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 .
DETAILED ACTION
1. This application is a 371 of PCT/GB2021/050156 01/22/2021. FOREIGN APPLICATIONS:UNITED KINGDOM 2001023.7 01/24/2020.
Claims 1-2, 6-19, 23-24 are pending.
Restriction/Election Maintained
2. Applicant’s election of group I and the species, compound 101, in the reply filed on August 18, 2025 was previously acknowledged.
According to applicants’ representative claims 1-2, 4-19 read on the elected species. Claims 2, 10, do not read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 2, 10, which does not read on the elected species is withdrawn.
Response to Arguments/Amendments
3. The rejections of canceled claims are withdrawn. The rejection of claim 8, 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for a broad range and narrow range within the same claim is withdrawn based on the amendments. The rejection of claims 1, 6-9, 11-15, 19 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 for an open-ended Markush using the comprising language is maintained. Applicants’ representative’s arguments submitted on March 10, 2026 have been fully considered but are unpersuasive.
The rejection of claims 1, 8-9, 11-15, 19 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement is withdrawn based on the amendments. The rejection of claim(s) 1, 8-9, 11-12, 19 under 35 U.S.C. 102(a)(1) as being anticipated by Saito is withdrawn based on the amendments.
The rejection of claim(s) 1, 6-9, 11, 19 under 35 U.S.C. 103 as being unpatentable over Yang and Kraker is maintained. Applicants’ representative’s arguments submitted on March 10, 2026 have been fully considered but are unpersuasive. According to the argument on page 16 Yang is only related to inhibitors of HDAC6 as the HDAC ligand tethered to the ligase, however Yang does prepare HDAC degraders with different HDAC selectivity profiles, “A similar effect was also observed when pan-HDAC inhibitor 2c, the “warhead” of HDAC6 degrader 9c, was used as the competitive ligand for HDACs (Fig. 2C).” Both Vorinostat, the HDAC6 selective compound, and compound 2c, the pan inhibitor, were effective. Compound 2c being a pan-degrader. Applicants’ representative admits this on the second to last paragraph where it is argued, “Yang teaches that the combination of an HDAC 1 – 3 inhibitor at an E3 ligase does not necessarily yield and HDAC 1 – 3 degrader.” So on the one hand applicant argues that this concept of HDAC 1 – 3 degrader is not taught but then admits that it is but it doesn’t work. Applicant tacitly admits that it’s not that it doesn’t work on other HDACs but that the selectivity for HDAC6 is higher. In fact looking at box A of Figure 1 on page 2495, the amounts of HDAC1 and HDAC2 are clearly reduced as compared to that of control, although not as much as HDAC6. It is interesting that the selectivity of degradation does not parallel that of inhibition and Yang makes note of this in the first paragraph in column 1 on page 2495. According to Yang, “the selective degradation of HDAC 6 over other age HDACs is unexpected, but not surprising, because it has been reported that selective degraders can be developed by tethering nonselective kinase inhibitors or BRD ligands with a E3 ubiquitin ligase ligand.” (Citing to references 49 and 44 to support the statement). “In summary, we have developed the first-in-class small molecule degraders for zinc-dependent HDACs by conjugating a pan-HDAC inhibitor with thalidomide analogues. Cell-based assays indicated that these HDAC degraders could selectively degrade HDAC6 over other HDACs.” Since in the paradigm of the Yang disclosure all that is required of this moiety, linker-E3 ligand-HDAC-ligand, is ubiquitin targeting linked to HDAC ligand, it cannot be considered inventive to simply substitute one known HDAC targeting moiety for another.
Applicant’s representative further argues that the HDAC ligand in Yang is not that claimed in formula I, however this lacuna is filled by Kraker who discloses the instantly claim ligand. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Finally it’s argued that Kraker’s compound is an HDAC 1-2 inhibitor but not an HDAC 1-3 degrader however it is expected that conjugation of the inhibitor to the E3 ligase would at least result in degradation of HDAC 1-2. Moreover Yang, quoted above, indicates degradation may be more selective, than what was indicated by inhibition. While Kraker shows inhibition of HDACs 1 and 2 there is no direct teaching that the compound does not inhibit HDAC 3. Kraker only has data for those two isoforms. Absence of evidence is not absent evidence of absence of the propery of HDAC3 inhibition. In response to applicant's argument that HDAC 3 degradation is a new property, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The rejection of claim(s) 1, 6-9, 11-17, 19 under 35 U.S.C. 103 as being unpatentable over Fischer WO 2021092151 A1 and Kraker is maintained. Applicants’ representative’s arguments submitted on March 10, 2026 have been fully considered but are unpersuasive. In a similar manner applicant argues that Fischer like Yang is only concerned with HDAC 6, however Kraker working in the same area discloses CI-994, which is claim 1 Formula I, as an HDAC inhibitor that would be expected to function the same. Since in the paradigm of the Fischer disclosure all that is required of this moiety, linker-E3 ligand-HDAC-ligand, is ubiquitin targeting linked to HDAC ligand, it cannot be considered inventive to simply substitute one known HDAC targeting moiety for another. Choosing the ligand of Kraker is obvious because it was “a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC2 in a concentration-dependent fashion.”
