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 Claims
Pursuant to the amendment filed on March 22, 2024, claims 4-12, 14, 16, 17, 21, 24 and 25 have been amended and claims 18-20 are cancelled. Claims 1-17 and 21-25 are pending.
Priority
This application, filed on March 22, 2024, is a National Stage entry from International Application No. PCT/GB2022/052408, filed on September 23, 2022, which claims priority to the Great Britain Application No. GB2113656, filed on September 24, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) filed on March 22, 2024, April 2, 2024, and July 18, 2024 have been acknowledged and considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means,” “said,” and “comprise” should be avoided.
The Abstract recites “The present invention concerns…” and “comprise.”
Appropriate correction is required.
Claim Objections
Claim 23 is objected to for minor informalities. Claim 23 recites, “…wherein the mutation occurs in one of more bromodomains…” The intended claim limitation appears to be “one or more bromodomains.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
Claims 1–10, 13, and 21–25 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter that was not described in the Specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit stated “the hallmark of written description is disclosure.” A specification adequately describes an invention when it “reasonably conveys to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.” Id. “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). In Ariad, the Federal Circuit explained what is required to meet the written description requirement:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357–58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
Further, the written description of a genus, such as a chemical genus, “requires a precise structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit commented on that case in the Ariad decision:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed.Cir.1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed.Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
The factors outlined in the above Federal Circuit cases are analyzed with respect to the claimed invention in turn below.
(A) The nature and scope of the claim invention in view of the specification: the claimed invention relates generally to the chemical art and more specifically to a degrader compound of formula (IA):
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, wherein variable D’ is the product of a reactive group, D, with a pro-linker to form D’-L, L is a molecule capable of binding to D’ to B, and B is a molecule capable of binding to an E3 ubiquitin ligase.
Claim 11 defines D′ as any one selected from the group consisting of (CH2)pC(O), (CH2)qNH, (CH2)qS, (CH2)qO, (CH2)q and 1,2,3-triazolylene, wherein p is an integer from 0 to 4 or is 0 and q is an integer from 1 to 4 or is 1. Claim 12 defines D′ as C(O).
Claim 14 defines L as formula (VIA)
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, wherein the wavy lines indicate the positions of attachment; X1 is optionally present and is any one selected from the group consisting of O(CH2)s, NH(CH2)s and C(O)(CH2)s; X2 is optionally present and is selected from the group consisting of O(CH2)uC(O), (CH2)uNH, (CH2)uO and (CH2)uC(O);
L′ is selected from the group consisting of O(CH2)t, CH2, alkynylene, triazolylene, piperazinylene and piperidinylene; s is an integer from 0 to 4, u is an integer from 1 to 4 and t is an integer from 1 to 4. Claim 15 states X1 is any one selected from the group consisting of O(CH2)2 and HN(CH2)2; X2 is OCH2C(O) or CH2NH; and L′ is O(CH2)t, wherein t is 2 or 3.
Claim 16 defines B is any one of the structures represented by any one of formulae (VIIA) to (XIA):
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, wherein R7 is H or methyl and Z is F or CN.
The Specification provides examples of D’, L, and B (Spec., p.p. 17-20). Those examples are the same as those recited in claims 11, 12, and 14–16 noted above. Exemplary compounds either have the D’ groups as C(O)OH or C(O)NH2, the L are all polyethylene glycol (PEG) linkers with 3-4 repeating units, and the B groups are all VHL E3 ubiquitin ligands.
The Specification does not provide examples of any other D’, L, or B groups.
(B) The extent and content of the prior art: The compounds of formula I are degrader compounds to selectively degrade a protein of interest to identify its importance to cellular growth and function and establishes whether the target protein is a modulator of a disease state or condition (Spec., p. 5, lines 8-13).
According to a review article, (Troup et al., Explor. Target Antitumor Ther. (2020) 1, 273-312), while high-affinity ligands for MDM2, VHL, and CRBN have been discovered, there are over 600 E3 ligases that have been identified in the human proteome and a general dearth of high affinity ligands available for them. Other E3 ligase targets identified are CUL4-DDB1, RNF4, and Keap1. (p. 276, PROTAC anchors).
