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 with traverse of Group I, claims 68-79, drawn to a bifunctional chemical epigenetic modifier, in the reply filed on March 7, 2025 is acknowledged. Additionally elected the species of (A) a bromodomain inhibitor, which is readable on claims 68, 69 and 71-79. The traversal is on the ground(s) that the examiner has not shown that a serious burden would result if all of the claims were to be examiner together, specifically that the restriction requirement does not provide sufficient basis to indicate that examination of more than one or more of the groups or species would overly burden the examiner.
3. This is not found persuasive because: restriction for examination purposes as indicated is proper because Groups I and II are independent or distinct for the reasons given in the previous office action and there would be a serious search and examination burden if restriction were not required because one or more of the following reasons apply:
(a) the inventions have acquired a separate status in the art in view of their different classification;
(b) the inventions have acquired a separate status in the art due to their recognized divergent subject matter;
(c) the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries).
4. In this case, the claims presently embrace a bifunctional CEM comprising a molecule of FK506 or any derivative thereof, any linker, and any bromodomain inhibitor OR any CBP/p300 inhibitor (classified in CPC A61K 47/55), and its method of use (classified in CPC A61P 35/00), such that a bifunctional CEM comprising tacrolimus, a homobifunctional linker and the pan-BET bromodomain inhibitor i-Bet762 would require different search strategy and parameters than a method of treating a patient with cancer comprising administering a bifunctional CEM comprising tacrolimus, a heterotrifunctional linker and the BET BD1/2-selective bromodomain inhibitor olinone.
The requirement is still deemed proper and is therefore made FINAL.
5. Claims 80-86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 70 and 77 are withdrawn as directed to nonelected species.
6. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
7. Claims 68-79 are under examination with the elected species and are the subject of this office action.
Priority
8. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed provisional applications, Application No.’s 62/541,343 and 62/654,958 each fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application, because neither Application describes bromodomain inhibitors including iBet762 or any CBP/p300 inhibitors. As such, the instant claims are afforded benefit of priority to PCT Application No. PCT/US2018/045266, filed August 3, 2018.
Information Disclosure Statement
9. The information disclosure statement (IDS) submitted on July 15, 2025, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Drawings
10. The drawings are objected to because of the following informalities:
Figures 1A and 1B, the compound structures are blurry/ missing bonds and are difficult to read.
Figures 2B and 2C, the compound structures are blurry/ missing bonds and are difficult to read.
Figure 5A, the compound structure is blurry/ missing bonds and is difficult to read.
Figures 9A, 10A, 11B, and 29, the compound structures are blurry, and the heteroatoms as well as the bonds and stereochemistry are difficult to distinguish.
11. 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.
Claim Rejections - 35 USC § 112
12. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
13. Claims 68-79 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
14. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. In particular, support cannot be found for a bifunctional chemical epigenetic modifier comprising FK506 and any linker, and any bromodomain modifier or CBP/p300 inhibitor, as instantly claimed.
15. The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the Applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.”
16. In the instant case, it is evident that the genera of functional compounds embraced by each of “a molecule of FK506 or derivative thereof,” “linker,” and “bromodomain inhibitor” have substantial variance. Regarding the “derivative thereof” recited in claims 68, 69, and 71, “derivatives” of those compounds in the claims could read on any analog, prodrug, and/or metabolite thereof, having widely varying groups that can be substituents of these compounds. It is noted that the specification fails to define or limit “derivatives” such that any chemical structures or substituents can be employed as “derivatives” and there is no clear structural limitation showing what substituents/modifications could be made to the FK506 compound and/or the bromodomain inhibitor of claim 69. Thus the genus of derivatives thereof is virtually without limit.
