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 .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1, 5-8, 25-29, and 52), a compound of formula (I), in the reply filed on June 1, 2016 is acknowledged. The traversal is on the ground that the pending claims have unity under 37 CFR § 1.475(b)(2) since they are drawn to products and processes of use of the products. This is not found persuasive because unity only exists if the shared feature is a special technical feature beyond the art. As described in the restriction requirement mailed April 13, 2026, the feature shared between groups I and II (a compound of formula (I)) is obvious in view of Choudhary and Olson. Therefore, the shared feature does not make a contribution over the prior art and is not a special technical feature. Furthermore, groups III and IV have a priori lack of unity as they do not share the feature of a compound of formula (I). Thus, the lack of unity is deemed proper. Claims 30, 32-35, 41-42, 46, and 59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 1, 5-8, 25-30, 32-35, 41-42, 46, 52, and 59 are pending.
Claims 30, 32-35, 41-42, 46, and 59 have been withdrawn from consideration.
Claims 1, 5-8, 25-29, and 52 are under examination.
Information Disclosure Statement
The information disclosure statements filed on December 19, 2023 and March 4, 2025 are acknowledged and have been considered by the examiner.
Drawings
The drawings are objected to for the following informalities.
Figure 23 lacks adequate resolution. In its current form, it is not possible to clearly read the axes of the provided plots nor the values added to the interior of the plots. Thus, it is not possible to interpret the contents of the provided drawing.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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, 6, and 8 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.
Claim 1 is drawn to a broad genus claim encompassing a wide scope of molecules that could read on formula (I) through the various R group, X, Y, n, and n’ options. For such a genus claim, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, drawings, or by disclosure of relevant identifying characteristics (MPEP § 2163(II)(A)(3)(ii)). The applicant provides the structures of compounds 7a, 7b, 7c, 7e, and 7f, along with data describing some of the properties of these molecules. However, these compounds do not adequately represent the entire genus claimed. In no disclosed embodiments is X or Y anything other than -O-; R3 and R4 anything other than methyl (C1 alkyl); R1, R2, R5, and R6 anything other than hydrogen; and R7 anything other than hydrogen or methyl (C1 alkyl). In the pharmaceutical art, substituting a hydrogen for an alkyl group (or vice versa) or changing the length of an alkyl group can have a significant impact on the function of a molecule. Thus, the disclosed examples are not a representative number of species. It is not clear that all molecules within the scope of claim 1 would share similar properties to those disclosed through examples. Therefore, it is understood that the specification does not provide sufficient written support to describe all embodiments of the claimed compounds of formula (I).
Regarding claims 6 and 8, as discussed above, the disclosed examples do not include embodiments wherein R3 and R4 anything other than methyl (C1 alkyl); R1, R2, R5, and R6 anything other than hydrogen; and R7 anything other than hydrogen or methyl (C1 alkyl). Furthermore, only C1 alkyl examples are provided. It is not clear that C2-C6 alkyl variants would maintain the same properties as the disclosed examples. Thus, the provided examples are not representative of the claim scope in full. Therefore, the specification does not provide sufficient written support to describe embodiments in which each of R1, R2, R3, R4, R5, R6,and R7 of formula (I) is C1-C6 alkyl or hydrogen.
Claim Rejections - 35 USC § 103
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, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Choudhary (US 2021/0324357 A1) in view of Olson (Olson, C. M.; et al., Nat. Chem. Biol., 2017).
Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). TMP dTAG is very similar to the compound of formula I as defined in claim 1 of the instant application where R1, R2, R5, R6, and R7 are all hydrogen; R3 and R4 are C1 alkyl (methyl); X is oxygen, Y is -CR1R2-, n is 1 and n’ is 2. Choudhary teaches the point of attachment of the amine to the TMP-linker conjugate to the phthalimide ring of the thalidomide moiety at the 5-position. Choudhary teaches that this degrader may be used to modulate the functions of a protein (pg. 20, [0177]). Choudhary teaches that the degrader can target a protein to the proteasome for degradation (pg. 4, [0032]). Choudhary specifically teaches using such a degrader to modulate variants of CRISPR Cas proteins containing an FK506 binding protein (FKBP) domain, which is a tag that enables the degrader to act on the CRISPR Cas protein (pg. 20, [0175]). TMP dTAG may also be used for therapeutic applications, including regulating the strength, efficacy, timing, and dosage of a therapeutic RNA-guided nuclease (pg. 29, [0251]).
Choudhary does not teach attaching the TMP-linker conjugate amine to the phthalimide ring in the 4-position.
Olson teaches a PROTAC molecule for the degradation of CDK9 (pg. 163, Abstract). The molecule THAL-SNS-032 of Olson comprises a CDK9-binding ligand (SNS-032); a linker comprising an amide, a 3-polyethylene glycol region, and an amine group on the end; and the amine group attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). Olson teaches that THAL-SNS-032 effectively degrades CDK9, making it an effective PROTAC molecule (pg. 165, Figure 2C).
