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 .
Application Status
Applicant's amendment and response, submitted July 6, 2026 has been reviewed by the examiner and entered of record in the file. Claim 68 is amended, and claims 69-75 are canceled.
3. Claims 80-86 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), with traverse, as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 77 remains withdrawn as directed to a nonelected species.
4. Claims 68, 76, 78 and 79 are under examination with the elected species and are the subject of this office action.
Priority
5. 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.
Drawings
6. The drawings were previously objected to because Figures 1A and 1B, Figures 2B and 2C, Figure 5A, and Figures 9A, 10A, 11B, and 29, the compound structures are blurry, there are missing bonds and the compounds are generally difficult to read.
7. Applicant submitted replacement sheets for each of said Figures, however it is noted that the chemical structures depicted within Figures 2B and 2C, Figure 5A are still generally blurry and difficult to read.
Therefore, the objections are maintained for the drawings of Figures 2B and 2C, Figure 5A.
Previous Claim Rejections - 35 USC § 112
8. Claims 68-79 were previously 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, regarding possession of a bifunctional chemical epigenetic modifier comprising FK506 and any linker, and any bromodomain modifier or any CBP/p300 inhibitor, as previously claimed.
9. In view of Applicant’s amendment to claim 68 to delete the recitation of “a derivative thereof,” to limit the linker to a polyethylene glycol linker, and to limit the bifunctional ligand to three recited ligands, the previous written description rejection is withdrawn.
10. Applicant demonstrates support for CEM87 (comprising FK506 linked to iBET762 via a polyethylene glycol linker) in Figures 19B and 20 B; CEM88 (comprising FK506 linked to the bromodomain inhibitor
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via a polyethylene glycol linker) in Figures 19C and 20C; and CEM114 (comprising FK506 linked to the CBP/p300 inhibitor
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via a polyethylene glycol linker) in Figures 19D and 20D.
Previous Claim Rejections - 35 USC § 112(b)
11. Claim 68 was previously rejected for reciting the limitation “and a bromodomain inhibitor or a CBP/p300 inhibitor.” In view of Applicant’s amendment to claim 68 to delete the limitation(s) of a bromodomain inhibitor or a CBP/p300 inhibitor, the previous indefiniteness rejection is withdrawn.
12. The rejections of claims 69, 76, 78 and 79 as being dependent upon and including all of the limitations of claim 68 are also withdrawn.
13. Claim 73 was previously 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.”
In view of the cancellation of claim 73, the previous indefiniteness rejection is withdrawn.
New Claim Rejections - 35 USC § 112(b)
14. 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.
15. Claims 68, 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.
16. This rejection is newly applied as necessitated by Applicant’s amendment to the claims.
17. Claim 68 is confusing regarding the components of the CEM; i.e., the recitation of:
“a molecule of FK506, a polyethylene glycol linker and iBet762,
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,” is unclear because it is not clear if the bifunctional ligand is limited to just one of the ligands recited, or if iBet762 and an additional ligand selected from the last two compounds are intended.
Additionally, it is recommended that the claim recites the chemical structure(s) of FK506 and iBet762, for clarity and consistency with the recitation of the other chemical structures in the claim.
In view of a broadest reasonable interpretation, consistent with the CEM compounds demonstrated in the disclosure in Figures 19B, 19C, 19D, 20B, 20C, and 20D, the examiner construes the claim as follows:
“A bifunctional chemical epigenetic modifier (CEM) comprising
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, a polyethylene glycol linker, and a bifunctional ligand selected from the group consisting of:
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,
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, and
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.”
18. Claims 78 and 79 are rejected under 35 USC 112(b) as being dependent upon and including all of the limitations of claim 68.
Previous Claim Rejections - 35 USC § 103
19. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
20. Claims 68, 76, 78 and 79 remain 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).
21. This rejection has been modified as required by Applicant’s amendment to the claims.
Claim 68 is drawn to a bifunctional chemical epigenetic modifier (CEM) comprising a molecule of FK506, a polyethylene glycol linker, and iBet762,
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, more specifically the compound of claim 76:
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.
In view of a broadest reasonable interpretation, claim 68 is interpreted as follows:
“A bifunctional chemical epigenetic modifier (CEM) comprising
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(FK506), a polyethylene glycol linker, and a bifunctional ligand selected from the group consisting of:
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(iBet762),
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, and
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,”
(see paragraph “17” above).
22. Højfeldt et al. teach a drug conjugate comprising FK506 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).
23. 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).
24. Højfeldt et al. do not teach the bifunctional ligand iBet762.
25. 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 discuss 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).
26. 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 been motivated to substitute iBet762 for an HDAC inhibitor, having awareness that HDAC inhibitors lack efficacy and specificity for treating hematological malignancies and solid tumors, with a reasonable expectation of success
As such, claims 68 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).
27. 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).
28. 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.
29. 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.
