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 without traverse of Group I (claims 1 – 23) drawn to a compound of Formula I,
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wherein B, D, A, m, n, and o are defined and the species election of N,N'-(11-((2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)methyl)-11-methyl-3,6,9,13,16,19-hexaoxahenicosane-1,21-diyl)bis(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide) with the structure
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in the reply filed on October 31st, 2025 is acknowledged.
Claims 26 – 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II (a method for the prophylaxis or treatment of a disease or condition in a subject), there being no allowable generic or linking claim. Moreover, claims 8, and 13 – 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. Election was made without traverse in the reply filed on October 31st, 2025.
Hence claims 1 – 7, 9 – 12, and 22 – 23 are being examined on the merits herein.
Drawings
The drawings are objected to because the table description of Figure 19 contains an embedded hyperlink. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. The location of the embedded hyperlink is page 34 line 21. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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.
Claim 6 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 6 recites, the compound according to claim l, wherein at least one of: B and D are each a chemical moiety which binds to a protein within the bromo- and Extra-terminal (BET) family of proteins; B and D may each be a chemical moiety which induces degradation of the BRD2, BRD3, and/or BRD4 proteins within the bromo- and Extra-terminal (BET) family of proteins; B and D are each independently selected from:
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. However, the claim is missing a conjunction in between the 2 second and last B and D options; thus the claim recites a non-closed list of alternatives. As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of whether the B and D can only be the listed three options or whether B and D can be other options that have not been directed listed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 – 6, 9, and 22 – 23 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2019/201123 A1 to Cai et. al. (herein after Cai’123; cited on the ISR form; translation included).
Regarding claims 1 – 6, 9, and 22 – 23, Cai’123 teach that proteolysis-pargeting chimeric (PROTAC) technology utilizes the ubiquitin-proteasome system in cells to induce the degradation of target proteins (page 2 paragraph 0002; WO translation). Furthermore, Cai’123 teach that PROTAC molecules are bifunctional small molecules formed by linkers connecting target protein ligands and E3 ubiquitin ligase ligands (page 2 paragraph 0002; WO translation). Moreover, Cai’123 teach that PROTAC molecules have many potential advantages over traditional small molecule drugs: which include targeting protein groups that are currently undruggable, the reuse of low selectivity ligands as selective PROTAC molecules, reduction in targeted protein levels by protein degradation which can overcome the drug resistance problem caused by bypass activation of traditional small molecule inhibitors (pages 2 – 3 paragraph 0002; WO translation). Furthermore, Cai’123 teach that the PROTAC molecules of the disclosure contain two target protein ligands which can degrade two target proteins, achieve a synergistic effect in efficacy, or improve the degradation efficiency of a single target protein which has the advantage of high efficiency, low toxicity, and overcoming drug resistance (page 4 paragraph 0003; WO translation).
Cai’123 teach PROTACs of either structure
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(page 27 lines 1 – 3; original WO document); wherein reference L is
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(claim 1) (page 27 line 4; original WO document); reference M is C; reference J1 and J2 are (-OCH2CH2-) and reference x and y are 3 (claims 2 – 4); reference z is 0 (claim 5); reference G is the part that binds to the ubiquitin ligase (claim 1) and can be covalently linked to reference L and may be the same or different each time it appears (page 6 paragraph 0007; WO translation); and reference D is a portion that binds to a target protein and can be covalently linked to reference L and each occurrence of D can be the same or different (page 6 paragraph 0008; WO translation).
Specifically, Cai’123 teach an embodiment wherein reference G is a von Hippel-Lindau VHL ubiquitin ligase binding ligand (claim 9) (page 20 paragraph 0041; WO translation) of structure G5
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with an unprotected amine (page 9 line 6; original WO document). Moreover, Cai’123 teach an embodiment wherein reference D are compounds targeting human BET bromodomain-containing proteins (claim 6) (pages 22 – 23 paragraph 0054) of the structure D247
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with a methyl ester instead of an amide (page 21 row 3 4th compound; original WO document). Additionally, Cai’123 teach that the PROTAC compounds of the disclosure can be formulated into pharmaceutical compositions comprising or prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers (claim 23) (pages 104 – 105 paragraph 0265; WO translation).
However, Cai’123 fails to specifically exemplify a compound of Formula I
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(claim 1). Moreover, Cai’123 fails to specifically teach the elected species N,N'-(11-((2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)methyl)-11-methyl-3,6,9,13,16,19-hexaoxahenicosane-1,21-diyl)bis(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide) with the structure
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(claims 22).