17. The genus of linkers embracing hundreds of millions of potential groups or combinations of groups, bearing no structural resemblance to one another what-so-ever. The specification describes the linker:
“[i]n an aspect, the linker can be a homofunctional linker or a heterofunctional linker. The linker can be a covalent bond. The homofunctional linker can be a homobifunctional, homotrifunctional, or homotetrafunctional linker comprising two, three, or four reactive groups, respectively, that react with a primary amine, a thiol group, a hydroxyl group, or a carbohydrate. The heterofunctional linker can be a heterobifunctional, heterotrifunctional, or heterotetrafunctional linker comprising at least one reactive group that reacts with a primary amine, a thiol group, a hydroxyl group, or a carbohydrate. In an aspect the linker can be a heterobifunctional, heterotrifunctional, or heterotetrafunctional linker comprising a group reactive with a primary amine and a group reactive with a thiol group. Among the commercially available homobifunctional cross-linkers are: BSOCOES (Bis(2- [Succinimidooxy-carbonyloxy]ethyl) sulfone; DPDPB (1,4-Di-(3'-[2pyridyldithio]- propionamido) butane; DSS (disuccinimidyl suberate); DST (disuccinimidyl tartrate); Sulfo DST (sulfodisuccinimidyl tartrate); DSP (dithiobis(succinimidyl propionate); DTSSP (3,3'- Dithiobis(sulfosuccinimidyl propionate); EGS (ethylene glycol bis(succinimidyl succinate)); and BASED (Bis(p-[4-azidosalicylamido]-ethyl)disulfide iodinatable).
Examples of linkers include pyridinedisulfide, thiosulfonate, vinylsulfonate,
isocyanate, imidoester, diazine, hydrazine, thiol, carboxylic acid, multi-peptide linkers, and acetylene. Alternatively, other linkers than can be used include BS3 [Bis(sulfosuccinimidyl)- suberate], NHS/EDC (N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide, sulfo-EMCS ([N-E-maleimidocaproic acidjhydrazide, hydrazide. Another useful linker is SATA (N-succinimidyl-Sacetylthioacetate).”
Applicant goes on to describe cleavable linkers:
“Suitable linkers include, but are not limited to, disulfide linkers, acid labile linkers (including dialkoxybenzyl linkers, Sieber linkers, indole linkers, t-butyl Sieber linkers, electrophilically cleavable linkers. nucleophilically cleavable linkers. photocleavable linkers, cleavage under reductive conditions, oxidative conditions, cleavage via use of safety-catch linkers, and cleavage by elimination mechanisms.
Electrophilically cleaved linkers are typically cleaved by protons and include
cleavages sensitive to acids. Suitable linkers include the modified benzylic systems such as trityl, p-alkoxybenzyl esters and p-alkoxybenzyl amides. Other suitable linkers include tert-butyloxycarbonyl (Boc) groups and the acetal system. The use of thiophilic metals such as nickel, silver or mercury in the cleavage of thioacetal or other sulphur-containing protecting groups can also be considered for the preparation of suitable linker molecules.”
“Nucleophilic cleavage is also a well-recognized method in the preparation of linker molecules. Groups such as esters that are labile in water (i.e., can be cleaved simply at basic pH) and groups that are labile to non-aqueous nucleophiles, can be used. Fluoride ions can be used to cleave silicon-oxygen bonds in groups such as triisopropyl silane (TIPS) or t- butyldimethyl silane (TBDMS).”
“Photocleavable linkers have been used widely in carbohydrate chemistry. It is preferable that the light required to activate cleavage does not affect the other components of the modified nucleotides. For example, if a fluorophore is used as the label, it is preferable if this absorbs light of a different wavelength to that required to cleave the linker molecule.”
“Suitable linkers include those based on O-nitrobenyl compounds and nitroveratryl compounds. Linkers based on benzoin chemistry can also be used (Lee et al., J. Org. Chem. 64:3454-3460, 1999).”
Applicant describes safety-catch linkers and linkers comprising spacer units:
“…in some aspects the linker can comprise a spacer unit. The spacer distances the FK506 or derivative thereof or the bifunctional ligand from the cleavage site. Examples of protospacer sequences are in Table 4.
“In an aspect, the linker can comprise a disulfide, acid labile Sieber, indole,t-butyl Sieber, electrophilically cleavable, or nucleophilicially cleavable moiety.
“To form covalent bonds, one can use as a chemically reactive group a wide variety of active carboxyl groups (e.g., esters) where the hydroxyl moiety is physiologically acceptable at the levels required to modify the peptide. Particular agents include N-hydroxysuccinimide (NIS), N-hydroxy-sulfosuccinimide (sulfo-NHS), maleimide-benzoyl-succinimide (MBS), gamma-maleimido-butyryloxy succinimide ester (GMBS), maleimido propionic acid (MPA), maleimido hexanoic acid (MIIA), and maleimido undecanoic acid (MUA).
