compounds (see e.g., paragraph [0809]). The specification provides working examples and activity data for selected PMS2 PROTAC compounds. However, the disclosure does not provide a representative number of species across the full breadth of the Formula I genus encompassed by claims 1–3.
In particular, the examples appear concentrated around selected PMS2-binding cores, selected linker types, and selected E3 ligase-binding moieties. The specification does not provide sufficient representative species showing possession of the full range of PMS2-binding core substitutions, linker structures, and E3 ligase-binding moieties encompassed by claim 1.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
According to MPEP 2163 I, “[t]o satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116… An applicant shows that the inventor was in possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the inventor was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991)”.
Additionally, according to MPEP II-A-3-a-ii, “[t]he written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406”; “[a] ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).”; and “’[a] patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
In the instant case, the claims encompass a broad genus of compound of Formula I. and a broad genus of indolines, linker L and E3 ligase-binding moieties. In contrast, the specification only describes a few species of indolines (i.e.,
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) as the representative of species of the genus. For instance, Applicant describe R4,
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the instant case only has METHYL group available. The specification only describes a few species of linker (i.e.
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a couple of PEG units
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C5-C9) as the representative of species of the genus. The specification only describes a few species of E3 ligase-binding moieties(i.e.
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) as the representative of species of the genus. Applicant does not have to exemplify every possible combination for the compound of Formula I or a salt thereof to satisfy the written description requirement; However, applicant needs to provide enough representative species from different corners of the range to represent the claimed genus fairly. In other words, while applicant does not necessarily need to exemplify every single species, applicant should give concrete examples that reflect the diversity of what they are claiming. Since the claims recite a large set of possible R², R⁴, R⁶, A₁, A₂, A₄, L, Q, and related substituents, applicant must provide a reasonable sampling of them —a representative number of compound species— so that a relevant artisan can see applicant truly envisioned the whole range.
The specification provides working examples and activity data for selected compounds, including certain CRBN-recruiting and VHL-recruiting compounds. However, the disclosure does not provide a representative number of species across the full breadth of the claimed genus. In particular, the examples appear concentrated around selected PMS2-binding cores, selected linker types, and selected E3 ligase ligands, while the claims extend to numerous unrepresented PMS2-binding moiety/linker/E3-ligase-binding moiety combinations.
Applicant does not have to exemplify every possible compound within Formula I. However, for a broad chemical genus, the specification must provide either a representative number of species or common structural features sufficient to show possession of the claimed genus. Here, the mere disclosure of selected exemplified PMS2 PROTAC compounds, without representative species across the breadth of the claimed variables, does not reasonably convey possession of the full scope of claims 1–3.
This lack of support is especially significant because PROTAC activity depends not merely on the presence of a PMS2-binding moiety and an E3 ligase-binding moiety, but also on linker length, linker flexibility, linker attachment point, cellular permeability, E3 ligase recruitment, productive ternary complex formation, and ubiquitination of the target protein. The specification’s selected activity data show PMS2 degradation for certain exemplified compounds, but do not establish possession of the full breadth of compounds encompassed by claims 1–3.
Accordingly, the specification does not demonstrate that Applicant was in possession of the full genus of PMS2-targeted PROTAC compounds encompassed by claims 1–3. Claims 1–3 are therefore rejected under 35 U.S.C. §112(a) for lack of written description.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
Claims 1–3 are rejected under 35 U.S.C. §112(a) because the specification, while enabling for selected exemplified PMS2 PROTAC compounds, including the compounds of Examples 1-30 that are synthesized and/or evaluated for PMS2 degradation in Tables A1 and A2(p. 149), does not reasonably provide enablement commensurate with the full scope of the claims. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention without undue experimentation.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The nature of the invention
The invention is directed to PMS2-targeted PROTAC compounds that bind to PMS2 and promote degradation of PMS2 protein. The specification states that the compounds may be used as binders to and degraders of PMS2 protein and may be used to treat diseases or conditions mediated by inappropriate PMS2 activity, for example cancer.
The invention is not merely a conventional small-molecule inhibitor invention. A PROTAC compound must bind the target protein, bind an E3 ubiquitin ligase, form a productive ternary complex, promote ubiquitination, enter the relevant cell type, and cause degradation of the target protein. PROTACs function by recruiting an E3 ligase to a target protein through a bifunctional molecule having a target-binding moiety, a linker, and an E3 ligase-binding moiety. This makes the claimed invention complex and dependent on multiple structural and biological variables. Because PMS2 degradation depends on multiple structural and biological features, the nature of the invention weighs against enablement of the full genus.