A person of ordinary skill in the art would have recognized that both Choudhary and Olson teach PROTAC molecules in which similar linear linker groups are attached to the phthalimide ring of thalidomide via an amine. Both linkers comprise (from left to right in the aforementioned depictions of the molecules) a heteroatom of the targeting molecule bound to a linker C1 alkyl chain, an adjacent amide, a linear alkyl or polyethylene glycol-like chain, and an amine connection to the thalidomide portion of the molecule. It would be recognized that both of these molecules are capable of degrading the desired proteins of interest effectively. Thus, it would be understood that it is known in the art that targeted degraders can be prepared using either the 4- or 5-position of the phthalimide ring of the thalidomide moiety as the connection point for the linker (MPEP § 2143(I)(A)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the TMP dTAG structure of Choudhary by switching the linker attachment position on the phthalimide ring of the thalidomide moiety from the 5-position to the 4-position taught by Olson. This would result in the predictable result of an effective trimethoprim and thalidomide-containing PROTAC that reads on an embodiment of the compound of formula (I) as defined in claim 1 of the instant application.
Regarding claim 1, Choudhary teaches a bifunctional degrader comprising a trimethoprim moiety linked to a thalidomide moiety (TMP dTAG) (Fig. 1A). Olson teaches a similar PROTAC molecule with a connection between the linker and the thalidomide moiety at an amine at the 4-position of the phthalimide ring (pg. 164, Figure 1a). The modification of the attachment point applied to Choudhary would result in the following structure of Formula X:
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This structure reads on the claimed formula (I) wherein R1, R2, R5, R6, and R7 are all hydrogen; R3 and R4 are C1 alkyl (methyl); X is oxygen, Y is -CR1R2-, n is 1 and n’ is 2. Therefore, the combined teachings of Choudhary and Olson render claim 1 obvious.
Regarding claim 5, as described above, the combination of Choudhary and Olson results in the above structure X. In this structure, R1, R2, R5, R6, and R7 are hydrogen. This meets the criteria of at least one of R1, R2, R3, R4, R5, R6,and R7 being hydrogen. Therefore, the combined teachings of Choudhary and Olson render claim 5 obvious.
Regarding claim 7, as described above, the combination of Choudhary and Olson results in the above structure X. In this structure, R3 and R4 are C1 alkyl groups (methyl). This meets the criteria of at least one of R1, R2, R3, R4, R5, R6,and R7 being C1-C6 alkyl. Therefore, the combined teachings of Choudhary and Olson render claim 7 obvious.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary and Olson, as applied to claims 1, 5, and 7 above, and further in view of Desantis (US 2023/0132823 A1).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). The combination of Choudhary and Olson results in a structure of Formula X.
Choudhary and Olson do not teach a linking group comprising two ethylene glycol repeats between the amide nitrogen and the thalidomide-attaching amine.
Desantis teaches PROTAC molecules for the proteasomal degradation of the androgen receptor (pg. 3, [0028]-[0029]). Desantis teaches that such compounds possess the structure described by ARB-linker-E3LB wherein ARB is an androgen receptor binder and E3LB is an E3 ligase binder (pg. 17, [0077]-[0078]). Desantis teaches that the linker may take many forms with variable alkyl or polyethylene glycol repeat regions (pg. 28-30, [0182]-[0183]). One embodiment of the linker of Desantis is reproduced below (pg. 28, [0182]):
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Furthermore, Desantis provides examples of such a linker being used to connect a thalidomide moiety to an androgen receptor binding ligand in Examples 4-6 of the table on pages 8-17. Desantis teaches a method of making a molecule with such a linker in Schemes 2 and 3 (molecules O, P, and Q in Scheme 2 (example 34) and examples 4-6 in Scheme 3) (pg. 48-49).
A person of ordinary skill in the art would have recognized that each of Choudhary, Olson, and Desantis teach PROTAC molecules in which similar linear linker groups are attached to the phthalimide ring of thalidomide via an amine. In view of these disclosures, it would be understood that E3 ligase targeting ligands and target protein ligands in PROTAC molecules may be linked by a variety of ligands, including those with alkyl chains or ethylene glycol repeats. It would be recognized that these linker groups are largely interchangeable (MPEP § 2143(I)(B)) and can be adapted and optimized.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula X taught by the combination of Choudhary and Olson by substituting in the ethylene glycol repeat linker taught by Desantis in place of the alkyl chain between the amide nitrogen and the thalidomide-attaching amine. This would result in the predictable result of an effective trimethoprim and thalidomide-containing PROTAC compound.