Examples of amine-to-carboxyl linkers include carbodiimide compounds (e.g., DCC (N,Ndicyclohexylcarbodimide) and EDC (1-ethyl-3-[3-dimethyl-aminopropyl]carbodiimide)).”
“Examples of sulfhydryl-to-nonselective linkers include pyridyldithiol/aryl azide compounds (e.g., APDP ((iV-[4-(/;-azidosalicylamido)butylJ-3-(2-pyridyldithi o)propionamidc)).Examples of sulfhydryl-to-carbohydrate linkers include maleimide/hydrazide compounds(e.g., BMPH (A-[p-maleimidopropionic acidhydrazide), EMCH ([A-E-malcimidocaproic acid hydrazide), MPBH 4-(4-A-maleimidophenyl)butyric acid hydrazide), and KMUH (A-[k- maleimidoun-decanoic acidjhydrazide)) and pyridyldithiol/hydrazide compounds (e.g., PDPH (3-(2-pyridyldithio)propionyl hydrazide)). Exemplary carbohydrate-to-nonselective linkers include hydrazide/aryl azide compounds (e.g., ABH (p-azidobcnzoyl hydrazide)). Examples of hydroxyl - to-sulthydryl linkers include isocyanate/maleimide compounds (e.g., (N-[pmaleimidophenyljisocyanate)). Examples of amine-to-DNA linkers include NHS ester/psoralen compounds (e.g., SPB (succinimidyl-[4-(psoralen-8-yloxy)]-butyrate)).”
“In an aspect, the linker can be a chemical conjugate. In an aspect, the chemical conjugate can be polyethylene glycol (PEG). Tn an aspect, the number of PEG units can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more. In aspect, the number of PEG units can be of sufficient length to separate the FK506 or derivative thereof from the bifunctional ligand to prevent any steric interference between the FK506 or derivative thereof and the bifunctional ligand. In an aspect, the linker can include 3 PEG units. In an aspect, the linker can include a propyl linker.”
18. The genus of bromodomain inhibitors includes any/all drugs that target any bromodomain(s) and their derivatives including BRD2, BRD3, BRD4 and BRDT, which embrace many classes including selective BRD inhibitors, pan-BET inhibitors, and PROTACS (proteolysis targeting chimeras), for example: iBETS, JQ1, Birabresib, Apabetalone, SGC-CBP30, ABBV-075, FT-1101, BMS-986158, PFI-1, CPI-203, CPI-0610, TEN-010, or their derivatives thereof etc. (see webpage printout of https://en.wikipedia.org/wiki/BET_inhibitor#:~:text=I%2DBET%20151%20(GSK1210151A),CPI%2D0610).
19. Yet, the instant Specification fails to describe any bromodomain inhibitor compounds other than one bifunctional CEM compound species comprising a bromodomain inhibitor, iBET762: CEM87; and only two structurally related bifunctional CEM compound species comprising a CBP/p300 inhibitor: CEM88 and CEM114 (page 10 under “Compositions”).
20. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of just one CEM comprising a bromodomain inhibitor and just two structurally related CEMs comprising CBP/p300 inhibitor does not adequately describe a subgenus embracing hundreds of millions of additional compound species bearing no structural relationship with those three disclosed compounds. That is, the Specification does not disclose a sufficient variety of species to reflect the extreme variance in the genus.
21. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
22. As such, claims 68, 69, 71-76, 78 and 79 are rejected.
Claim Rejections - 35 USC § 112
23. 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.
24. Claims 68, 69, 71-76, 78 and 79 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.
25. Claim 68 is rejected for reciting the limitation “and a bromodomain inhibitor or a CBP/p300 inhibitor,” which is confusing, because CBP/p300 is a bromodomain. Therefore a “CBP/p300 inhibitor” is a “bromodomain inhibitor,” and it is not clear if the recitation of a CBP/p300 inhibitor is intended to be exemplary of a bromodomain inhibitor and therefore not required, or an alternative to a type of bromodomain inhibitor. Clarification is requested.
26. Claims 69, 71-76, 78 and 79 are rejected for being dependent upon and including all of the limitations of claim 68.
27. Claim 73 is rejected for reciting the limitation(s):
wherein the homofunctional linker comprises reactive groups “that react with a primary amine, a thiol group, a hydroxy group, or a carbohydrate,” and
wherein the heterofunctional linker comprises “at least one reactive group that reacts with a primary amine, a thiol group, a hydroxyl group, or a carbohydrate.” It is not clear what reactive groups are embraced by the functional limitation “reactive groups… that react with a primary amine, a thiol group, a hydroxy group, or a carbohydrate,” or how said groups react, as claims 73 and 74 are drawn to a product, not a process.
