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 and Response to Restriction Requirement
Claims 1-12, 14-19, 21-26, 28-29, 31-35, 37-38, 40 and 43-44 are pending as of the response filed 01/20/2026. Claims 13, 20, 27, 30, 36, 39 and 41-42 are cancelled. Applicant’s election of group I claims 1-12, 14-19, 21-26, 28-29, and 31-34 is acknowledged. Claims 35, 37-38, 40 and 43-44 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election of a species of the compound shown below without traverse is acknowledged.
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Applicants have noted that claims 1, 3-4, 8-10, 18-19, 21-22, 25-26 and 32-34 encompass the elected species. The examiner notes that claims 1, 3-4, 8-10, 17-19, 21-22, 25-26 and 32-34 encompass the elected species. Claims 2, 5-7, 11-12, 14-16, 23-24, 28-29 and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Therefore, claims 1, 3-4, 8-10, 17-19, 21-22, 25-26 and 32-34 have been examined to the extent to which they are readable on the above identified elected species.
Applicants right for rejoinder of any withdrawn claims that require all the limitations of an allowable claim as provided in MPEP § 821.04 is acknowledged.
Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The following prior art that renders obvious the elected species has been found and is discussed in the 103 rejection below.
Priority
This application is a 371 of PCT/US2021/064880 filed 12/22/2021, which claims priority to PRO 63/273,388 filed 10/29/2021 and PRO 63/130,150 filed 12/23/2020.
Applicant’s claim for the benefit of a prior filed application under 35 U.S.C. 119(e) or under or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or earlier-filed nonprovisional application or provisional application for which benefit is claimed). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. PRO 63/130,150 fails to provide adequate support and enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The ‘150 application does not disclose all the linkers as in instant claim 25 and all recited species of bifunctional compounds as in instant claim 32. Accordingly, claims 25 and 32 have an effective filing date of 10/29/2021, the subject matter of which is supported in PRO 63/273,388 filed 10/29/2021, while claims 1, 3-4, 8-10, 17-19, 21-22, 26 and 33-34 get the priority benefit of the earliest ‘150 provisional application and have an effective filing date of 12/23/2020.
Information Disclosure Statement
The information disclosure statement submitted on 06/22/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 32 is objected to because of the following informalities:
In claim 32, line 2 should read “of structures 1-[[26]]33”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 8-10, 17-19, 21-22, 26 and 34 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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.
Instant claim 1 is drawn to a bifunctional compound defined predominantly by the functional properties of the compound, for example, comprising a targeting ligand that binds at least one of phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2A), PIP4K2B, and PIP4K2C and a degron covalently attached to the targeting ligand by a linker, wherein the compound has a structure represented by formula (I), with variables as defined and degron is a moiety that binds an E3 ligase.
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The claim encompasses any and every molecule, i.e. combination of targeting ligand, linker (L), and degron (D), that would provide the claimed properties and functionality. The targeting ligand is described with some level of specificity, but the other portions of said molecule are defined by function only. Thus, the genus of bifunctional compounds claimed, encompass a highly divergent variety of core structures, which includes species that do not share both a substantial structural feature and a common function that flows from the substantial feature. In the instant case, the degron and the linker materially affect the function of the inventive compound. The choice of each part of the molecule, i.e., the targeting ligand, linker and degron, is critical to the functioning of the molecule as a whole, to provide the claimed sufficiency. Further, the different portions of the molecule must work in concert to provide an intricate ternary complex in three-dimensional space that brings together the target protein and the ubiquitination machinery to effect the degradation, which is a remarkably unpredictable venture. The scope of claim 1 constitutes a vast array of permutations and combinations for the targeting ligand, linker and degron moieties of the bifunctional compound, rendering it broad. The different binding moieties, linkers and degron moieties would be presumed by one of ordinary skill in the art to have different physical properties (e.g. solubility, stability, etc.) that would lead to different biological activities (e.g. ADME and PK/PD, efficacy, toxicity, etc.).
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. Whether the specification shows that the inventor was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163 (II) 3 (a) (i).
A chemical genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has substantial variance, the disclosure must describe a sufficient number of species to reflect the variation within that genus. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 i)(C) above). 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). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. "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. See MPEP 2163 (II) 3 (a) (ii).