Regarding claim 25, as described above, the combination of Choudhary and Olson teach a molecule of Formula X. Additionally, Desantis teaches PROTAC molecules wherein an androgen receptor binder and thalidomide-based E3 ligase binder are connected by a linker (pg. 17, [0077]-[0078]). Desantis teaches that the linker may take many forms with variable alkyl or polyethylene glycol repeat regions (pg. 28-30, [0182]-[0183]). This includes the embodiments depicted in Examples 4-6 in the table on page 9. Modifying Formula X with the linker region taught by Desantis results in structures of Formula Y:
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This is a structure that reads on that of compound (7a) in claim 25 wherein there are two ethylene glycol repeats. Furthermore, example 4 of Desantis depicts a linker with two ethylene glycol repeats between the linker amide nitrogen and the thalidomide-attaching amine, which is a linker that reads on that of compound (7a) in claim 25. Therefore, the combination of Choudhary, Olson, and Desantis render claim 25 obvious.
Claims 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Choudhary, Olson, and Desantis, as applied to claim 25 above, and further in view of Natarajan (WO 2022/051616 A1).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). The combination of Choudhary and Olson results in a structure of Formula X. Furthermore, Desantis teaches that a PROTAC linker may take many forms with variable alkyl or polyethylene glycol repeat regions (pg. 28-30, [0182]-[0183]). This includes ethylene glycol repeat linkers between an intra-linker amide and the nitrogen of an amine attachment point to the thalidomide moiety (pg. 9, Table, Examples 4-6; and pg. 28, [0182]).
Choudhary, Olson, and Desantis do not teach a linking group comprising a C3 alkyl chain to the left of the amide (on the other side from the ethylene glycol repeats; on the trimethoprim moiety or targeting group side of the molecule).
Natarajan teaches PROTAC molecules of the formula A-L-B wherein A is a CDK binding moiety, B is an E3 ligase binding moiety, and L is a linking group (pg. 1, [0004]). Natarajan teaches that the E3 ligase binding moiety may be thalidomide or pomalidomide (pg. 13, [0035]). Natarajan teaches that the linker can vary, teaching several examples of linkers with alkyl chains, ethylene glycol repeats, intra-linker amides, nitrogen attachments to the E3 binding ligand, and oxygen attachments to the target protein binding ligand (pg. 7-10, [0031]). Among these embodiments are examples in which the linker comprises an oxygen attachment to the target protein binding ligand, a C3 alkyl chain, an amide, ethylene glycol repeats, and a nitrogen connection to the E3 binding ligand (5th example on pg. 7 and 3rd example on pg. 8). Specific examples of Natarajan include Compound 4, in which a C3 alkyl is connected to two ethylene glycol repeats via an amide in the linker group (pg. 43, [0149]) and Compound 7, in which a C3 alkyl is connected to three ethylene glycol repeats via an amide in the linker group (pg. 44, [0155]). In these specific examples, the attachment of the linker to the target protein binding ligand is through an oxygen connected to an aryl group.
A person of ordinary skill in the art would have recognized that each of Choudhary, Olson, Desantis, and Natarajan teach PROTAC molecules in which similar linear linker groups are attached to the phthalimide ring of thalidomide via an amine. In view of these disclosures, it would be understood that E3 ligase targeting ligands and target protein ligands in PROTAC molecules may be linked by a variety of ligands, including those with alkyl chains and/or ethylene glycol repeats or combinations of alkyl and ethylene glycol repeat regions connected by an amide. It would be recognized that these linker groups are largely interchangeable (MPEP § 2143(I)(B)) and can be adapted and optimized.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula Y taught by the combination of Choudhary, Olson, and Desantis by substituting in the C3 alkyl linker region between the target protein binding ligand and the linker amide as taught by Natarajan in place of the C1 alkyl group. This would result in the predictable result of an effective trimethoprim and thalidomide-containing PROTAC compound.
Regarding claim 26, as described above, the combination of Choudhary, Olson, and Desantis teach a molecule of Formula Y. Additionally, Natarajan teaches PROTAC molecules wherein the linker group contains different combinations of alkyl and ethylene glycol chains connected by an amide (pg. 7-10, [0031]). Among this list includes examples in which the linker comprises an oxygen attachment to the target protein binding ligand, a C3 alkyl chain, an amide, ethylene glycol repeats, and a nitrogen connection to the E3 binding ligand (5th example on pg. 7 and 3rd example on pg. 8). Modifying Formula Y with the C3 alkyl group results in the structure of Formula Z:
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In the embodiment of Formula Z in which the ethylene glycol portion of the molecule has 1 instance of ethylene glycol, this reads on compound (7b) of claim 26. Therefore, the combined teachings of Choudhary, Olson, Desantis, and Natarajan render claim 26 obvious.