The same review article discusses the importance of not just the PROTAC anchor and the PROTAC warhead (Id., p. 277) for the E3 ligase and the protein of interest, respectively, but also a suitable linker allowing a productive ternary complex formation and protein of interest ubiquitination (p. 278, PROTAC linkers). A survey of 400 published degrader structures, showed a majority of the structures containing PEG and alkyl linkers of varying length, however there have been reports of degrader compounds containing alkynes, triazoles, and saturated heterocycles like piperazine and piperidine. Troup et al. states: “By far the most common motifs incorporated into PROTAC linker structures are PEG and alkyl chains of varying lengths, and these are the sole motif in approximately 55% and 30% of linkers respectively. Around 65% of structures in the database contained both an alkyl and PEG segment. A further 15% used modifications of the individual glycol units, incorporating additional methylene moieties to access different chain lengths. Other represented motifs include alkynes (7%), triazoles (6%) and saturated heterocycles such as piperazine and piperidine (4% each).” (p. 279, Table 1).
Accordingly, the prior art discloses variability in PROTAC degrader compounds with respect to linkers and PROTAC anchors, of at least 400 reported degraded compounds, wherein most of the compounds contain a PEG and/or alkyl linker motif.
(C) The maturity of the science or technology: while degrader compounds with varying ligands of E3 ligases and varying linkers, the claims are directed to degrader compounds with all possible linker combinations and all possible E3 ligase ligands. Based on the prior art, most of the degrader compounds reported contain a PEG and/or alkyl linker motif and various PROTAC anchors targeting MDM2, VHL, CRBN, CUL4-DDB1, RNF4, and Keap1, however there are over 600 E3 ligases in the human proteome, a majority of which have a dearth of high affinity ligands. As such, the science relevant to the claimed invention is in its infancy.
(D) The predictability of the aspect at issue: the pharmaceutical art is generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The art describes at least 400 degrader compounds, with several possible linkers and E3 ligands currently reported. Id. However, there are over 600 E3 ligases in the human proteome, lacking high affinity ligands. The art requires each potential degrader compound to be assessed for its capacity to degrade a protein of interest, and therefore possess a high degree of unpredictability. The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement.
Conclusion regarding written description
When the factors and evidence discussed above are considered as a whole, one of skill in the art would conclude the specification (in view of the prior art) does not adequately describe a representative number of species to support the claimed genera of degrader compounds of formula IA, wherein variable D’ is the product of a reactive group, D, with a pro-linker to form D’-L, L is a molecule capable of binding to D’ to B, and B is a molecule capable of binding to an E3 ubiquitin ligase. That functional language possibly encompasses thousands to millions of compounds based on combinations of D’, L, and B. By contrast, the application (claims and specification) describe a limited number of examples for D’, L, and B. Accordingly, the Specification does not reasonably convey to those skilled in the art the Applicant had possession of the broadly claimed subject matter as of the filing date.
Examiner recommends amending claim 1 to incorporate the limitations of claims 11, 12, and 14–16, which are not rejected because they define D’, L, and B with structures having support in the disclosure, rather than the functional language currently recited in claim 1.
Claims 2-10, 13, and 21-25 do not rectify the written description issue present in claim 1 and are therefore rejected by virtue of their dependency.
Claim Rejections - 35 USC § 112(b)
Claim 23 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.
Claim 23 recites, “…wherein the mutation occurs in one of more bromodomains which are present in the protein…” Claim 23 depends from claim 22, which depends from claim 21. Claim 22 recites “the target protein,” and claim 21 refers to “a target protein” and “a fusion protein.” Therefore, claim 23 is indefinite because it is unclear which protein the claim is referring to.
Appropriate correction is required.
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 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over WO2016146985 (“Ciulli”) in view of Bond et al., Org. Biomol. Chem., 18, 7533, Published August 5, 2020 (#1 in NPL in IDS filed on April 2, 2024) (“Bond”).
Ciulli teaches small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility as Proteolysis Targeted Chimeras (PROTACs). The PROTACs are taught to bind to a protein within the bromo- and Extra-terminal (BET) family of proteins which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins (Abstract).
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Ciulli teaches a group of PROTACs that link together specific von Hippel-Lindau (VHL) ligands and BET bromodomain ligands. The VHL ligands taught are VHL-1 and VHL-2 (p. 34, lines 23-25, Fig. 1a) and the BET inhibitor taught is JQ1 (p. 34, lines 26-29). The linkers connecting the VHL ligands and JQ1 ligand are of different lengths comprising polyethylene glycol chains with either 3-4 ethylene glycol units (p. 34, lines 30-32, Fig. 1a). The linker bears an azide on one end and a carboxylic acid on the other, the ester of JQ1 reacts with the azide of the linker and the carbamate of VHL reacts with the carboxylic end (p. 35, lines 1-6, Fig. 1a). Three of the compounds taught comprise the JQ1 molecule conjugated with the VHL-1 ligand through a polyethylene glycol linker wherein n =3 (shown below).
Ciulli does not teach JQ1 alkylated at the methylene position.