In the instant case, there is no evidence Applicants had possession of the full genus of compounds at the time of filing, because the specification does not conclusively demonstrate the structure-activity relationship of the claimed vast array of bifunctional compounds, towards their PROTAC functionality. Specifically, the specification discloses the synthesis of a handful of the claimed bifunctional compounds, mostly directed to wherein the targeting ligand is represented by the structure (TL1) and (TL2), to a handful of linkers and wherein the degron is represented by the structure (D1-a) and (D1-c). The instant specification does not describe enough species of compounds having the PIP4K protein degradation activity within the scope of the claimed invention. The specification discloses the selective degradation of PIP4K2C, IC50 value of just one single compound, compound 1, the instantly elected species of compound (Para. [0294] of the instant specification). These are not viewed as being reasonably representative of the genus of bifunctional compounds in its claimed scope because no readily apparent combination of identifying characteristics are provided, other than the disclosure of those specific species as examples of the claimed genus. It is not readily apparent that the genus of bifunctional compounds claimed have a structural entity in common, that leads to the recruitment of PIP4K proteins for degradation by the ubiquination system.
Additionally, the state of the prior art teaches that the nature of the individual portions of the molecule clearly affect the overall outcome and functionality of the instant class of compounds.
Troup et al. (Current strategies for the design of PROTAC linkers: a critical review, 30 October 2020, herein after Troup); Pfaff et al. (Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs, 17 September 2019, hereinafter Pfaff).
Troup teaches that the length and composition of the linker plays a critical role on the physico-chemical properties and bioactivity of PROTACs (Abstract; Pg. 282, first paragraph – third paragraph). Troup teaches the overall degradation efficiency does not simply rely on the affinities of the anchor/warhead for the E3 and protein of interest (POI) respectively, but rather on the judicious combination of anchor and warhead connected by a suitable linker, allowing productive ternary complex (TC) formation and POI ubiquitination (Pg. 278, last paragraph). Troup teaches that a minimum distance between the warhead and anchor is usually required for a PROTAC to be effective (Pg. 280, last paragraph) and that PROTAC linker optimization is very resource intensive (Pg. 290, last paragraph). Troup teaches devising bioactive PROTACs is often complicated by issues surrounding their pharmacokinetic properties, notably cell permeability, metabolic stability, and solubility. As a result, the cell activity of a PROTAC is difficult to predict (Pg. 301, last paragraph). Troup concludes that the important relationship between the overall degradation efficiency, selectivity, and properties of PROTACs and the characteristics of its linker, such as length, chemical composition, and the site and vector of conjugation are of paramount importance to the efficient design of PROTACs (Pg. 301, continued paragraph).
Pfaff teaches the design of photoswitchable PROTACs by including ortho-F4-azobenzene linkers between the warhead ligands (Abstract). Pfaff teaches the azo-trans-isomer is active while the azo-cis-isomer is inactive because the distance defined by the linker is prohibitively short to permit ternary complex formation between the protein binding partners (Abstract; Pg. 1686, first column, last paragraph – second column, continued paragraph; Figure 4; Figure 5). Pfaff evidences that changing the geometry of only one bond within the linker can render a normally effective PROTAC molecule inactive.
Thus, considering the state of the art and that a sufficient number of species of compounds having selective degradation of the PIP4K protein has not been disclosed, the written description requirement for the claimed genus of bifunctional compounds has not been met.
Claims 3-4, 8-10, 18-19, 21-22, 26 and 34 do not remedy the written description rejection and are similarly rejected for depending from a rejected base claim.
In response to this rejection, the Applicant can amend the claim(s) to recite only individual species or grouping of species that share a substantial structure as well as a common function that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claim(s) in fact share a common function that flows from the substantial structural feature.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 21- 24 are 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.
Regarding claims 21 and 23, the claims recite “at either or both termini” in parentheses. The presence of limitations in parentheses renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Thus, the metes and bounds of the claim are indefinite.
For the purpose of applying prior art, claim 21 has been interpreted without the parentheses to read “wherein the linker comprises an alkylene chain or a bivalent alkylene chain, either of which may be interrupted by, and/or terminate at either or both termini with at least one of …”.
For the purpose of applying prior art, claim 23 has been interpreted without the parentheses to read “wherein the linker comprises a polyethylene glycol chain which may be interrupted by, and/or terminate at either or both termini with at least one of …”.