Regarding claim 27, the embodiment of Formula Z in which the ethylene glycol portion of the molecule has 2 instances of ethylene glycol reads on compound (7c) of claim 27. This ethylene glycol linker region is also taught in example 4 of Desantis (pg. 9 Table) and Compound 4 of Natarajan (pg. 43, [00149]). Therefore, the combined teachings of Choudhary, Olson, Desantis, and Natarajan render claim 27 obvious.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary, Olson, Desantis, and Natarajan, as applied to claims 26 and 27 above, and further in view of Choi (US 2023/0078961 A1).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). Desantis teaches that a PROTAC linker may take many forms with variable alkyl or polyethylene glycol repeat regions (pg. 28-30, [0182]-[0183]). This includes ethylene glycol repeat linkers between an intra-linker amide and the nitrogen of an amine attachment point to the thalidomide moiety (pg. 9, Table, Examples 4-6; and pg. 28, [0182]). Additionally, Natarajan teaches PROTAC molecules with varying linkers, teaching several examples of linkers with alkyl chains, ethylene glycol repeats, intra-linker amides, nitrogen attachments to the E3 binding ligand, and oxygen attachments to the target protein binding ligand (pg. 7-10, [0031]). Among these embodiments are examples in which the linker comprises an oxygen attachment to the target protein binding ligand, a C3 alkyl chain, an amide, ethylene glycol repeats, and a nitrogen connection to the E3 binding ligand (5th example on pg. 7 and 3rd example on pg. 8). The combination of Choudhary, Olson, Desantis, and Natarajan results in a structure of Formula Z.
Choudhary, Olson, Desantis, and Natarajan do not teach a linking group comprising six ethylene glycol repeats between an amide and a thalidomide-attaching amine.
Choi teaches PROTAC molecules comprising an HMG-CoA reductase binding moiety, an E3 ubiquitin ligase binding moiety, and a linker group (pg. 1, [0011]). Such degrader compounds can include thalidomide and pomalidomide-type E3 ubiquitin ligase binding moieties (pg. 3, [0040]). The linking group may take a variety of forms and may contain alkyl, cycloalkyl, ethylene glycol, amine, amide, and other groups (pg. 10, [0100] through pg. 12, [0120]; and the molecules of Table 1, pg. 18-65). Among the examples includes Compound 6 (Table, pg. 19), Compound 44 (Table, pg. 30), and Compound 50 (Table, pg. 31). Choi further teaches the methods of synthesizing Compound 6 (pg. 77-79, [0223]-[231]), Compound 44, and Compound 50 (pg. 148-149, [0532]-[0539]). These specific examples contain a linker comprising an amide group, six ethylene glycol repeats, and an amine connection point to the thalidomide moiety.
A person of ordinary skill in the art would have recognized that each of Choudhary, Olson, Desantis, Natarajan, and Choi teach PROTAC molecules in which similar linear linker groups are attached to the phthalimide ring of thalidomide via an amine. In view of these disclosures, it would be understood that E3 ligase targeting ligands and target protein ligands in PROTAC molecules may be linked by a variety of ligands, including those with alkyl chains and/or ethylene glycol repeats or combinations of alkyl and ethylene glycol repeat regions connected by an amide. It would be recognized that these linker groups are largely interchangeable (MPEP § 2143(I)(B)) and can be adapted and optimized.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula Z taught by the combination of Choudhary, Olson, Desantis, and Natarajan by substituting in the six ethylene glycol repeats in the linker region between the amide and the thalidomide-attaching amine as taught by Choi in place of the 1-5 ethylene glycol repeat region. This would result in the predictable result of an effective trimethoprim and thalidomide-containing PROTAC compound.
Regarding claim 28, as described above, the combination of Choudhary, Olson, Desantis, and Natarajan teach a molecule of Formula Z. Additionally, Choi teaches PROTAC molecules wherein the linker group contains six ethylene glycol repeats: Compound 6 (Table, pg. 19), Compound 44 (Table, pg. 30), and Compound 50 (Table, pg. 31). Furthermore, Natarajan suggests that linker length may contribute to the selectivity and potency of PROTAC molecules (pg. 7, [0029]); and Desantis states that linker length contributes to the effectiveness of degradation molecules (pg. 2, [0012]), providing additional motivation to modify and optimize the linker region of such a molecule. The modification of Formula Z with the six ethylene glycol repeats as taught by Choi results in a compound that reads on Compound (7e) of claim 28. Therefore, the combined teachings of Choudhary, Olson, Desantis, Natarajan, and Choi render claim 28 obvious.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary, Olson, Desantis, and Natarajan, as applied to claims 26 and 27 above, and further in view of Gray (US 2021/0338825 A1).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). Desantis teaches that a PROTAC linker may take many forms with variable alkyl or polyethylene glycol repeat regions (pg. 28-30, [0182]-[0183]). This includes ethylene glycol repeat linkers between an intra-linker amide and the nitrogen of an amine attachment point to the thalidomide moiety (pg. 9, Table, Examples 4-6; and pg. 28, [0182]). Additionally, Natarajan teaches PROTAC molecules with varying linkers, teaching several examples of linkers with alkyl chains, ethylene glycol repeats, intra-linker amides, nitrogen attachments to the E3 binding ligand, and oxygen attachments to the target protein binding ligand (pg. 7-10, [0031]). Among these embodiments are examples in which the linker comprises an oxygen attachment to the target protein binding ligand, a C3 alkyl chain, an amide, ethylene glycol repeats, and a nitrogen connection to the E3 binding ligand (5th example on pg. 7 and 3rd example on pg. 8). The combination of Choudhary, Olson, Desantis, and Natarajan results in a structure of Formula Z.
