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 .
FINAL ACTION
Priority
Instant application 17/925,776 filed on 11/16/2022 claims benefit as follow:
CONTINUING DATA:
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Status of the Application
The amendment filled on 05/11/2025 has been entered.
Claims 1-23 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/04/2024 and 11/16/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Election/Restrictions
Claims 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/2025.
Claims 3, 7 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/20/2025.
Response to Arguments/Amendments
The amendment filled on 05/11/2025 has been entered.
Regarding the Improper Markush Grouping rejection, Applicant’s arguments, filed on 05/11/2026 have been fully considered and are persuasive. The Improper Markush Grouping rejection is withdrawn.
Regarding the 103 rejections of record, Applicant's arguments filed 05/11/2025 have been fully considered but they are not persuasive.
Applicant submitted that “Assuming CI-994 of Smalley is substituted with 24b of Li,
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the phenyl ring 2 of 24b would be bonded to E3 ligase targeting moiety X. The phenyl ring 2 does not fall under L1 as defined in claim 1. L1 is covalently bonded to E3 ligase targeting moiety X, and does not include a phenyl ring as provided in 24b of Li.”
Applicant’s argument has been considered but is not persuasive because PROTACs disclosed by Smalley comprises the E3 ligase of X, a C2-C12 linker of L1, Y is L5-A-L6 wherein A is an aryl, L5 is an amide, L6 is omitted, and L2 is an aryl. Further, it should be noted that compound 24b of Li reads on the following structural limitations: R is C3 alkyl, L2 is monocyclic aryl group (aryl 1), Y is L5-A-L6 wherein A is unsubstituted monocyclic aryl group (aryl 2), L6 is omitted and L5 is an amide group.
Further, Applicant submitted that “Assuming CI-994 of Smalley is substituted with SR-3558 of Liao,
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, the phenyl ring 2 of SR-3558 would be bonded to E3 ligase targeting moiety X. The phenyl ring 2 does not fall under L1 as defined in claim 1. L1 is covalently bonded to E3 ligase targeting moiety X and does not include a phenyl ring as provided in SR-3558 of Liao.”
Applicant’s argument has been considered but is not persuasive because instant claim 12 recites:
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and instant claim 15 recites:
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.
Starting from Smalley (rotated for convenience):
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and replacing the
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moiety (marked read) with SR-3558 of Liao:
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one of ordinary skill in the art would arrive at a compound that falls under instant formula 1.
It should be noted that instant claim 15 recites:
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The above compound, recited in instant claim 15, bears C2 linker in L1 position wherein the compound obtained after substitution of
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in Smalley with SR-3558 of Liao would bear C4 linker in L1 position. It should be noted that instant Formula 1 allows for C2-C12 linkers. Further, the compound obtained after substitution with SR-3558 of Liao, would bear C4 linear alkyl in R position (in the above compound recited in claim 15, R is C3 linear alkyl). It should be noted that instant Formula I allows for R to be C1 to C6 linear alkyl.
Claim 15 is not rejected under 103. (Starting from Smalley, one of ordinary skill in the art would need to perform more than two modifications to arrive at the above compound recited in claim 15; without suggestion from a prior art one of ordinary skill would not have been motivated to simultaneously pick C2 linker (L1) and C3 alkyl (R)).
However, it is examiner position that the compound bearing C4 linker (L1) and C4 alkyl (R) would have been obvious over Smalley in view of Liao.
Therefore, the 103 rejections are maintained.
The new claim 21 is also rejected under 103 because the claim allows for the Y to be L5-A-L6 (as recited in instant claim 1).
Regarding the provisional double patenting rejection, since no arguments are present the rejection is maintained.
Allowable Subject Matter
Claims 22 and 23 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closes prior art of record, Smalley (Smalley JP, et al., Chem Commun (Camb). 2020 Apr 21;56(32):4476-4479; published March 11, 2020) teaches PROTACs comprising HDAC inhibitor (CI-994) linked to a E3 ligase targeting moiety (see abstract and Figures 1 and 2). The PROTACs disclosed by Smalley comprises the E3 ligase of X, a C2-C12 linker of L1, Y is L5-A-L6 wherein A is an aryl, L5 is an amide, L6 is omitted, and L2 is an aryl.