Claims 22 and 24 depend from the rejected base claim and are similarly rejected.
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, 3-4, 8-10, 17-19, 21-22, 25-26 and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Sivakumaren (A Chemical Biology Approach Towards Targeting Understudied Lipid Kinases in Cancer and Ebola, May 2019, in the IDS) in view of Zheng et al. (WO 2019/144117 A1, 25 July 2019, hereinafter Zheng) and Galdeano et al. (Structure-Guided Design and Optimization of Small Molecules Targeting the Protein−Protein Interaction between the von Hippel−Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities, 28 August 2014, hereinafter Galdeano).
Regarding instant claim 1, Sivakumaren teaches a pan-PI5P4K inhibitor, THZ-P1-2, that binds to cysteines on a disordered loop in PI5P4Kα/β/γ (i.e., encoded by genes PI5P4KA, PI5P4KB, PI5P4KC respectively) (Pg. 14, Abstract; Pg. 15, first paragraph). Sivakumaren teaches THZ-P1-2 having the following structure (Pg. 19, Figure 2.1 A).
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Sivakumaren teaches synthesizing bifunctional molecules by fusing the PI5P4K-targeting component (THZ-P1-2 or analogs) to the phthalimide CRBN-targeting
moiety (Pg. 54, first paragraph). Sivakumaren teaches the exemplary bifunctional compound, TM-03-102-02 (Pg, 54, Figure 2.16).
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The bifunctional compound TM-03-102-02 overlaps the scope of the compound represented by formula (I) as in claim 1, wherein
in the targeting ligand, n is 1, R1 is heteroaryl having 1 heteroatom which is N; n1 is 1, R2 is H; Q is
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, n2 is 1, R3 is H; n3 is 1;
the linker is
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.
The bifunctional compound TM-03-102-02 differs from the instantly elected species of compound in the degron attached to the linker.
Sivakumaren teaches TM-03-102-02 showed potent PI5P4K inhibition (Pg, 55, Figure 2.17). Sivakumaren teaches the designed PROTACs were not sufficiently effective at inducing degradation of PI5P4Ks and need to be optimized further (Pg. 55, first paragraph- Pg, 56, continued paragraph). Sivakumaren suggests improving the PROTAC approach by exploring further linkers and VHL-targeted ligands (Pg. 60, first full paragraph).
Zheng teaches bivalent compounds useful as protein degraders in the treatment of cancers which have a E3 ligase binding moiety at one end, such as von Hippel-Landau (VHL) E3 ligase binding moiety (Para. [0003]; Para. [0021]). Zheng teaches exemplary E3 ligase binding moieties that include the moiety shown below in specific embodiments (Para. [0026]; Paras. [0035]-[0036]).
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The above E3 ligase binding moiety of Zheng anticipates the degron that binds VHL represented by structure (D1-a) of instant claim 26, i.e., the same degron of the instantly elected species of compound. Zheng teaches both VHL and cereblon (CRBN) are E3 ligase binding moieties in a bifunctional PROTAC that target proteins for proteasomal degradation by the ubiquitin proteasome system (Para. 0021]). Zheng teaches a composition of the invention comprises a compound as an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent (Para. [0025]; Para. [0038]).
Galdeano teaches E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system (Abstract). Galdeano teaches the von Hippel−Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation (Abstract). Galdeano teaches the design and optimization of a ligand series with nanomolar binding affinities (Abstract). Galdeano teaches the exemplary ligand, ligand 7, as a potent degrader with a Kd of 185 nM (Pg. 8659, second column, first full paragraph – third paragraph; Table 1; Table 2).