Choudhary, Olson, Desantis, and Natarajan do not teach a compound comprising trimethoprim and thalidomide connected by a linker wherein the thalidomide moiety is modified by a methyl group on the nitrogen of the pyridinyl group.
Gray teaches PROTAC compounds comprising a hepatitis C virus NS3/4A targeting ligand, a linker, and a degron moiety that binds to an E3 ubiquitin ligase (pg. 6, [0060]). Gray teaches that the linker can vary, providing examples of linear linkers containing alkyl, cycloalkyl, ethylene glycol, and amide groups (pg. 8-12, [0069]-[0076]). Gray teaches that the degron group may contain thalidomide and pomalidomide-like structures (pg. 14-16, [0083]). Gray also teaches compounds containing a methyl substitution on the nitrogen of the pyridinyl group in the thalidomide moiety: Compound 19 (pg. 65-66, [0216]-[0218]), Compound 20 (pg. 66-67, [219]-[221])., and Compound 21 (pg. 70-71,[222]-[224]). In the disclosed syntheses, Choi uses an N-methyl modified thalidomide derivative as the starting material instead of the N-H form used in the syntheses of the other examples. Choi teaches that this methyl substitution abolished binding to cereblon (the E3 ubiquitin ligase) (pg. 73, [0235]) and used such compounds as negative controls in protein degradation experiments (pg. 72-73, [0232]-[0234], Fig. 3, and Fig. 4).
A person of ordinary skill in the art would have recognized that each of Choudhary, Olson, Desantis, Natarajan, and Gray teach PROTAC molecules in which similar linear linker groups are attached to the phthalimide ring of thalidomide via an amine. It would also be recognized that negative controls are useful components of scientific experimentation and pharmaceutical development. It would be recognized that the N-methyl modification of the thalidomide moiety taught by Gray prevents the E3 ubiquitin ligase targeting required by active PROTAC compounds while still being a molecule with a similar structure to the active molecule, meaning that this compound has similar chemical properties, making it a useful negative control. As this N-methyl modification does not alter the portion of the thalidomide moiety being attached to the linker group, preparation of such N-methyl variants of thalidomide-containing PROTAC molecules can be done similar to the synthesis of the active compounds with just substituting the starting thalidomide derivative reagent with the N-methyl modified form (MPEP § 2143(I)(B)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula Z taught by the combination of Choudhary, Olson, Desantis, and Natarajan by substituting in the N-methyl modified thalidomide derivative as taught by Gray in place of the N-H form of the molecule. This would result in the predictable result of a useful negative control for experimentation with trimethoprim and thalidomide-containing PROTAC compounds.
Regarding claim 29, as described above, the combination of Choudhary, Olson, Desantis, and Natarajan teach a molecule of Formula Z. Additionally, Gray teaches N-methylation of the nitrogen of the pyridinyl group of the thalidomide-based degron produces a molecule useful as a negative control in PROTAC activity assays (pg. 72-73, [0232]-[0235]). The modification of the embodiment of Formula Z containing two ethylene glycol repeats with this N-methylation results in a compound that reads on Compound (7f) of claim 29. Therefore, the combined teachings of Choudhary, Olson, Desantis, Natarajan, and Gray render claim 29 obvious.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary and Olson, as applied to claims 1, 5, and 7 above, and further in view of Reyba (ES 0428624 A1 – provided by applicant in IDS filed December 19, 2023).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). The combination of Choudhary and Olson results in a structure of Formula X.
Choudhary and Olson do not teach a molecule in which each of R1, R2, R3, R4, R5, R6,and R7 of formula (I) is hydrogen.
Reyba teaches methods of preparing pyrimidine derivatives (Abstract). Example 1 of Reyba teaches a method of synthesis of trimethoprim (pg. 2-3). In this method, Reyba uses 5-[2,4-diamino-5-pyrimidinyl)methyl]-1,2,3-benzenetriol as the starting reagent (pg. 2, lines 19-24).
A person of ordinary skill in the art would have recognized that both Choudhary (and the combination of Choudhary and Olson) and Reyba teach trimethoprim-related molecules. It would be recognized that the 5-[2,4-diamino-5-pyrimidinyl)methyl]-1,2,3-benzenetriol starting material of Reyba could be used for the synthesis of a trimethoprim-derivative PROTAC compound. Furthermore, it would be understood that in the art of organic synthetic chemistry, targeted functionalization of an individual hydroxyl would be possible through reagent selection, protecting groups, and purification and separation techniques standard in the art. Thus, any hydroxyl of the starting reagent of Reyba could be used for the attachment point of the linking group. Therefore, the trihydroxy starting reagent of Reyba could be used similarly to a trimethoprim starting reagent and be substituted in the method of preparing a PROTAC compound and produce a predictable result wherein there are hydroxy groups instead of methoxy groups on the benzyl group of the trimethoprim derivative (MPEP § 2143(I)(B)). This trihydroxy reagent is known in the art to be capable of use for generating a trimethoprim product (MPEP § 2143(I)(A)) and thus could be used as a starting reagent for PROTAC synthesis and an intermediate later modified to generate the methoxy form instead of hydroxyl groups.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula X taught by the combination of Choudhary and Olson by substituting in the 5-[2,4-diamino-5-pyrimidinyl)methyl]-1,2,3-benzenetriol core of Reyba in place of the trimethoprim group, as this is an alternative molecule of similar structure known in the art that could be used toward the synthesis of the trimethoprim containing final product. This would result in the predictable result of an intermediate for the preparation of a trimethoprim and thalidomide-containing PROTAC compound of the following structure (Formula H).