Bond teaches the synthesis of allele-specific BET inhibitors, namely derivatives of JQ1. The ET-JQ1-OMe ester was prepared as a BET inhibitor and showed exquisite selectivity for Leu-Ala and Leu-Val mutants over the wildtype bromodomain (p. 7533, Abstract). Bond teaches a method of inhibiting the Brd4(2) domain wherein Leu is mutated to Ala at position 387 (L387A) and Leu is mutated to Val at the same position (L387V) (p. 7536, Fig. 3, 1st column, 1st indented ¶). Bond states: “Access to carboxylic derivatives retaining enantiomeric purity enables functionalization into conjugates such as biotinylated and fluorescent probes and PROTACs, which will further expand the scope and utility of this new synthetic strategy for chemical biology investigation.”
Ciulli and Bond are considered analogous art to the claimed invention because they are in the same field of deploying Brd4 selective inhibitors of the BET family for inhibition. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), before the effective filing date of the claimed invention, to modify the BET inhibitor, JQ1, in the PROTAC taught in Ciulli with ET-JQ1 taught by Bond to arrive at the invention instantly claimed. Based on the teachings of Ciulli, there is a need for intra-BET selective inhibitors within the BET family of proteins as probes for target validation (p. 2, lines 20-24). The teachings of Bond rectify this need by providing modified JQ1 inhibitors with either a methyl or an ethyl group on the methylene position of JQ1 (vide supra). The teachings of Ciulli shows the preparation of the PROTAC requires an ester of the BET inhibitor JQ1, therefore it would have been prima facie obvious to substitute the JQ1 inhibitor used to prepare the PROTAC in Ciulli for the ET-JQ1-OMe taught by Bond because Bond teaches ET-JQ1-OMe shows exquisite selectivity for mutant Brd4 and provides motivation to incorporate the “bumped”, i.e., the alkylated, inhibitor into a PROTAC for chemical biology investigation (vide supra). Furthermore, the JQ1 and ET-JQ1-OMe BET inhibitors are equivalents known for the same purpose, inhibiting Brd4, therefore the substitution of JQ1 for ET-JQ1-OMe would have been prima facie obvious to a PHOSITA (MPEP §2144.06(II)) to arrive at a PROTAC with formula XXIA. Accordingly, claims 1-5, 7-17 are prima facie obvious.
Regarding claim 6, instant claim 1 recites n(R3) wherein n is in the range of 0-4, and therefore claim 6 incorporates by reference the range of n, which includes n=0. Therefore, substitution of the ET-JQ1-OMe Brd4 inhibitor taught by Bond for the JQ1 BET inhibitor taught by Ciulli would have been prima facie obvious to a PHOSITA.
Claims 21-25 are rejected under 35 U.S.C. 103 as being unpatentable over Ciulli in Bond further in view of Nowak et al., J. Med. Chem. 2021, 64, 11637−11650 (#4 in NPL in IDS filed April 2, 2024) (“Nowak”).
The teachings of Ciulli and Bond are discussed above and are incorporated by reference herein.
Regarding claims 21-24, Ciulli and Bond do not teach a method of studying an effect of degrading a target protein within a cell comprising endogenously expressing a fusion protein comprising the target protein and a polypeptide comprising a hole-modified mutant bromodomain, and contacting the fusion protein with a degrader compound.
Nowak teaches targeted protein degradation for rapid and dose-dependent protein depletion through the use of protein fusion tags. Nowak teaches the BRD4BD1L94V degradation tag and the PROTAC compound XY-06-007 for degradation of a target protein using the dTAG approach (p. 11637, Abstract). Nowak also teaches a method of contacting cells expressing a fusion protein with the hole-modified (p, 11639, 1st column) BRD4BD1L94V degradation tag fused to EGFP with degrader molecules, to study the effects of degradation (pp. 11641-42, Fig. 3A).
Ciulli, Bond, and Nowak are considered analogous art to the claimed invention because they are in the same field of deploying Brd4 selective inhibitors of the BET family for inhibition and/or degradation of a target protein. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), before the effective filing date of the claimed invention, to modify the BET inhibitor, JQ1, in the PROTAC taught in Ciulli with ET-JQ1 taught by Bond, and deploy the resulting compound in the method taught by Nowak to arrive at the method instantly claimed. Based on the teachings of Nowak, Flp293T cells stably expressing the fusion protein BRD4BD1L94V−EGFP were contacted with the degrader molecules targeting the same mutated BRD4 protein (vide supra).