Response to Arguments
30. Applicant traverses the previous obviousness rejection of Hojfeldt in view of Perez-Salvia, and argues the following points:
(i) Applicant argues that Hojfeldt is limited to teaching targeting the catalytic site of HDAC1 using bifunctional ligands but is silent regarding using an HDAC1 inhibitor, let alone a bromodomain inhibitor. Applicant alleges that Hojfeldt's bifunctional molecule, composed of a Dex moiety with a PEG linker to a FK506 molecule, utilizes the Dex moiety as a recruitment ligand to bind the glucocorticoid receptor (GR) and the DNA target site, i.e. “[t]he FK506 moiety of Hojfeldt's bifunctional molecule binds to an exogenous fusion to HDAC1 as shown in FIG. 5. Hojfeldt's bifunctional molecule is not only different from the claimed bifunctional chemical epigenetic modifier (CEM), but the fundamental principle of operation of Hojfeldt's bifunctional molecule is different from the claimed bifunctional CEM.”
Applicant argues that the claimed molecule of FK506 is used to bind protein at the DNA target site, not to an exogenous fusion to HDAC1 as taught by Hojfeldt. Applicant alleges that the claimed bifunctional CEMs and the bifunctional ligands disclosed in Hojfeldt may both use a FK506 moiety and a PEG-based linker, however they are functionally distinct and used in opposite roles of the bifunctional molecule, such that one of ordinary skill in the art would have understood that such a substitution would not only have altered the fundamental principle of operation of Hojfeldt, but would have also rendered Hojfeldt inoperable for its intended use by removing the Dex moiety as a recruitment ligand to bind the glucocorticoid receptor (GR) and thus the DNA target site. Applicant contends that modifying Hojfeldt by substituting iBet762 as claimed for Dex/RU486 of Hojfeldt would render the bifunctional molecule of Hojfeldt inoperable in the system taught by Hojfeldt as the linking of a bromodomain in this fashion would result in a molecule that would not have any affinity for the glucocorticoid receptor and would therefore not recruit the FKBP-HDAC1 fusion to the target site.
Applicant argues that the specificity of HDACi vs. bromodomain inhibitors is not described in Perez-Saliva as a reason to favor one versus another approach but as a general weakness of HDAC (Seep. 333). Moreover, in bifunctional chemistry, one of ordinary skill in the art at the time of the invention would understand that it is not always as simple as swapping out one kind of chemical moiety acting as a recruitment warhead for another, and one of ordinary skill in the art would not have been motivated to combine Hojfeldt with Perez-Salvia with an expectation of success given that Hojfeldt is limited to affecting the efficacy of either dexamethasone or RU-486 at an endogenous locus.
(ii) Applicant argues that one of ordinary skill in the art at the time of the invention would have understood that Perez-Salvia teaches that "[a]lterations in enzymes that "writers," "erasers," or "readers" of histone modification marks are common (Abstract). Perez-Salvia also teaches that HDACs are "erasers" and bromodomains are "readers" (4th and 5th paragraphs of the introduction, p. 323, respectively). Applicant alleges that one of ordinary skill in the art at the time of the invention would also have understood that Hojfeldt refers to targeting HDAC1, an eraser, and would not look to Perez- Salvia at least because Perez-Salvia discloses a list of readers - a different class of inhibitor (e.g., bromodomain inhibitors in which iBet762 is one among the long list (see, Table 1 of Perez-Salvia)). Further, based on the teachings of Hojfeldt, one of ordinary skill in the art would move away from combining a FK506 moiety that targets any type of histone enzyme at least because Hojfeldt demonstrates that that "in the presence of FKBP-HDAC1 coregulator, the maximal response...was significantly blunted" (p. 254).
Applicant further contends that there is no expectation of success that bonding a molecule of FK506, a linker, and bromodomain inhibitor into a synthetic molecule will work even in the same field of endeavor. In biotechnology, fusion molecules and their uses thereof, especially involving small molecules comprising multiple components, is challenging, complex and unpredictable. As such, there is no expectation of success that swapping components from the bifunctional ligands made as FK506 conjugates disclosed in Hojfeldt that allow deliberate extrinsic reprogramming of the glucocorticoid receptor with a bromodomain inhibitor that binds the acetylated lysines in histone tails, the recognition of the acetyl group being decisive for the recruitment of other chromatin factors and transcriptional machinery, and thereby the regulation of gene transcription, will work. Applicant also submits that there is no evidence or suggestion that modifying the bifunctional ligands of Hojfeldt, useful for its anti-inflammatory and immuno-suppressive effects, with a different small molecule, a bromodomain inhibitor, as disclosed in Perez-Salvia would produce, much less allow for a functioning composition that would target cancer. Applicant contends that one of ordinary skill in the art would not reasonably expect success by modifying the teaching of Hojfeldt to substitute the bromodomain inhibitor iBet762 for Dex/RuU486 to target the bromodomain active site.