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Regarding claim 6, as described above, the combination of Choudhary and Olson teach a molecule of Formula X. Additionally, Reyba teaches using 5-[2,4-diamino-5-pyrimidinyl)methyl]-1,2,3-benzenetriol as the starting reagent for the preparation of trimethoprim (pg. 2, lines 19-24). The use of this trihydroxy starting reagent in the preparation of a PROTAC like the one of Formula X would result in the generation of the structure of Formula H. This is a structure that reads on formula (I) of claim 1 wherein X is O; Y is -CR1R2-; n is 1; n’ is 2; and R1, R2, R3, R4, R5, R6,and R7 are all hydrogen. Thus, this is a molecule in which each of R1, R2, R3, R4, R5, R6,and R7 is hydrogen. Therefore, the combined teachings of Choudhary, Olson, and Reyba render claim 6 obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary and Olson, as applied to claims 1, 5, and 7 above, and further in view of Gray, Heinrich (US 2022/0062258 A1), and Sellmyer 2017 (Sellmyer, M. A.; et al., PNAS, 2017 – provided by applicant in IDS filed December 19, 2023).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). The combination of Choudhary and Olson results in a structure of Formula X.
Choudhary and Olson do not teach a molecule in which each of R1, R2, R3, R4, R5, R6,and R7 of formula (I) is C1-C6 alkyl.
As described above, Gray teaches PROTAC compounds comprising various linear linkers containing alkyl, cycloalkyl, ethylene glycol, and amide groups (pg. 8-12, [0069]-[0076]) and thalidomide and pomalidomide-like degron moieties (pg. 14-16, [0083]). Gray also teaches compounds containing a methyl substitution on the nitrogen of the pyridinyl group in the thalidomide moiety: Compound 19 (pg. 65-66, [0216]-[0218]), Compound 20 (pg. 66-67, [219]-[221])., and Compound 21 (pg. 70-71,[222]-[224]). In the disclosed syntheses, Choi uses an N-methyl modified thalidomide derivative as the starting material instead of the N-H form used in the syntheses of the other examples. Choi teaches that this methyl substitution abolished binding to cereblon (the E3 ubiquitin ligase) (pg. 73, [0235]) and used such compounds as negative controls in protein degradation experiments (pg. 72-73, [0232]-[0234], Fig. 3, and Fig. 4).
Heinrich teaches PROTAC compounds for the targeted degradation of MetAP-2 (pg. 1, [0012]). Heinrich discloses several example compounds containing a thalidomide moiety E3 ubiquitin ligase binding group and a linear alkyl or ethylene glycol-based linker attached to the 4-position of the phthalimide ring by an amine and having an amide on the other side of the linking group: Compound A1 (pg. 15), Compound A5 (pg. 20), Compound A9 (pg. 22), Compounds A15-A28 (pg. 24-28), Compound A44 (pg. 39-40), and Compound A45 (pg. 40-43). In Compound A45, both the nitrogen at the attachment to the thalidomide moiety and the nitrogen of the intra-linker amide are methylated. Heinrich teaches that Compound A45 has an IC50 in HUVEC cells of 610 nM (pg. 90, Table 1).
Sellmyer 2017 teaches imaging bacterial infections in mice using an 18F-labeled trimethoprim derivative (pg. 8372, Abstract and pg. 8374, Fig. 4). Sellmyer 2017 teaches the synthesis of the [18F]FPTMP imaging molecule (pg. 8373, Fig. 1). In the synthesis of this trimethoprim derivative, Sellmyer 2017 teaches using Boc protecting groups to protect the primary amines on the trimethoprim core (pg. 8373, Fig. 1). The Boc protecting groups are present for intermediate molecules but are removed to generate the final product.