The PROTACs disclosed by Smalley do not bear acyl hydrazide (-C(O)NHNHR) group necessary present in compounds of instant Formula I, and the PROTACs disclosed by Smalley bear Y that is L5-A-L6 wherein A is an aryl wherein the compounds recited in instant claims 22 and 23 bear Y that is L2-piperazine-L4.
Starting from the compounds disclosed by Smalley, one of ordinary skill in the art would need to perform at least two modifications to arrive at the compounds recited in instant claims 22 and 23. Without suggestions from prior art, one of ordinary skill in the art would have not been motivated to substitute L5-aryl-L6 with L2-piperazine-L4 with a reasonable expectation of success.
Maintained Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4-6 and 9-11, 16 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Smalley (Smalley JP, Adams GE, Millard CJ, Song Y, Norris JKS, Schwabe JWR, Cowley SM, Hodgkinson JT. PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes. Chem Commun (Camb). 2020 Apr 21;56(32):4476-4479; published March 11, 2020) in view of Li (Li X, Jiang Y, Peterson YK, Xu T, Himes RA, Luo X, Yin G, Inks ES, Dolloff N, Halene S, Chan SSL, Chou CJ. Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity. J Med Chem. 2020 May 28;63(10):5501-5525; published April 22, 2020).
Smalley teaches PROTACs comprising HDAC inhibitor (CI-994) linked to a E3 ligase targeting moiety (see abstract and Figures 1 and 2):
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Smalley discloses (see Figure 2):
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The above PROTACs disclosed by Smalley comprises the E3 ligase of X, a C2-C12 linker of L1, Y is L5-A-L6 wherein A is an aryl, L5 is an amide, L6 is omitted, and L2 is an aryl.
The PROTACs disclosed by Smalley do not bear acyl hydrazide (-C(O)NHNHR) group necessary present in compounds of instant Formula I.
However, HDAC inhibitors bearing hydrazide moiety have been disclosed in prior art.
Li teaches HDAC compounds 24a, 24b and 24c (see Scheme 4, page 5503):
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wherein R6 is
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It should be noted that compound 24b reads on the following structural limitations: R is C3 alkyl, L2 is monocyclic aryl group, Y is L5-A-L6 wherein A is unsubstituted monocyclic aryl group, L6 is omitted and L5 is an amide group.
Regarding instant claim 11, it should be noted that the above compound bears a propyl group at a position corresponding to instant R variable.
Therefore, applying KSR prong (B), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to replace the HDAC inhibitor/moiety (CI-994), present in compounds disclosed by Smalley, with HDAC targeting moiety (24b), disclosed by Li, to arrive at compounds of instant Formula I. The skilled person would have been motivated to prepare additional PROTACs comprising HDAC inhibitors linked to a E3 ligase targeting moiety.
The above combination of teachings of Smalley and Li does not explicitly teach one single lead compound. However, “It should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound. As a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure. Thus, Office personnel should recognize that in certain situations, it may be proper to reject a claimed chemical compound as obvious even without identifying a single lead compound.” (MPEP 2143 I, Example 10, last paragraph).
Regarding instant claim 16, since Smalley teaches effective amounts of the disclosed PROTACs (see Fig. 4 and 5) and Smalley teaches that “Such degraders have potential in the development of novel therapeutics in cancer and other diseases related to class I HDACs” (see page 4479, last paragraph), a person of ordinary skill would be motivated to prepare pharmaceutical compositions comprising a therapeutically effective amount of additional PROTACs comprising HDAC inhibitors linked to a E3 ligase targeting moiety. Smalley also formulates said HDAC PROTAC ligands in the pharmaceutically acceptable carriers of DMSO to run in western blots in the working figures (see Fig. 3 on page 4477). DMSO (cell media) read on the claimed limitations of pharmaceutically acceptable carrier.
Claims 1, 2, 4-6 and 9-14, 16 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Smalley (Smalley JP, Adams GE, Millard CJ, Song Y, Norris JKS, Schwabe JWR, Cowley SM, Hodgkinson JT. PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes. Chem Commun (Camb). 2020 Apr 21;56(32):4476-4479; published March 11, 2020) in view of Liao (US-10,807,944-B2, PTC Filed Mar. 30, 2015).