Applicant argues that while Perez-Salvia discloses over 25 bromodomain inhibitors of which iBet762 is among those listed, Perez-Salvia is silent with regard to combining a specific bromodomain inhibitor (e.g., iBet762) in combination with a molecule of FK506 as alleged by the Office Action. Applicant alleges that nowhere in Perez-Salvia is there any disclosure or teaching of any bifunctional compositions or any bifunctional chemical epigenetic modifiers that have any target domain such as a FK506 moiety for the over 25 bromodomain inhibitors to selectively control the chromatin landscape and repress genes in a specific manner, much less the combination as claimed.
31. Applicant's arguments have been fully considered but they are not persuasive. 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). In this case, Højfeldt is relied upon for teaching a drug conjugate comprising FK506 linked via a thiourea polyethylene glycol (PEG) linker to a bifunctional ligand, which is the same system that is instantly recited in claims 68 and 76. Højfeldt go on to suggest that HDAC1 could be targeted by bifunctional ligands. Perez-Salvia is relied upon for teaching the disadvantages of HDAC inhibitors, and suggesting the use of bromodomain inhibitors, specifically naming I-BET762.
Regarding Applicant’s allegation that modifying Hojfeldt by substituting iBet762 would render the conjugate inoperable, “[e]ven if a reference discloses an inoperative device, it is prior art for all that it teaches” (Beckman Instruments v. LKB Produkter AB, 892 F.2d 1547 (Fed. Cir. 1989)). Therefore, “a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103” (Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569 (Fed. Cir. 1991)).
And, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." 27 F.3d at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
(iii) Secondary Considerations
Applicant argues that it was surprisingly found that combining a FK506 molecule, a linker, and iBet762 can bind to a FKBP fusion transcription factor and increasing BFP reporter expression (see, paragraph [00191] and Example 8 of the published application), and alleges that the claimed composition produces a superior composition. Applicant contends that Example 8 demonstrates that the claimed composition is capable of binding to a FKBP fusion transcription factor and increasing BFP reporter expression (see, paragraph [0191] and Example 8 of the published application). In addition, Example 8 demonstrates that the claimed CEM (CEM87) significantly increased BFP (Blue Fluorescent Protein) driven by a Tre3G promoter that has low expression) expression by 7.5 fold compared to untreated cells (FIG. 21B, paragraph [0191] of the published application). Moreover, the claimed composition yields a more effective and highly dosable system demonstrating that "transcriptional activity, as measured by mean fluorescence, can be tightly controlled with CEMa concentration" (FIG. 21D, paragraph [0193] of the published application.
Applicant alleges that nothing in Hojfeldt with Perez-Salvia demonstrate specific changes to both the epigenetic state and the expression of a target gene, such that there is a superior result by specifically combining in a single construct a molecule of FK506 and a bromodomain inhibitor, namely, iBet762 (CEM87) to recruit FKBP fusion transcription factor and BFP.
33. Applicant's arguments have been fully considered but they are not persuasive. While Applicant alleges unexpected results of the conjugate comprising a FK506 molecule, a linker, and iBet762, which binds to a FKBP fusion transcription factor and increases BFP reporter expression and is “a more effective and highly dosable system demonstrating that transcriptional activity, as measured by mean fluorescence, can be tightly controlled with CEMa concentration” (Applicant’s Remarks, pages 19-20), it is noted that according to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." Thus, the previous claim amendments of July 6, 2026 don’t capture Applicant’s alleged unexpected results of Example 8; wherein Example 8 demonstrates that the claimed CEM (CEM87) significantly increased BFP (Blue Fluorescent Protein) driven by a Tre3G promoter that has low expression) expression by 7.5 fold compared to untreated cells (FIG. 21B). As such, the examiner recommends limiting the claimed conjugate to the compound of claim 76, i.e., a FK506 molecule, a PEG linker, and iBet762.
Previous Double Patenting Rejections
34. 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).
35. 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).
36. 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.
37. 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.
38. Claims 68, 76, 78 and 79 remain 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, a linker and iBet762,
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Claim 76 is drawn to claim 68, wherein the CEM has the structure:
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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).
39. 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
40. 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.
41. U.S. Pat. No. 11,905,537 B2 does not recite that the bifunctional ligand is a bromodomain inhibitor.
42. 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).
43. 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).
44. 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, 76, 78 and 79 are prima facie obvious over claims 1-4 of U.S. Pat. No. 11,905,537.
Response to Arguments
45. As Applicant has not addressed the previous obviousness-type double patenting rejections, said rejections are maintained.
Conclusion
46. Claims 68 and 76-86 are present in the application. Claims 80-86 are presently withdrawn as directed to a non-elected invention/ non-elected subject matter.
Claims 68, 76, 78 and 79 are rejected. No claim is presently allowed.
47. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