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Galdeano indicates ligand 7 to be the best in class ligand with increased affinity towards pVHL, which may be further optimized in designing the arsenal of linkable pVHL ligands for proteolysis-targeting chimeras (PROTACs) small-molecule approaches (Pg. 8661, first column, first full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the invention, in view of the teachings of Sivakumaren, Zheng and Galdeano to have optimized the PROTAC (TM-03-102-02) of Sivakumaren by including a VHL ligand in place of a phthalimide cereblon (CRBN) targeting ligand, to arrive at the instantly elected species of bifunctional compound, with a reasonable expectation of success. Sivakumaren teaches a pan-PI5P4K inhibitor, THZ-P1-2, that binds to cysteines on a disordered loop in PI5P4Kα/β/γ (i.e., encoded by genes PI5P4KA, PI5P4KB, PI5P4KC respectively). Sivakumaren teaches synthesizing bifunctional molecules by fusing the PI5P4K-targeting component (THZ-P1-2 or analogs) to the phthalimide CRBN-targeting moiety. Sivakumaren teaches the exemplary bifunctional compound, TM-03-102-02. The bifunctional compound TM-03-102-02 anticipates the targeting ligand and linker group of the instantly elected species of compound. Sivakumaren teaches TM-03-102-02 showed potent PI5P4K inhibition but were not sufficiently effective at inducing degradation of PI5P4Ks. Sivakumaren suggests improving the PROTAC design for effective degradation of PI5P4Ks by exploring further linkers and VHL-targeted ligands. Zheng teaches bivalent compounds useful as protein degraders in the treatment of cancers with E3 ligase binding moiety, specifically a von Hippel-Landau (VHL) E3 ligase binding moiety at one end. Zheng teaches an exemplary E3 ligase binding moiety, that anticipates the degron of the instantly elected species of compound.
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Instantly elected species of bifunctional compound
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PROTAC of Sivakumaren E3 ubiquitin ligase binding unit of Zheng
Zheng teaches both VHL and cereblon (CRBN) are E3 ligase binding moieties in a bifunctional PROTAC that target proteins for proteasomal degradation by the ubiquitin proteasome system. Galdeano teaches E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system. Galdeano teaches the exemplary von Hippel−Lindau protein (pVHL) ligand, ligand 7 with nanomolar binding affinities, as a potent degrader with a Kd of 185 nM. Therefore, Galdeano provides strong motivation to a PHOSITA to choose instant degron (D1-a) in the design of PROTACs since Ligand 7 of Galdeano has close structural similarity to the degron of the instantly elected species (differing only in the methyl attached to the benzylic carbon).
Therefore, one of ordinary skill in the art would have been motivated to substitute the CRBN E3 ligase binding moiety of Sivakumaren, with the VHL E3 ligase binding moiety of Zheng, with a reasonable expectation of success that the resulting bifunctional compound would function to recruit PI5P4K proteins to an E3 ubiquitin ligase for degradation. Further, such a substitution would have resulted in the predictable result of optimizing desired effects.
According to MPEP 2144.06 (I), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”. In the instant case, the CRBN E3 ligase binding moiety of Sivakumaren and the VHL E3 ligase binding moiety of Zheng, both function to recruit proteins for proteasomal degradation by the ubiquitin proteasome system, and are considered equivalents in the art (Zheng, Para. 0021]). Moreover, Sivakumaren provides motivation to replace the CRBN E3 ligase binding moiety with a VHL E3 ligase binding moiety to effect efficient degradation of PI5P4Ks.
Thus, the instantly elected species of compound is rendered prima facie obvious in view of the combined teachings of Sivakumaren, Zheng and Galdeano. Therefore, the limitations of instant claims 3-4, 8-10, 17-19, 21-22, 25-26 and 32-33, that are encompassed by the instantly elected species are also rendered prima facie obvious.
Moreover, the pharmaceutical composition of instant claim 34 is rendered prima facie obvious by the combined teachings of Sivakumaren, Zheng and Galdeano.
Note to Applicant: While maintaining the election of species requirement, in an effort to provide compact prosecution, it is brought to the Applicant’s attention that the bifunctional compound of Sivakumaren, TM-03-102-02, anticipates the degron represented by (D2-a) of withdrawn claim 29, wherein
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X1 is C(O) and X2 is NR”1R”2, R”1 is H, R”2 is C1 alkyl (methylene). Therefore, TM-03-102-02 of Sivakumaren anticipates the limitations of instant claims 1, 3-4, 8-10, 17-19, 21-22, 25, 29.
Additionally, Sivakumeran teaches various other PI5P4K inhibitor analogs of THZ-P1-2, that binds to cysteines on a disordered loop in PI5P4Kα/β (Pg. 37, Table 2).
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The above R groups anticipate generating the targeting ligands (TL-3), (TL-4), (TL-6), (TL-7) and (TL-8) as in instant claim 19.
Conclusion
Claims 1, 3-4, 8-10, 17-19, 21-22, 25-26 and 32-34 are rejected.
Claim 32 is objected to.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627