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 .
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
Claims 1-20 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
Applicant’s election without traverse of Group I in the reply filed on 11/20/2025 is acknowledged.
Claims 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Regarding species election, Applicant’s election without traverse of compound 28c in the reply filed on 11/20/2025 is acknowledged.
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Claims 3, 7 and 8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
Examination will begin with the elected species. In accordance with the MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As per MPEP 803.02, the Examiner will attempt to determine whether the entire scope of the claims is patentable. Applicants' elected species, as shown above, does make a contribution over the prior art. Therefore, according to MPEP 803.02: should the elected species appear allowable; the search of the Markush-type claim will be extended. The search and examination should be continued until either (1) prior art is found that anticipates or renders obvious a species that falls within the scope of a proper Markush grouping that includes the elected species, or (2) it is determined that no prior art rejection of any species that falls within the scope of a proper Markush grouping that includes the elected species can be made. The Examiner need not extend the search beyond a proper Markush grouping.
Species Election
A careful review of the prior art has indicated that elected species is free of the prior art. A claim directed to the elected species in independent form would be free of the prior art.
The examiner has moved onto alternative species embodied within the general formula recited in the instant claim 1, and subsequent examination is based on this species expansion.
Claim Rejections - 35 USC § 112
Improper Markush Grouping Rejection
Claims 1, 2, 4-6, 9-13 and 16 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the compounds of instant formula I comprising “X-L1-Y-L2-” moiety, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The species of the Markush group of compounds of instant formula I do not share a “single structural similarity” because there are no required structural features within each variable definition such that each member of the group would have at least one structural feature, which feature is essential to the activity/function of the claimed compounds, in common.
This rejection applies for the Markush groups used to define each of variables X, L1, and L2. Instant claim 1 encompass a wide variety of chemical species which are in different recognized physical classes and would embrace different chemical compounds that do not share any single structural similarity between the species. Such is evidenced by the fact that each position in instant formula I encompassed by the claims is a variable (i.e., no single position in the chemical formula can be construed as being common among each member of the Markush group). The claims recite a Markush grouping for each position in claimed formula I.
For the purposes of providing an example, it is noted that the X variable, for instance, in independent claim 1 encompasses a wide variety of X that comprises different E3 ligase targeting moiety. The E3 ligase targeting moiety encompass a wide variety of chemical species which are in different recognized physical classes.
For example, the E3 ligase targeting moiety are bearing different chemical groups and do not share any single structural similarity between the species.
For example, E3 ligase targeting moiety comprise piperidinedione moiety (aka glutarimide) or thiazole moiety.
piperidinediones are classified as CPC C07D 211/+,
triazoles are classified in CPC C07D 249/+,
Further, it is noted that the L1 and L2 variable, for instance, in independent claim 1 encompasses a wide variety of a monocyclic aryl group, a substituted or unsubstituted monocyclic heteroaryl group, or a combination thereof.
For example, monocyclic heteroaryl group are separately classified such as;
triazoles are classified in CPC C07D 249/+,
tetrazoles are classified in CPC C07D 257/+;
oxadiazoles are classified in CPC C07D 271/+;
thiadiazoles are classified in CPC C07D285/+;
pyridines are classified in CPC C07D 213/+; and
pyrimidines are classified in CPC C07D 239/+.
This demonstrates that not all members recited in this Markush group belong to the same recognized chemical class; i.e., the species fail to share a single structural similarity or any substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
It should be noted that instant claim 2 recites specific E3 ligase targeting moiety, however the claim does not limit the L1 and L2 variables. Similarly, for example, claim 5 limits L1, but does not resolve the deficiency for X and L2.
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.
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 and 16 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 and 16 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.
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 and 9-16 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
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