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
Applicant’s response filed on November 19, 2025 has amended claim 1 to delete functional language and introduce structural recitations regarding the linker and degron set forth in claims 2, 4, and 7, to include:
Claims 2 and 4 have been amended to delete parentheses.
Claim 2 has also been amended to delete "or a bivalent alkylene chain, either of"
Claim 7 has been amended to delete specific chemical structures and to complete
the valencies of "N" and "C" in the definition of Y".
Claims 8 and 9 have been amended with respect to claim dependency.
Applicant’s amendments are acknowledged. Claims 1-15, 17, 19, and 21 are pending and are examined on their merits.
Information Disclosure Statement
The Information Disclosure Statement filed on November 19th 2025 (7 references) is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
Double Patenting Rejection-Overcome by Amendment
Applicant has amended claim 1 with the respect to the degrons identified as structures (DI-a) to (Dl-f) and therefore removed prior reference to the degron structures in the copending application. The present claims do not overlap with claims 1-12, 14, 16 and 18 because the compounds of the '992 application contain degrons represented by any one of structures (Dla) to (Dld).
Accordingly, the rejection is removed.
35 U.S.C. § 103 Rejections Maintained
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.
Claims 1-15, 17, 19 and 21 are rejected under 35 USC § 103 as obvious by Vesci et al., WO 2018/178060, published on October 4, 2018 (hereinafter referred to as “Vesci”), in view of Wu et.al., Development of Multifunctional Histone Deacetylase 6 Degraders
with Potent Antimyeloma Activity, J. Med. Chem. 2019, 62, 7042−7057, Yang et.al., Development of the first small molecule histone deacetylase 6 (HDAC6) degraders, Bioorganic & Medicinal Chemistry Letters 28 (2018) 2493–2497, Zoppi et. al., Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel−Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7, J. Med. Chem. 2019, 62, 699−726 and Girardini et.al., Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs, Bioorganic & Medicinal Chemistry Volume 27, Issue 12, 15 June 2019, Pages 2466-2479 is maintained.
Response to Applicant’s Arguments:
Applicants have amended the claims and raised a number of arguments as to why they disagree with the rejection.
First, Applicants effectively allege for all practical purposes that none of the references anticipate the amended claims:
“The claimed compounds as amended define the degron in terms of specific small molecule groups that bind von Hippel Landau (VHL) suppressor protein. The art of record does not demonstrate a single instance of selective degradation of an HDAC with a heterobifunctional compound containing a von Hippel Landau tumor suppressor (VHL) degron, e.g., a proteolysis-targeting chimera (PROTAC). The collective teachings of the cited art fall short in several respects. Also, the claimed invention achieves an unexpected.”
Reply, page 24.
As Applicants should be able to note, the rejection was based on obviousness, not anticipation.
Applicants continue to allege that there was a misconstruction of the art based on the term “degron” and that the prior art taken as whole does not proper establish obviousness (see pages 24-26). Applicants’ arguments are misplaced about the obviousness rejection and the findings of fact from the prior art, and appear to be of the opinion that there are no obviousness arguments to be made in the protected art of PROTACs.
The obviousness analysis that is maintained in this Final Action, makes the comparison that of a compound in Vesci, which uses a modular molecular approach to target a diseased tissue. Namely, Vesci utilizes on one end, an HDAC targeting means with a spacer unit/linker between the second end which is a biological means that induces a controlled response by the host to assist in treatment of the disease.
Applicant’s claimed invention utilizes the same generic approach, and a significant replica of Vesci, namely the same chemical means of the HDAC used in Vesci with a spacer unit/linker, and a different biological means that induces a controlled response by the host to assist in treatment of the disease (i.e., E3 ubiquitin ligase ligand instead of an antibody). The argument is not based solely on the similarity of the compounds, but the recognition of the interchangeability of a modular approach in treating disease. Both approaches have a cellular targeting moiety, a linker, and a means for inducing the host to utilize its own biological approach to tissue attack.
Wu and Yang show that HDAC inhibitors can be used in PROTAC fashion similar to the claims, and Applicant’s claimed invention; Zoppi shows PROTACS with Applicant’s claimed von Hippel-Lindau moiety; and Girardini shows how those of ordinary skill in the art can use the same building blocks of heterobifuntional molecules, yet utilize different points of attachment of the building blocks.
This argument is unpersuasive because the applicant’s remarks (miss the point of the obviousness rationale, are misplaced or are inapposite).
35 U.S.C. § 103—Reiterated Rejections:
Applicant’s claimed invention is directed to heterobifunctional compounds for the treatment of HDAC-related cancers. Applicant purports that they are the first to have discovered a class particular class of heterobifunctional molecules comprising either a dacinostat or a panobinostat core feature having a chemical linking moiety that joins to a degron1.