The rejection of claim(s) 18 under 35 U.S.C. 103 as being unpatentable over Fischer WO 2021092151 A1 and Kraker as applied to claims 1, 6-9, 11-17, 19 above, and further in view of Hines is maintained. Applicants’ representative’s arguments submitted on March 10, 2026 have been fully considered but are unpersuasive. According to the arguments Hines is concerned with degrading BRD4, but does not mention HDAC. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The compounds are nothing more than known E3 ligase ligands linked to known HDAC inhibitors.
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.
4. Claims 1, 6-9, 11-15, 19 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. Claim 1 states “L is a linker comprising one or more one groups, the each group being independently selected from”. MPEP § 2173.05(h), states “A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group ‘comprising’ or ‘consisting essentially of’ the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim.”
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.
5. Claim(s) 1, 6-9, 11, 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang “Development of the first small molecule histone deacetylase 6 (HDAC6) Degraders “Bioorganic & Medicinal Chemistry Letters, 2018, 28(14), 2493-2497 and Kraker “Modulation of Histone Acetylation by [4-(Acetylamino)-N-(2- Amino-phenyl) Benzamide] in HCT-8 Colon Carcinoma” Molecular Cancer Therapeutics Vol. 2, 401–408, April 2003. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art:
Yang “herein report the development of the first small molecule HDAC6 degraders by conjugating non-selective HDAC inhibitor 2, derived from our previous strategy, to a thalidomide-type E3 ligase ligand with various linkers. The profiling of the resulting products in cellbased assays revealed that our bifunctional small molecules selectively promoted the degradation of HDAC6 through the UPS.” [page 2494]. Yang uses Vorinostat as the HDAC ligand resulting in compounds 9a-9d:
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The linker is a PEG type linker with an triazole which is the subject of claim 9 where L9 is a PEG.
Kraker teaches the compound CI-994 AKA Tacedinaline (N-acetyldinaline) as shown in Figure 1 on page 402:
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Kraker explains that ”CI-994 is a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC2 in a concentration-dependent fashion.” (abstract). “The results of the experiments presented here provide evidence that the antitumor activity of CI-994 is linked to its ability to inhibit HDACs.” (Conclusion).
Ascertaining the differences between the prior art and the claims at issue.
The compounds of the instant claims differ from those of Yang by the use of an alternative HDAC ligand. Yang uses Vorinostat, while the instant claims use CI-994 AKA Tacedinaline (N-acetyldinaline) as the HDAC ligand.
Resolving the level of ordinary skill in the pertinent art
One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have similar properties. While Yang limited HDAC targeting moieties to Vorinostat, Kraker working in the same area discloses CI-994, which is claim 1 Formula I, as an HDAC inhibitor that would be expected to function the same. Since in the paradigm of the Yang disclosure all that is required of this moiety, linker-E3 ligand-HDAC-ligand, is ubiquitin targeting linked to HDAC ligand, it cannot be considered inventive to simply substitute one known HDAC targeting moiety for another. The compounds of Yang give HDAC degradation with different HDAC ligands, “A similar effect was also observed when pan-HDAC inhibitor 2c, the “warhead” of HDAC6 degrader 9c, was used as the competitive ligand for HDACs (Fig. 2C).” Both Vorinostat and compound 2c were effective. Compound 2c being a pan-degrader. “In summary, we have developed the first-in-class small molecule degraders for zinc-dependent HDACs by conjugating a pan-HDAC inhibitor with thalidomide analogues. Cell-based assays indicated that these HDAC degraders could selectively degrade HDAC6 over other HDACs.” [Conclusion] Finally Yang suggests that the additional ligands which bind HDAC can be used. “Our mechanistic investigations indicate that the CRBN E3 ligase and proteasome are responsible for the degradation of HDAC6. The HDAC degraders derived from pan HDAC inhibitors also inhibit other HDACs, as indicated by the increased acetylated histone level.”