Clarification is requested.
28. Accordingly, claims 73 and 74 have not been further treated on the merits. See In re Steele, 305 F.2d 859,134 USPQ 292 (CCPA 1962) (it is improper to rely on speculative assumptions regarding the meaning of a claim and then base a rejection under 35 U.S.C. 103 on these assumptions).
Claim Rejections - 35 USC § 103
29. 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.
30. 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.
31. 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.
32. Claims 68, 69, 71, 72, 75, 76, 78 and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Højfeldt et al., Molecular Endocrinology 2014 (cited on Applicant’s IDS of July 17, 2025), in view of Perez-Salvia and Esteller, Epigenetics 2017, as evidenced by the webpage printout of AVT-Pharmaceutical (accessed January 2, 2026) and as evidenced by the webpage printout of PurePEG.com (posted on October 16, 2025).
Claim 68 is drawn to a bifunctional chemical epigenetic modifier (CEM) comprising a molecule of FK506 or derivative thereof, a linker and a bromodomain inhibitor or a CBP/p300 inhibitor, (more specifically the bromodomain inhibitor Bet762 or a derivative thereof (claim 69)), wherein the linker couples the FK506 or derivative thereof to the bromodomain inhibitor (claim 71),
wherein the linker is a homofunctional linker or a heterofunctional linker (claim 72) that is cleavable (claim 75), and wherein the CEM has the structure:
PNG
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221
597
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(claim 76).
33. Højfeldt et al. teach a FK506 molecule linked via a thiourea polyethylene glycol (PEG) linker to bifunctional ligand, wherein the ligand is an agonist of dexamethasone (Dex) or an antagonist RU-486 (see page 251, Materials and Methods, first paragraph; and page 252, Figure 2). Højfeldt et al. discuss the favorable pharmacokinetic properties of FK506 when employed in drug conjugates comprising bifunctional ligands:
“Our data also indicate that the FK506 moiety enhances the cellular potency of Dex (Figure 4) as well as RU486-based bifunctional ligands (Figure 6) relative to their intrinsic receptor affinities (Figure 3), an effect observed even in the absence of designed FKBP fusion proteins (Figure 6B, left panel). The enhanced potency may be a reflection of increased cellular uptake or retention provided by the FK506 group, particularly because FK506 can serve as a substrate and inhibitor of drug efflux transporters such as multidrug resistance protein 1 (41). Notably, the favorable pharmacokinetic properties provided by FK506 have been recently demonstrated for drug conjugates both in vitro and in vivo (42, 43).”
(page 257, Figure 2; right column, first full paragraph). And as evidenced by PurePEG.com, PEG linkers can be heterobifunctional or homobifunctional, as well as cleavable (see page 2 of webpage printout).
Højfeldt et al. teach that the FK506-Dex ligand demonstrates a maximal inhibitory effect on HDAC1 (see Table 1 at page 257). And, Højfeldt et al. go on to teach:
“It is also important to note that HDACs can play key scaffolding roles in corepressor complexes that do not depend on their HDAC activity (34, 40). Consistent with this view, initial data indicate that the catalytic activity of HDAC1 is not required for its ability to suppress GR transactivation in the extrinsic recruitment approach (data not shown). This would indicate that the catalytic site of HDAC1 could be targeted by bifunctional ligands to recruit functional corepressor complexes.”
(at p. 257, left column, first paragraph, sentences 3-5).
34. Højfeldt et al. do not teach wherein the bifunctional ligand is a bromodomain inhibitor.
35. Yet, Perez-Salvia teaches that histone deacetylases (HDACs, “erasers” of acetyl marks) are cancer targets because they are overexpressed in tumors, and
“have provided the basis for the development of HAT and HDAC inhibitors, some of which had already proved successful in clinical oncology. However, they have two common weaknesses: a lack of efficacy and a lack of specificity.”