Specifically, claim 1 is directed to a compound, comprising:
an (E)-3-(4-(((2-(1H-indol-3-yl) ethyl) amino) methyl) phenylacrylamidyl moiety chemically linked to a degron moiety through a chemical linker, wherein the compound has a structure represented by formula (I) or (II):
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wherein R1 is either hydroxy or phenylamine.
Similar to Applicant’s invention, Vesci teaches heterobifunctional compounds having a dacinostat or a panobinostat core feature chemically linked through a linker to certain anticancer antibodies. Vesci states:
“The present invention is directed to novel Histone Deacetylase Inhibitors (HDACi) based antibody drug conjugates useful for the treatment of proliferative diseases. The invention particularly relates to an antibody-drug-conjugate comprising an antibody directed to ErbB1, ErbB2, ErbB3 receptors or related molecular targets. The invention further provides new HDAC inhibitor drugs comprised by the antibody drug-conjugates. Moreover, the invention relates to ADCs pharmaceutical compositions and their use in the treatment of cancer or tumors and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.”
Vesci, page 1, first paragraph.
Vesci prepares a few different compounds including a dacinostat and a panobinostat core features, as well as other HDAC inhibitors chemically linked to anti-cancer antibodies. One of these antibody derivatized structures is shown from left to right with a derivatized HDAC inhibitor-chemical linker-Cetuximab antibody2 is shown as follows:
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Vesci, page 20.
Vesci also derivatizes both dacinostat and panobinostat with functional reactive chemical linkers and suggest creating antibody conjugates as already illustrated above. A panobinostat derivative exemplified by Vesci in the following illustrations of the points of attachment to dacinostat and panobinostat may be introduced through liners, and a panobinostat-linker are shown:
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Vesci, page 30, and:
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Vesci, page 17. Vesci teaches that this compound is also to be used to bind to and anti-cancer antibodies on page 20 (i.e., compounds 1-23).
Although Vesci teaches the use of the claimed heterobifunctional HDAC inhibitor and chemical linking moiety in anti-cancer treatments, Vesci utilizes anti-cancer antibodies to attack the cancerous cells (e.g., [HDAC inhibitor]-[chemical linker]-[antibody]), rather than Applicant’s claimed approach of using a degron to recruit ubiquitin ligase for inducing cell death. However, one of ordinary skill in the art would have had a reasonable expectation of success in substituting the antibodies of Vesci with the claimed degrons, because it is known in the art that heterobifunctional compounds comprised of compounds having the generic arrangement of [inhibitors]-[chemical linker]-[degron moiety] also induce cellular death, but via the use of E3 ubiquitin ligase being recruited to attack the cell rather than the direct use of an antibody. For example, see the teachings of Wu, Yang, Zoppi, and Girardini.
Wu teaches heterobifunctional compounds comprising an HDAC inhibitor-chemical linker-degron moiety, and provides an illustrated schematic of how these compounds work at targeting and killing certain cancerous tissues:
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Wu, Figures 1A and 1B, page 7043.
Yang’s approach is very similar to Wu’s approach, where Yang teaches using heterobifunctional compounds comprising and HDAC-inhibitor-chemical linker-E3 ubiquitin ligase ligand, to treat cancer:
“Histone deacetylases (HDACs) decrease the acetylation level of histones and other non-histone proteins. Over expression of HDACs have been observed in cancers and other diseases. Targeted protein degradation by “hijacking” the natural ubiquitin-proteasome-system (UPS) recently emerged as a novel technology to “knock-out” endogenous disease-causing proteins. We applied this strategy to the development of the first small molecule degraders for zinc-dependent HDACs by conjugating non-selective HDAC inhibitors with E3 ubiquitin ligase ligands. Through cell-based assays, we discovered novel bifunctional molecules (dHDAC6) that could selectively degrade HDAC6. Further mechanistic studies indicated that HDAC6 was selectively removed by the UPS”
Yang, Abstract (emphasis added); and further states:
“Targeted protein degradation (TPD) by heterobifunctional small molecules or proteolysis targeting chimeras (PROTACs) has emerged as a promising therapeutic strategy for the removal of various overexpressed disease-causing proteins.26–28 TPD takes advantage of the cell’s own ubiquitination-proteasome system (UPS), one of the major pathways for protein degradation,29 by bringing an E3 ubiquitin ligase in close proximity to the protein of interest (POI) for ubiquitination and proteasome degradation through a bifunctional small molecule or PROTAC, which can bind simultaneously to the POI and the E3 ligase.”
Yang, page 2493, right column, second paragraph, and concludes on the progress and future develop of PROTACs:
“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. 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. The development of more selective HDAC6 degraders by conjugating selective HDAC6 inhibitors with E3 ligase ligands using various types of linkers are ongoing and will be reported in due course.”
Yang, page 2496, final paragraph (emphasis added).