The state of the art
A PROTAC degrader generally requires a target-binding ligand, a linker, and an E3 ligase ligand. The target protein and E3 ligase must be brought into proximity so that the target protein can be ubiquitinated and degraded. The art also recognizes that PROTAC development requires attention to target selection, E3 ligase selection, linker design, ternary complex formation, cell permeability, and degradation efficiency. A Nature Reviews Drug Discovery review ( Bekes et al. Nature Reviews Drug Discovery volume 21, pages181–200 (2022)) describes PROTACs as an emerging therapeutic modality and identifies key future issues including determining suitable target classes and expanding E3 ligase use. The Nature review cites work on the impact of linker length on PROTAC activity and current strategies for PROTAC linker design, indicating that linker optimization is a recognized and target-dependent part of PROTAC development. The art also shows that PROTAC design was not predictable across arbitrary targets, arbitrary linkers, and arbitrary E3 ligases, the rational design of PROTACs was highly empirical and unpredictable across arbitrary targets, linkers, and E3 ligases. Successful degradation relied heavily on trial-and-error due to the complex, non-additive ways these components interact to form a functional ternary complex(Park et al. Pharmaceuticals 2025, 18(12), 1793; https://doi.org/10.3390/ph18121793).
Known PROTAC design requires a target-binding moiety, linker, and E3 ligase-binding moiety. However, the state of the art did not provide sufficient compensatory guidance to predict which of the numerous claimed PMS2-binding core/linker/E3-ligase combinations would degrade PMS2. The prior art therefore may help explain the general PROTAC strategy, but it does not fill the gap for the full scope of the claimed PMS2 PROTAC genus.
The relative skill of those in the art
The level of ordinary skill is high. A person of ordinary skill would likely have experience in medicinal chemistry, protein degradation, cellular degradation assays, protein biochemistry, and drug discovery. Such a person could synthesize and screen candidate PROTAC compounds.
However, even with this high level of skill, the artisan would not be able to predict which combinations of PMS2-binding moiety, linker, and E3 ligase-binding moiety would successfully degrade PMS2 across the full claimed scope. Screening of candidate PROTACs may be routine in the sense that assays are known, but identifying a therapeutically useful PMS2 degrader across the entire claimed genus is not routine or predictable.
The predictability or unpredictability of the art
The art is unpredictable, the rational design of PROTAC was highly empirical and unpredictable across arbitrary targets, linkers, and E3 ligases. Successful degradation relied heavily on trial-and-error due to the complex, non-additive ways these components interact to form a functional ternary complex.
The unpredictability is shown by the specification’s own activity results. The specification provides data showing that some selected compounds reduce PMS2 protein levels in SW620 colorectal carcinoma cells. The assay incubated SW620 cells with test compounds for 24 hours, followed by protein analysis normalized to actin and DMSO control. Some examples leave 50–25% PMS2 remaining, while others leave less than 10% PMS2 remaining under the same 1 μM, 24-hour assay conditions. This supports that degradation is compound-specific and not predictable across the full genus.
The Breadth of the claims
The claims are very broad.
Claim 1 recites a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, with numerous structural variables, including R², R⁴, R⁶, R⁸, A¹, A², A⁴, R¹¹, R¹², R¹⁴, L, and Q. Claim 1 covers a broad genus of PMS2-targeted bifunctional compounds, not merely the specific compounds made and tested in the specification.
Thus, the claims encompass a very large genus of PMS2-targeted PROTAC compounds across many target-binding cores, linkers, E3 ligase-binding moieties, compositions, and therapeutic uses, the claim breadth substantially exceeds the working examples and guidance provided.
The amount of direction or guidance provided
The specification provides some guidance for preparing and testing selected compounds, but not enough guidance for the full genus. The specification gives synthetic examples and a PMS2 degradation assay using SW620 colorectal cancer cells. However, it does not provide a general rule or predictive structure-activity relationship that would allow a skilled artisan to select successful PMS2 degrader combinations across the entire scope of Formula I, the full linker scope, and the full E3 ligase list. Thus, the specification appears to provide adequate direction for making and testing the specific compounds actually exemplified.
However, the specification does not provide sufficient guidance to make and use the full scope of claims 1–3. The working examples do not represent the full breadth of E3 ligases in the full breadth of Formula I variables in claim 1. The disclosure also does not provide sufficient structure-activity relationship guidance that would allow one of ordinary skill to predict which untested combinations would successfully degrade PMS2.
Therefore, the amount of direction is sufficient for selected exemplified PMS2 degraders, but not for the full claimed genus.
The presence or absence of working examples
The specification contains working examples, but they are limited.
Tables A1 and A2 report PMS2 degradation data for selected examples. The activity scale reports 50–25%, 25–10%, or less than 10% PMS2 protein remaining after incubation with 1 μM compound for 24 hours. However, the working examples do not represent the full breadth of claim 1.
The quantity of experimentation necessary
The quantity of experimentation required would be substantial.
To practice the full scope of claims 1–3, one of ordinary skill would need to synthesize and test numerous combinations of PMS2-binding cores, linker lengths, linker compositions, linker attachment points, and E3 ligase-binding moieties. Such testing would need to determine whether each combination binds PMS2, binds the selected E3 ligase, forms a productive ternary complex, enters relevant cells, causes PMS2 ubiquitination, and produces PMS2 degradation, examine cell types relevant to cancer and triplet repeat disorders, degradation potency, degradation maximum, target selectivity, and functional biological effects.