(page 323, right column, first two paragraphs). Perez-Salvia teach that bromodomain proteins (“readers” of acetyl marks), in particular bromodomain and extra terminal (BET) proteins are highly involved in cancer, and teach that BET inhibitors as a class demonstrate efficacy across a variety of hematological malignancies and solid tumors, specifically naming I-BET762 (aka Applicant’s recited iBet762), (see Figure 3 at page 327 and Table 1 at page 328). Perez-Salvia go on to discusses I-BET762:
“I-BET762, like JQ1, arrests the growth of NMC-malignant cells. GSK started clinical trials for the treatment of this malignancy that were subsequently extended to other types of cancer, such as small cell lung cancer, non-small cell lung cancer, colorectal cancer, neuroblastoma, castration-resistant prostate cancer, triple-negative breast cancer, estrogen receptor-positive breast cancer, and MYCN driven solid tumor subjects (Table 1). I-BET762 has also been reported to exert antiproliferative effects and to induce apoptosis in multiple myeloma in vitro and in vivo.96 It is also effective in prostate cancer, whereby tumor growth is reduced by inhibiting MYC.97”
(page 329, right column, last paragraph- page 330, left column, first paragraph). Perez-Salvia suggest the administration of bromodomain inhibitors as drugs for cancer therapy due to their improved specificity and potency, in particular, I-BET762 (page 333, left column, last paragraph).
36. Therefore it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the FK506-PEG linker-Dex/RU486 bifunctional ligand taught by Højfeldt et al. by substituting the bromodomain inhibitor iBet762 for the known Dex/RU486 ligand, in order to target the bromodomain active site for targeting solid tumors, for example. As guided by the combined prior art of record, one skilled in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success in substituting iBet762 for an HDAC inhibitor, having awareness that HDAC inhibitors lack efficacy and specificity, for treating hematological malignancies and solid tumors.
As such, claims 68, 69, 71, 72, 75 and 76 are prima facie obvious.
Claim 78 is drawn to a pharmaceutical composition comprising the composition of claim 68 and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated for intravenous or subcutaneous administration (claim 79).
37. Højfeldt et al. additionally teach that said compounds are placed in a HEPES, EDTA, sodium molybdate buffer (page 251, left column under “Materials and Methods”). And, it is clear as evidenced by AVT-Pharma that HEPES is a non-toxic pharmaceutical grade carrier (buffer) that exhibits excellent buffering capacity and is widely utilized in the preparation of liposomes, antibody drugs, nucleic acid drugs, as well as vaccines (see page 1 of webpage printout).
38. Regarding the functional limitation in claim 79, wherein the pharmaceutical composition is “formulated for intravenous or subcutaneous administration,” it is noted that the claim is drawn to a pharmaceutical composition (i.e., a product). The recitation of the intended use of the claimed invention (i.e., “for intravenous or subcutaneous administration”) must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this case, the claim is drawn to a product previously taught by Højfeldt et al. and the manner in which it is to be administered does not sufficiently distinguish from the prior art of record.
39. Therefore it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the FK506-PEG linker-Dex/RU486 bifunctional ligand taught by Højfeldt et al. by substituting the bromodomain inhibitor iBet762 for the known Dex/RU486 ligand, in order to target the bromodomain active site, wherein the FK506-PEG-iBet762 ligand is in the form of a pharmaceutical composition, with a reasonable expectation of success.
As such, claims 78 and 79 are prima facie obvious.
Double Patenting
40. 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).
41. 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).
42. 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.
43. 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.
44. Claims 68, 69, 71, 72, 75, 76, 78 and 79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,905,537 B2 in view of Perez-Salvia and Esteller, Epigenetics 2017, as evidenced by the webpage printout of PurePEG.com (posted on October 16, 2025).
Instant claim 68 recites a bifunctional chemical epigenetic modifier (CEM) comprising a molecule of FK506 or derivative thereof, a linker and a bromodomain inhibitor or a CBP/p300 inhibitor, (more specifically the bromodomain inhibitor Bet762 or a derivative thereof (claim 69)), wherein the linker couples the FK506 or derivative thereof to the bromodomain inhibitor (claim 71),
wherein the linker is a homofunctional linker or a heterofunctional linker (claim 72) that is cleavable (claim 75), and wherein the CEM has the structure:
PNG
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(claim 76).
Claim 78 recites a pharmaceutical composition comprising the composition of claim 68 and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated for intravenous or subcutaneous administration (claim 79).