Nevertheless, given the prior art specifically taught the individual components of instant B, instant D, and instant A as well as a trivalent scaffold for linking these components together it would have been routine optimization for one of ordinary skill in the out to combine these components into a single PROTAC molecule. Since the technology of PROTAC lends itself to modulization and optimization. Moreover, given that the prior art of Cai’123 specifically taught instant A, instant B, instant D, and the instant trivalent linker it would have been within the purview of one of ordinary skill in the art to combine these components in such a way to that made N,N'-(11-((2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)methyl)-11-methyl-3,6,9,13,16,19-hexaoxahenicosane-1,21-diyl)bis(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f)[1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide) during the process of optimizing the PROTAC. Therefore, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)(MPEP 2144.06(I)).
Claims 6 – 7 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2019/201123 A1 to Cai et. al. (herein after Cai’123; cited on the ISR form; translation included) in view of Ali et. al. ((2014), Input of Isosteric and Bioisosteric Approach in Drug Design, J. Chem. Soc. Pak., 36, 150 – 169).
The teachings of Cai’123 as they relate to claim 1, from which claims 6 – 7 depend, are given previously in this office action and are fully incorporated here.
However, Cai’123 fails to teach a compound according claim 1, wherein at least one of B or D is
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(claim 7) that is has an amide group or a compound according to claim 1 wherein B and D each are independently selected from group that contains
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(claim 6).
Nevertheless, Ali et. al. teach that isosterism or bioisosterism is one of the approaches most frequently used in the design of new molecules (page 150 column 1 paragraph 1). Moreover, Ali et. al. teach that bioisosteres may be identified as any two compounds or structures that show similar biological activities and share analogous topology, volume, electronic arrangements or physicochemical properties (page 150 column 1 paragraph 1). Furthermore, Ali et. al. teach that isosteric replacement approach is a practical and, possibly, better substitutes to recent lead optimization techniques to improve its pharmacokinetic i.e. absorption, distribution, metabolism and excretion (ADME) or pharmacodynamic i.e. receptor, enzyme or channel level behavior (page 150 column 1 paragraph 1). Additionally, Ali et. al. teach in Table 7 that amide and esters have an isosteric or bioisosteric relationship. Thus Ali et. al. teach that amides and esters, as general structural features, are isosteres of each other.
Therefore, it would have been obvious before the effective filing date of the instant application to modify reference D247 of structure
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as taught by Cai’123 in view of Ali et. al. that is to substitute the methyl ester for an amide bond. One of ordinary skill in the art would have been motivated to make this modification techniques to improve its pharmacokinetic i.e. absorption, distribution, metabolism and excretion (ADME) or pharmacodynamic i.e. receptor, enzyme or channel level behavior. Moreover, one of ordinary skill in the art would have had a reasonable expectation of success because amide and esters are bioisosteres and would be expected to show similar biological activities.
Claims 10 – 12 are rejected under 35 U.S.C. 103 as being unpatentable over International Publication Number WO 2019/201123 A1 to Cai et. al. (herein after Cai’123; cited on the ISR form; translation included) in view of Isidrol-Llobet et. al. ((2009), Amino Acid-Protecting Groups, Chem. Rev. Pak., 109, 2455 – 2504).
The teachings of Cai’123 as they relate to claim 1, from which claims 10 – 12 depend, are given previously in this office action and are fully incorporated here.
However, Cai’123 fails to teach the compound according to claim 1, wherein A is selected from:
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(claims 10 – 12).
Nevertheless, Isidrol-Llobet et. al. teach that synthetic organic chemistry is based on the concourse of reagents and catalysts to achieve the clean formation of new bonds, and appropriate protecting groups are required to prevent the formation of undesired bonds and side reactions (page 2455 column 1 paragraph 1). Moreover, Isidrol-Llobet et. al. teach the mechanisms for the formation of protected amines using dipeptides as the example
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(page 2457 column 2 Figure 1). Furthermore, Isidrol-Llobet et. al. teach example protecting groups in Table 1 (page 2459), Table 2 (page 2461), Table 3 (page 2464), and Table 4 – 5 (page 2466) that can be chosen that would leave an acetyl group on the amine for further coupling , that is to the PROTAC linker.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the structure of G5
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as taught by Cai’123 in view of Isidrol-Llobet et. al. to protect the free amine. One of ordinary skill in the art would have been motivated to make this modification to prevent the formation of undesired bonds and side reactions. One of ordinary skill in the art would have had a reasonable expectation of success because the use of protecting groups in organic chemistry is well understood.
Conclusion
Claims 1 – 7, 9 – 12, and 22 - 23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627