A person of ordinary skill in the art would have recognized that each of Choudhary, Olson, Gray, and Heinrich teach PROTAC molecules. Such molecules can each be described in a modular form as containing a target protein binding group, a linking group, and an E3 ubiquitin ligase binding group. It would be recognized that each of these components of the PROTAC molecules serve similar purposes between the analogous groups and that each chemical group can be readily substituted between each other to achieve predictable results (MPEP § 2143(I)(B)). It would be recognized that linking groups, such as the N-methyl modified linker taught by Heinrich, are highly interchangeable and can be varied for optimization. It would also be recognized that negative controls are useful components of scientific experimentation and pharmaceutical development. It would be recognized that the N-methyl modification of the thalidomide moiety taught by Gray prevents the E3 ubiquitin ligase targeting required by active PROTAC compounds while still being a molecule with a similar structure to the active molecule, meaning that this compound has similar chemical properties, making it a useful negative control. Furthermore, it would be recognized that both Choudhary (and the combination of Choudhary and Olson) and Sellmyer 2017 teach trimethoprim derivative molecules. Amine protection with Boc groups is well understood in the art of organic synthesis and it would be recognized that the Boc protected intermediates of Sellmyer 2017 enabled targeted functionalization at other parts of the molecule.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Formula X taught by the combination of Choudhary and Olson by substituting in the N-methyl modified ethylene glycol repeat linker from the thalidomide to the amide group as taught by Heinrich in place of the alkyl linking group, the N-methyl modified thalidomide derivative as taught by Gray in place of the N-H form of the molecule, and the Boc-protection on the primary amines of the trimethoprim group as taught by Sellmyer 2017. This would result in the predictable result of an intermediate for the preparation of a useful negative control for experimentation with trimethoprim and thalidomide-containing PROTAC compounds of the following structure (Formula M).
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Regarding claim 8, as described above, the combination of Choudhary and Olson teach a molecule of Formula X. Additionally, Gray teaches N-methylation of the nitrogen of the pyridinyl group of the thalidomide-based degron produces a molecule useful as a negative control in PROTAC activity assays (pg. 72-73, [0232]-[0235]). Furthermore, Heinrich teaches N-methyl modification of a linear ethylene glycol-based linker region at the linker ends that are the nitrogen of an amine connecting to a thalidomide moiety and the nitrogen of an intra-linker amide (Compound A45, pg. 40-43). Additionally, Sellmyer 2017 teaches the synthesis of trimethoprim derivatives using bis-Boc protection of primary amines on the trimethoprim core (pg. 8373, Fig. 1). The combination of the modifications of Gray, Heinrich, and Sellmyer 2017 with the structure of Formula X results in Formula M. This is a structure that reads on formula (I) of claim 1 wherein X is O; Y is O; n is 1; n’ is 5; R3, R4, R5, R6,and R7 are methyl groups (unsubstituted C1 alkyl groups) and R1 and R2 are Boc groups, which can be interpreted to be substituted C1 alkyl groups. Thus, this is a molecule in which each of R1, R2, R3, R4, R5, R6,and R7 is C1-C6 alkyl. Therefore, the combined teachings of Choudhary, Olson, Gray, Heinrich, and Sellmyer 2017 render claim 8 obvious.
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Choudhary and Olson, as applied to claims 1, 5, and 7 above, and further in view of Sellmyer 2020 (Sellmyer, M. A.; et al., Mol. Ther., 2020 – provided by applicant in IDS filed December 19, 2023).
As described above, Choudhary teaches a heterobifunctional degrader molecule comprising a trimethoprim moiety linked to a thalidomide moiety, TMP dTAG (Fig. 1A). Olson teaches a degrader molecule comprising a CDK9-binding ligand (SNS-032) and a thalidomide moiety with the linker attaching to a thalidomide moiety at the 4-position of the phthalimide ring (pg. 164, Figure 1A). The combination of Choudhary and Olson results in a structure of Formula X. Furthermore, Choudhary teaches CRISPR Cas protein variants that have been modified with one or more FBKP12F36V domains (pg. 2, [0009]) and teaches that the heterobifunctional degrader molecules including TMP dTAG can be used to target this CRISPR Cas protein variant for ubiquitination and proteasomal degradation (pg. 1-2, [0008] and pg. 2-3, [0012]-[0014]). Choudhary teaches that the CRISPR Cas variant target protein can be provided into subjects or cells either in the form of the protein or a DNA construct that can be used by the cells to produce the protein (pg. 2, [0010]-[0011] and pg. 7-8, [0049]-[0052]). Choudhary teaches a method wherein a CRISPR Cas variant protein is introduced into cells or a subject and then compounds such as TMP dTAG are administered to cells to bind to the CRISPR Cas variant protein and exert the effect of degrading the CRISPR Cas variant protein (pg. 20, [0175]-[0176]). Choudhary also teaches a kit containing the variant CRISPR Cas protein that may further contain a heterobifunctional degrader molecule, including TMP dTAG (pg. 55, [0372]).
Choudhary and Olson do not teach a kit comprising both a compound of formula (I) and a dihydrofolate reductase enzyme construct.