Zoppi, like Wu and Yang, teaches the use of PROTACs having the generic formula of [inhibitor]-[chemical linker]-[degron moiety], and teaches certain of the claimed embodiments of PEG linkers and degron moieties:
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Zoppi, illustration within Abstract (page 699).
Zoppi teaches two different configurations of the chemical linker off of the E3 ubiquitin ligase ligand in the figure above, as well as the use of other ligands, chain length variations in various alkyl- and PEG-linker units, and measures their binding activity as a function of each variation.
Giradini is similar to Zoppi with regard to the selected systematic variation of between points of attachment at the E3 ubiquitin ligase ligand, and chemical composition and length of the linker attached at the other end to the inhibitor of choice.
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Giradini, Figure 2, page 2469.
Claim 2 further limits claim 1, by requiring that an alkylene unit within the linker chain between the claimed compound and the degron. Compound 17 in Vesci teaches an alkylene chain component within the linker (page 30), as do Zoppi and Girardini. Both Zoppi and Girardini teach how these variables (i.e., monomeric units and chain length), as well as point of attachment to the E3 ubiquitin ligase ligands are result effective variables and can be routinely optimized. For example, see Vesci (Abstract) where there are certain differences between the degree of degradation depending on the orientation of the ligand to the linker. See also Girardini, where a range of linkers and ligand attachment points are similarly characterized (see the Series 1, 2, and 3 schemes on pages 4-10, and the discussion therein). Accordingly, the claimed invention was prima facie obvious at the time it was filed as a routinely optimized, result-effective variable.
Claim 3 further limits claim 2, and requires that the alkylene chain be a length between 2 and 12 units;
Claim 4 further limits claim 1, and requires the linker comprises a series of Markush members, one of which is a polyethylene glycol (PEG) unit;
Claim 5 further limits claim 4, and requires the PEG units to range in number from 1-6;
Claim 6 and 7 further limit claim 1, by requiring the compound having a dacinostat core feature, and particular degron core feature, respectively, with a variable series linkers;
Claims 8-12 further limit the claims, by requiring a particular HDAC inhibitor/degron structural combination, with certain variable linkers;
Claim 15 is directed to a method of treating a disease using a pharmaceutical composition comprising the compounds of claim 1, and claim 17 depends from claim 15, and further requires a method for treating a patient population having a Markush listing of cancers, including NSCLC; both Vesci and Zoppi suggest using their teachings for the treatment of NSCLC (Vesci, pages 4 (NSCLC) and 7 (pharmaceutical composition); Zoppi, page 700);
Claim 19 depends from claim 15, and requires the treatment of neurological disorders; Vesci teaches HDACs to target neurological disorders (pages 1 and 23); and
Claim 21 depends from claim 15, and requires the treatment of autoimmune diseases such as diabetes; Vesci teaches autoimmune diseases including diabetes through reference (page 74).
Each of claims 3-12 are obvious for the same reasons as claims 1 and 2, namely, that the further limitations are taught by at least Zoppi and Girardini, as being modular linker building blocks as a routinely optimized, result-effective variable. The variables being the chemical composition and the length of the linker, as well as the orientation of the degron attached to the linker. The result being the effectiveness of the degradation (experimentally measured by each Zoppi and Girardini). Claims 15, 19, and 21, are obvious for the same reason as claim 1. Accordingly, the claimed invention was prima facie obvious at the time it was filed.
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.
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/P.R.G./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Applicant does not explicitly define the term “degron” in their specification; there are however examples of degrons listed in paragraphs 0053 to 0059. The art teaches that degrons are typically composed of 6 to 10 amino acids and are generally located within flexible regions of proteins so that the degrons can easily interact with other proteins. E3 ubiquitin ligases bind to specific degrons, enabling the attachment of multiple copies of ubiquitin to target proteins. The ubiquitin chains are a molecular signal that directs the proteins to the proteasome, where the tagged proteins are chopped up into pieces and recycled. The correct removal of proteins is important for many biological processes, such as regulating transcription and controlling the major steps during cell division. Regulated protein degradation also turns off the activity of some proteins that are activated by transient external signals. The encounter between the E3 ligase and the degron determines whether a protein lives or dies. There are ~600 different E3 ligases that are encoded in the human genome. Each of these E3 ligases targets a different set of proteins and operates under a different condition. This ubiquitin-mediated protein degradation process is regulated at multiple levels.
2 Cetuximab works by blocking a protein called the epidermal growth factor receptor (EGFR). EGFR is found on the surface of cancer cells and helps them grow and divide. By blocking EGFR, cetuximab can help to slow down the growth of cancer cells
3 Vesci references the teaching of Gray (Gray 2011 Epigenomics 3: 431-450) which speaks directly to Alzheimers.
4 Vesci reference Akhtar who teaches diabetes mellitus(Akhtar 2013 Plos One 8:e67813)