45. The claims of U.S. Pat. No. 11,905,537 B2 are as follows:
Claim 1. A bifunctional chemical epigenetic modifier (CEM) comprising a molecule of FK506 or derivative thereof, a linker and a histone deacetylase inhibitor, wherein the histone deacetylase inhibitor is suberanilohydroxamic acid, depsipeptide or a derivative thereof.
Claim 2. The bifunctional CEM of claim 1, wherein the linker couples the FK506 or derivative thereof to the histone deacetylase inhibitor.
Claim 3. The bifunctional CEM of claim 1, wherein the linker is a homofunctional linker or a heterofunctional linker, wherein the homofunctional linker is a homobifunctional, homotrifunctional, or homotetrafunctional linker comprising two, three, or four reactive groups, respectively, that react with a primary amine, a thiol group, a hydroxyl group, or a carbohydrate, and the heterofunctional linker is a heterobifunctional, heterotrifunctional, or heterotetrafunctional linker comprising at least one reactive group that reacts with a primary amine, a thiol group, a hydroxyl group, or a carbohydrate.
Claim 4. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier
46. As such, U.S. Pat. No. 11,905,537 B2 recites a bifunctional chemical epigenetic modifier (CEM) comprising a FK506 molecule linked via a linker (a homofunctional linker or a heterofunctional linker), to bifunctional ligand, wherein the ligand is a histone deacetylase inhibitor, wherein the histone deacetylase inhibitor is suberanilohydroxamic acid (SAHA), and its pharmaceutical composition thereof.
34. U.S. Pat. No. 11,905,537 B2 does not recite that the bifunctional ligand is a bromodomain inhibitor.
35. Yet, Butler et al. teach that SAHA is a potent inhibitor of histone deacetylase HDACi) causing growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo, and is clinical trials for the treatment of cancer (see abstract).
36. And Perez-Salvia teaches that histone deacetylases (HDACs, “erasers” of acetyl marks) are known cancer targets but HDAC inhibitors lack efficacy and specificity:
“have provided the basis for the development of HAT and HDAC inhibitors, some of which had already proved successful in clinical oncology. However, they have two common weaknesses: a lack of efficacy and a lack of specificity.”
(page 323, right column, first two paragraphs). Perez-Salvia teach that bromodomain proteins (“readers” of acetyl marks), in particular bromodomain and extra terminal (BET) proteins are highly involved in cancer, and teach that BET inhibitors as a class demonstrate efficacy across a variety of hematological malignancies and solid tumors, specifically naming I-BET762 (aka Applicant’s recited iBet762), (see Figure 3 at page 327 and Table 1 at page 328). Perez-Salvia go on to discusses I-BET762:
“I-BET762, like JQ1, arrests the growth of NMC-malignant cells. GSK started clinical trials for the treatment of this malignancy that were subsequently extended to other types of cancer, such as small cell lung cancer, non-small cell lung cancer, colorectal cancer, neuroblastoma, castration-resistant prostate cancer, triple-negative breast cancer, estrogen receptor-positive breast cancer, and MYCN driven solid tumor subjects (Table 1). I-BET762 has also been reported to exert antiproliferative effects and to induce apoptosis in multiple myeloma in vitro and in vivo.96 It is also effective in prostate cancer, whereby tumor growth is reduced by inhibiting MYC.97”
(page 329, right column, last paragraph- page 330, left column, first paragraph). Perez-Salvia suggest the administration of bromodomain inhibitors as drugs for cancer therapy due to their improved specificity and potency, in particular, I-BET762 (page 333, left column, last paragraph).
37. Therefore it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the FK506-PEG linker-HDACi recited in the claims of U.S. Pat. No. 11,905,537 by substituting the bromodomain inhibitor iBet762 for the HDACi SAHA, in order to target the bromodomain active site for targeting solid tumors, for example. As guided by the combined prior art of record, one skilled in the art before the effective filing date of the claimed invention would have had awareness that HDAC inhibitors lack efficacy and specificity, and therefore would have been motivated to substitute iBet762 for the HDACi SAHA, , for treating hematological malignancies and solid tumors, with a reasonable expectation of success.
As such, claims 68, 69, 71, 72, 75 and 76 are prima facie obvious over claims 1-4 of U.S. Pat. No. 11,905,537.
Conclusion
38. Claims 68-86 are present in the application. Claims 80-86 are presently withdrawn as directed to a non-elected invention/ non-elected subject matter.
Claims 68-79 are rejected. No claim is presently allowed.
39. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628