Sellmyer 2020 teaches PET imaging of CAR T cell trafficking within mice using CAR T cells modified to express a dihydrofolate reductase (DHFR) protein and an 18F-modified trimethoprim derivative probe (pg. 42, Abstract and pg. 44, Figure 2). Sellmyer 2020 teaches that the PET imaging probe is a derivative of trimethoprim (pg. 43, Figure 1B and pg. 45, left column, last paragraph). Sellmyer 2020 teaches that this trimethoprim derivative can bind to Escherichia coli DHFR (eDHFR) (in the form of eDHFR-tagged proteins) in cells and mice (pg. 43, left column, last paragraph and pg. 44, Figure 2). Sellmyer 2020 teaches that the eDHFR-tagged protein can be introduced into cells via a lentiviral vector DNA construct containing the genetic code for eDHFR fused to YFP (pg. 48, Cloning and Molecular Biology). Sellmyer 2020 teaches transducing CAR T cells with the aforementioned lentiviral construct containing eDHFR (pg. 48, CAR T Cell Generation), injecting the cells into mice (pg. 49, Tumor Uptake), and administering the 18F-modified trimethoprim derivative to the mice (pg. 49-50, CAR T Cell Tracking). Sellmyer 2020 teaches the combination of the introduction of eDHFR in a DNA construct and administration of the trimethoprim derivative as a useful combination for the imaging of CAR T cells in a living organism (pg. 44, Figure 2; pg. 46, Figure 4; and pg. 48, Conclusions).
A person of ordinary skill in the art would have recognized that both Choudhary (and the combination of Choudhary and Olson) and Sellmyer 2020 teach trimethoprim derivative molecules. It would also be recognized that both Choudhary and Sellmyer 2020 teach methods of using the trimethoprim derivative molecules wherein first a target protein is introduced into cells. Choudhary teaches the target protein can be provided as protein or as a DNA construct. Similarly, Sellmyer 2020 teaches introducing an eDHFR construct to cells by transduction of a DNA construct containing the code for the transcription and translation of an eDHFR-containing fusion protein. It would be recognized that Sellmyer 2020 teaches that trimethoprim derivatives can be used to target and study dihydrofolate reductase proteins in cells and subjects. It would also be understood that the compound of Formula X is also a trimethoprim derivative. It would be recognized that the compound of Formula X could also be used in combination with eDHFR and used like Choudhary and Olson teach it to degrade a target protein made by the construct by the cells (due to the thalidomide-containing portion targeting the bound molecule to an E3 ubiquitin ligase). It would be recognized that the kit taught by Choudhary containing the TMP dTAG compound and the CRISPR Cas variant protein (and thus the combination of Choudhary and Olson would teach a kit comprising a compound of Formula X and the CRISPR Cas variant protein). This kit is a combination of a trimethoprim derivative compound and its target for use in cells or living subjects. A person of ordinary skill in the art would recognize that a construct containing DHFR could be viewed as an alternative to the CRISPR Cas variant protein taught by Choudhary, as both could be introduced to cells and provide a target upon which the compound of Formula X would act. The functions of both the CRISPR Cas variant protein and the DHFR-containing construct are known in the art as discussed above and the substitution of the CRISPR Cas variant protein for the DHFR-containing construct would have predictable results, as these features would serve a similar purpose in the kit of providing a means to introduce a target of the compound of Formula X into a cell or living subject (MPEP § 2143(I)(B)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit containing the compound of Formula X and a CRISPR Cas variant protein taught by the combination of Choudhary and Olson by substituting in eDHFR-containing lentiviral construct taught by Sellmyer 2020 in place of the CRISPR Cas variant protein, as this is an alternative means of introducing a target of a trimethoprim derivative molecule into cells. This would result in the predictable result of a kit containing a trimethoprim derivative compound and the source of a target protein for its use in cells.
Regarding claim 52, as described above, the combination of Choudhary and Olson teach a molecule of Formula X, which reads on the limitation of a compound of formula (I). Furthermore, Choudhary teaches a kit comprising a variant CRISPR Cas protein and a thalidomide-trimethoprim heterobifunctional degrader (TMP-dTAG) (pg. 55, [0372]). Choudhary teaches that TMP-dTAG can be used to target this CRISPR Cas variant protein for degradation (pg. 1-2, [0008]; pg. 2-3, [0012]-[0014]; and pg. 20, [0175]-[0176]). Choudhary teaches that the CRISPR Cas variant target protein can be provided into subjects or cells either in the form of the protein or a DNA construct that can be used by the cells to produce the protein (pg. 2, [0010]-[0011] and pg. 7-8, [0049]-[0052]). Additionally, Sellmyer 2020 teaches that a trimethoprim derivative molecule can be used to bind to target eDHFR-containing proteins introduced into cells via a lentiviral construct (pg. 44, Figure 2; pg. 43, left column, last paragraph; pg. 48, Cloning and Molecular Biology; and pg. 48, CAR T Cell Generation). Sellmyer 2020 further teaches the combination of the introduction of eDHFR in a DNA construct and administration of the trimethoprim derivative as a useful combination for the imaging of CAR T cells in a living organism (pg. 44, Figure 2; pg. 46, Figure 4; and pg. 48, Conclusions). Therefore, the combined teachings of Choudhary, Olson, and Sellmyer 2020 render claim 52 obvious.
Conclusion
All claims are rejected.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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