This is not merely routine confirmation of a known active compound. The claims require broad PMS2 degradation activity across many structural combinations and many E3 ligase systems. The amount of experimentation required to practice the full scope of the claims would be undue.
In view of the eight Wands factors, claims 1–3 are not enabled across their full scope. The specification enables selected PMS2 PROTAC compounds. However, the specification does not enable the full scope of claims 1–3. The disclosure does not provide sufficient guidance, representative examples, or structure-activity relationships to enable one of ordinary skill in the art to make and use the full genus of PMS2-targeted PROTAC compounds across the full range of Formula I variables, linkers, E3 ligase-binding moieties, pharmaceutical compositions, and therapeutic uses without undue experimentation.
Accordingly, claims 1–3 are rejected under 35 U.S.C. §112(a) for lack of enablement.
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 1–3 are rejected under 35 U.S.C. §103 as being unpatentable over Williams et al. (US20110098290A1) in view of Dutta et al. (Trends Beachem. Sci. 2000, 25(1), 24-28), further in view of Crews et al. (WO2013106643A2).
Williams et al. teaches the substituted isoindoline/benzoyl target-binding scaffold. Williams et al. teaches substituted 1,3-dihydroisoindole/isoindoline benzoyl compounds useful as Hsp90 inhibitors (see e.g., [0073]-[0075]). Williams et al. discloses compounds containing hydroxy/isopropyl benzoyl isoindoline structures and 5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydroisoindole substituents (see e.g., [0137]). Williams et al. therefore teaches a structurally related isoindoline benzoyl scaffold corresponding to the target-binding portion of the compound recited in claim 1.
Williams et al. does not expressly teach PMS2 degradation, a linker L, or an E3 ubiquitin ligase-binding moiety Q.
Dutta et al. teaches the reason to apply the Williams Hsp90 ATPase-domain scaffold to MutL/MLH1/PMS2-type proteins. Dutta et al. teaches that Hsp90, DNA mismatch repair enzyme MutL, DNA topoisomerase II, and histidine kinases belong to a common GHKL ATP-binding superfamily having a conserved Bergerat ATP-binding fold (see e.g., [0137]). Thus, Dutta et al. provides a molecular rationale for considering Hsp90 ATP-site inhibitor scaffolds, including the isoindoline benzoyl scaffold of Williams et al., as starting points for designing compounds directed to MutLα, i.e., MLH1/PMS2, ATPase-domain proteins.
Crews et al. teaches the linker L and E3 ubiquitin ligase-binding moiety Q limitations. Crews et al. teaches PROTAC compounds in which a protein-targeting moiety is linked to an E3 ubiquitin ligase-binding moiety through a linker so that the target protein is brought into proximity with the E3 ligase for ubiquitination and degradation (see e.g., p. 3, line 2). Crews et al. further teaches small-molecule VHL ligands for PROTAC technology (see e.g., p. 3, line 7).
Claim 1 recites a Formula I compound comprising an indoline/isoindoline-type target-binding portion, linker L, and E3 ubiquitin ligase-binding moiety Q. Williams et al. teaches the structurally related isoindoline benzoyl target-binding scaffold. Dutta et al. teaches the recognized GHKL ATPase-domain relationship between Hsp90 and MutL/MMR proteins, thereby providing a reason to apply Hsp90 ATP-site inhibitor scaffolds toward MLH1/PMS2/MutLα ATPase-domain modulation. Crews et al. teaches adding a linker and an E3 ubiquitin ligase-binding moiety to a protein-binding moiety to form a bifunctional degrader.
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the structurally related Hsp90 ATPase-domain inhibitor scaffold of Williams et al. by attaching, through a linker, an E3 ubiquitin ligase-binding moiety as taught by Crews et al., and to apply the resulting bifunctional compound toward MLH1/PMS2/MutLα modulation in view of Dutta et al.’s teaching that Hsp90 and MutL/MMR proteins belong to the same GHKL ATP-binding superfamily.
A person of ordinary skill would have had a reasonable expectation of success because Williams et al. teaches a structurally related ATPase-domain inhibitor scaffold, Dutta et al. provides the molecular rationale for applying Hsp90 ATP-site inhibitor scaffolds to MutL/MLH1/PMS2 ATPase-domain proteins, and Crews et al. teaches the PROTAC architecture of a target-binding moiety linked to an E3 ligase-binding moiety through a linker. Although optimization of linker length, attachment point, and E3 ligase ligand would have been required, such optimization would have been routine medicinal chemistry once the target-binding scaffold and PROTAC architecture were selected.
Claims 2–3 depend from claim 1 and further limit the compound of claim 1. Williams et al. teaches multiple substituted isoindoline benzoyl compounds having close structural similarity to the claimed indoline/isoindoline core, and Crews et al. teaches linker/E3-ligase modifications for bifunctional degrader compounds. Therefore, claims 2–3 would have been obvious for the same reasons set forth above with respect to claim 1.
Therefore, claims 1-3 are unpatentable under 35 U.S.C. §103.
Conclusion
No claims are allowed.
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/G.S./ Examiner, Art Unit 1628 /AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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