The information provided in the Specification regarding the differences in the claimed invention and that of Nowak have been considered and are not enough to overcome the prima facie case of obviousness (Spec., p. 81, lines 16-28). The discussion of AGB1 being more significant than XY-06-007 at degrading a target protein is not persuasive in overcoming a prima facie case of obviousness, because the method of degrading a target protein by fusing it to a hole-modified mutant bromodomain are the relevant teachings of Nowak that render the method claims obvious. The compounds of the instant claim are rendered obvious through the teachings of Ciulli and Bond and their teachings of use of the JQ1 Brd4 inhibitor and derivatives thereof, which would have been prima facie obvious to a PHOSITA because they are equivalents known for the same purpose, inhibiting the Brd4 protein. Accordingly, claims 21-24 are prima facie obvious.
Regarding claim 25, Bond teaches ET-JQ1-OMe is selective for hole-modified Brd4 protein, namely the mutations Brd4(2)L387A and Brd4(2)L387V. It would have been prima facie obvious to substitute the Brd4BD1L94V mutation taught by Nowak for the mutations taught by Bond to arrive at the method instantly claimed because the mutations are made in part to pair with a “bumped” inhibitor, i.e., an inhibitor that is alkylated to selectively bind to the hole modified mutant (MPEP §2144.06(II)).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-17 and 21-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 11,179,373 (“ ‘373 “) in view of Bond and Nowak.
Although the claims at issue are not identical, they are not patentably distinct from each other because instant claims 1-17 and 21-25 are obvious over ‘373 in view of Bond and Nowak.
Claim 1 of ‘373 recites a compound having the structure A-L-B, wherein A is an E3 ubiquitin ligase protein binding ligand, L is a –(CH2CH2O)b group, and B is JQ1. Claim 2 of ‘373 recites compound MZ1 (RN: 1797406-69-9) which is a PROTAC comprising VHL-1 and JQ1 connected with a linker. Claim 3 recites the linker is PEG-3.
‘373 does not teach JQ1 alkylated at the methylene position nor does it teach a method of degrading a protein comprising contacting cells expressing a fusion protein with a degrader compound.
Bond teaches the synthesis of allele-specific BET inhibitors, namely derivatives of JQ1. The ET-JQ1-OMe ester was prepared as a BET inhibitor and showed exquisite selectivity for Leu-Ala and Leu-Val mutants over the wildtype bromodomain (p. 7533, Abstract). Bond teaches a method of inhibiting the Brd4(2) domain wherein Leu is mutated to Ala at position 387 (L387A) and Leu is mutated to Val at the same position (L387V) (p. 7536, Fig. 3, 1st column, 1st indented ¶). Bond states: “Access to carboxylic derivatives retaining enantiomeric purity enables functionalization into conjugates such as biotinylated and fluorescent probes and PROTACs, which will further expand the scope and utility of this new synthetic strategy for chemical biology investigation.”
Bond does not teach a PROTAC comprising the alkylated JQ1 nor does it teach a method of degrading a protein comprising contacting cells expressing a fusion protein with a degrader compound.
Nowak teaches targeted protein degradation for rapid and dose-dependent protein depletion through the use of protein fusion tags. Nowak teaches the BRD4BD1L94V degradation tag and the PROTAC compound XY-06-007 for degradation of a target protein using the dTAG approach (p. 11637, Abstract). Nowak also teaches a method of contacting cells expressing a fusion protein with the hole-modified (p, 11639, 1st column) BRD4BD1L94V degradation tag fused to EGFP with degrader molecules, to study the effects of degradation (pp. 11641-42, Fig. 3A).
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA), before the effective filing date of the claimed invention, to modify the BET inhibitor, JQ1, in the PROTAC taught in ‘373 with ET-JQ1 taught by Bond to arrive at the compounds instantly claimed. The teachings of ‘373 recite the PROTAC MZ1 comprising the inhibitor JQ1, therefore it would have been prima facie obvious to substitute the JQ1 inhibitor of the PROTAC in ‘373 for the ET-JQ1-OMe taught by Bond because Bond teaches ET-JQ1-OMe shows exquisite selectivity for mutant Brd4 and provides motivation to incorporate the “bumped” inhibitor into a PROTAC for chemical biology investigation (vide supra). Furthermore, the JQ1 and ET-JQ1-OMe BET inhibitors are equivalents known for the same purpose, inhibiting Brd4, therefore the substitution of JQ1 for ET-JQ1-OMe would have been prima facie obvious to a PHOSITA (MPEP §2144.06(II)). Furthermore, based on the teachings of Nowak it would have been prima facie obvious to deploy the resulting compound in the method taught by Nowak to arrive at the method instantly claimed. Based on the teachings of Nowak, Flp293T cells stably expressing the fusion protein BRD4BD1L94V−EGFP were contacted with the degrader molecules targeting the said mutated BRD4 protein (vide supra).
Conclusion
No claims are allowed.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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