Smalley teaches PROTACs comprising HDAC inhibitor (CI-994) linked to a E3 ligase targeting moiety (see abstract and Figures 1 and 2):
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Smalley discloses (see Figure 2):
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The above PROTACs disclosed by Smalley comprises the E3 ligase of X, a C2-C12 linker for L1, Y is L5-A-L6 wherein A is an aryl, L5 is an amide, L6 is omitted and L2 is an aryl.
The PROTACs disclosed by Smalley do not bear acyl hydrazide (-C(O)NHNHR) group necessary present in compounds of instant Formula I.
However, HDAC inhibitors bearing hydrazide moiety have been disclosed in prior art.
Liao (US-10,807,944-B2) teaches and claims:
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Further, Liao (US-10,807,944-B2) teaches and claims a pharmaceutical composition comprising a pharmaceutically acceptable carrier:
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Further, for example, Liao (US-10,807,944-B2) teaches HDAC inhibitor SR-3558 (see Table 6):
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It should be noted that compound SR-3558 reads on the following structural limitations: R is C4 alkyl, L2 is monocyclic aryl ring, Y is L5-A-L6 wherein A is unsubstituted aryl ring, L5 and L6 are omitted.
Applying KSR prong (B), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to replace the HDAC inhibitor/moiety (CI-994), present in compounds disclosed by Smalley, with HDAC targeting moiety disclosed by Liao (for example SR-3558), to arrive at compounds of instant Formula I. The skilled person would have been motivated to prepare additional PROTACs comprising HDAC inhibitors linked to a E3 ligase targeting moiety.
The above combination of teachings of Smalley and Liao does not explicitly teach one single lead compound. However, “It should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound. As a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure. Thus, Office personnel should recognize that in certain situations, it may be proper to reject a claimed chemical compound as obvious even without identifying a single lead compound.” (MPEP 2143 I, Example 10, last paragraph).
Further, instant claims 11 and 13 recite compounds wherein R is a propyl group. Starting from the compound of Smalley it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to replace the HDAC inhibitor/moiety (CI-994), present in compounds disclosed by Smalley, with HDAC targeting moiety disclosed by Liao (for example, SR-3558). Further, since Liao teaches that any alkyl group in that position (R5 in Liao’s Formula I) results in retention of activity, a person of ordinary skill in the art would expect retention of activity after substituting n-propyl for n-butyl in compound SR-3558. The case law states that “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).” (MPEP 2144.09 -Close Structural Similarity Between Chemical Compounds (Homologs, Analogues, Isomers)).
Regarding instant claim 16, since Smalley teaches effective amounts of the disclosed PROTACs (see Fig. 4 and 5) and Smalley teaches that “Such degraders have potential in the development of novel therapeutics in cancer and other diseases related to class I HDACs” (see page 4479, last paragraph), a person of ordinary skill would be motivated to prepare pharmaceutical compositions comprising a therapeutically effective amount of additional PROTACs comprising HDAC inhibitors linked to a E3 ligase targeting moiety. Smalley also formulates said HDAC PROTAC ligands in the pharmaceutically acceptable carriers of DMSO to run in western blots in the working figures (see Fig. 3 on page 4477). DMSO (cell media) read on the claimed limitations of pharmaceutically acceptable carrier.
Maintained 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.
Claim 1, 2, 4-6, 9-16 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 19 of copending Application No. 19/229044 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims of copending Application No. 19/229044 recite:
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Further, the claims of copending Application No. 19/229044 recite:
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It should be noted that YX968 is the same as instant compound 28 (see instant specification page 80, Aspect 28):
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Art Made of Record but not Applied
Wang (Yunfei Wang, Ryan L. Stowe, Christie E. Pinello, Guimei Tian, Franck Madoux, Dawei Li, Lisa Y. Zhao, Jian-Liang Li, Yuren Wang, Yuan Wang, Haiching Ma, Peter Hodder, William R. Roush, Daiqing Liao, Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases, Chemistry & Biology, Volume 22, Issue 2,2015, Pages 273-284).
Wang teaches HDAC-selective inhibitors (see Table 2, see for example SR-3205)):
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Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IZABELA SCHMIDT whose telephone number is (703)756-4787. The examiner can normally be reached Monday - Friday from 8 am to 5 pm.
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/I.S./ Examiner, Art Unit 1621
/GEORGE W KOSTURKO/ Primary Examiner, Art Unit 1621
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