6. Claim(s) 1, 6-9, 11-17, 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fischer WO 2021092151 A1 and Kraker “Modulation of Histone Acetylation by [4-(Acetylamino)-N-(2- Amino-phenyl) Benzamide] in HCT-8 Colon Carcinoma” Molecular Cancer Therapeutics Vol. 2, 401–408, April 2003. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art:
Fischer teaches the Degron-Linker-HDAC compounds of the formula (I) on page 13 shown below:
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The Degron is described on page 29 ff.:
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A number of examples are given including the thalidomide Degrons of claim 16, compound (Ic), (Ie) have the Degrons D1 and D2:
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The linker is disclosed on page 17:
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The linker of the elected species is disclosed on page 18:
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Other linkers of the instant claim 18-19 are disclosed on page 20:
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The example compounds on pages 32 ff. have these features with various HDAC inhibitors:
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Kraker teaches the compound CI-994 AKA Tacedinaline (N-acetyldinaline) as shown in Figure 1 on page 402:
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Kraker explains that ”CI-994 is a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC2 in a concentration-dependent fashion.” (abstract). “The results of the experiments presented here provide evidence that the antitumor activity of CI-994 is linked to its ability to inhibit HDACs.” (Conclusion).
Ascertaining the differences between the prior art and the claims at issue.
The compounds of the instant claims differ from those of Fischer by the use of an alternative HDAC ligand. Fischer uses a number of compounds, while the instant claims use CI-994 AKA Tacedinaline (N-acetyldinaline)
Resolving the level of ordinary skill in the pertinent art
One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have similar properties. While Fischer limited HDAC targeting moieties to those targeting HDAC6, Kraker working in the same area discloses CI-994, which is claim 1 Formula I, as an HDAC inhibitor that would be expected to function the same. Since in the paradigm of the Fischer disclosure all that is required of this moiety, linker-E3 ligand-HDAC-ligand, is ubiquitin targeting linked to HDAC ligand, it cannot be considered inventive to simply substitute one known HDAC targeting moiety for another.
Histone deacetylase (HDAC) is a known drug target in various cancers including hematological malignancies and as such biochemical HDAC degradation could offer a treatment of these cancers.
7. Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fischer WO 2021092151 A1 and Kraker “Modulation of Histone Acetylation by [4-(Acetylamino)-N-(2- Amino-phenyl) Benzamide] in HCT-8 Colon Carcinoma” Molecular Cancer Therapeutics Vol. 2, 401–408, April 2003. as applied to claims 1, 6-9, 11-17, 19 above, and further in view of Hines “MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53” Cancer Res January 2, 2019, (2019) 79 (1): 251–262. Fischer uses the E3 ligases discussed at page 29:
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There are other E3 ligases that can be used in PROTACs. According to Hines, “However, in light of the potential wide-ranging amenability of E3 ligases for repurposing into resources for PROTAC-mediated protein degradation, we reasoned that renewed effort concerning nutlin-based PROTACs was worthwhile considering that, among the E3 ligases currently used for PROTACs, MDM2 stands out in that its endogenous substrate, the tumor suppressor p53, plays a crucial tumor suppressor role. Indeed, the ability to manipulate p53 levels using nutlins holds therapeutic promise in the field for cancer treatment (30, 31). In this study, we present evidence showing not only that MDM2 is indeed amenable to being used for nanomolar-potency PROTAC-mediated target degradation, but moreover a nutlin based PROTAC retains the p53-stabilizing activity of the parent molecule allowing an MDM2-recruiting PROTAC to be more active against certain cancers than a counterpart VHL-utilizing PROTAC directed against the same target protein.”
Compound D on page 258 Figure 4 has the MDM2 E3 ligase ligand of the elected species and other compounds:
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Claim 18, which includes the elected species is drawn to the MDM2 targeting group of Hines.
“[T]his study shows that the E3 ligase MDM2 can serve as a valuable addition to the small number of E3 ligases that when harnessed can produce nanomolar PROTAC- mediated target protein degradation. Moreover, with further refinement, nutlin-based PROTACs could become extremely effective candidate anticancer therapeutics due to their dual-mode mechanism of action…” Based upon the foregoing it would be obvious to formulate a PROTAC with the MDM2 ligand of Hines, and the linker HDAC inhibitor of Fischer and Kraker to improve the anticancer activity of the compounds.
Conclusion
8. 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 DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/ Primary Examiner, Art Unit 1621
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