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 .
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.
Current Status of 18/726,567
This Office Action is responsive to the amended claims of 7 February 2025. Claims 1-26 have been examined on the merits. Claims 21-23 and 25 are currently amended.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 6 January 2022 for claims 2-16, 21-26 and claim 1 (compounds 1-15). The effective filing date is 6 January 2023 for claims 17-20 and claim 1 (compounds 16-19).
Information Disclosure Statement
Three information disclosure statements (IDSs) submitted on 10/15/2024, 11/26/2025 and 12/29/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s)1, 5, 7-8, 11-12, 16 and 21-26 are rejected under 35 U.S.C. 103 as being unpatentable over ANSARI (WO2022150555 A2, pub date: 7/14/2022. Referenced in IDS of 10/15/2024. Priority date: 1/8/2021. The priority document is referred as “PD”).
Note: The compound claims and composition and method claims will be discussed separately for the purpose of clarity.
Determining the scope and contents of the prior art
ANSARI teaches compounds or salts thereof for modulating expression of genes of formula X-L-Y, wherein X is a recruiting moiety that is capable of noncovalent binding to a regulatory moiety within the nucleus; Y is a DNA recognition moiety that is capable of noncovalent binding to one or more copies of the trinucleotide repeat sequence GAA; and L is a linker (para [0021], p 4, PD).
ANSARI also teaches the nucleic acid binding moiety (Y) of pyrrole-imidazole polyamides are cell-permeable small molecules that can be designed to bind a variety of DNA sequences with high DNA binding as shown below. For regulatory binding moiety (X), in certain embodiments, is chosen from variety of moieties (para [00195], p 39-41), among which one moiety X is shown in compounds 50 and 177-180 (see below).
ANSARI further teaches the linker (L) connects the first terminus (Y) and the second terminus (X) and brings the regulatory molecule in proximity to the target gene to modulate gene expression, and the length of the linker depends on the type of regulatory protein and also the target gene (paras [00198-[00199], p 42, PD). The linker comprises -(CH₂CH₂-O)ₓ₁- or…, and each x1, x2, and x3 is independently an integer from 1-15. (para [00221], p 46, PD). Various (PEG)2-8 and modified (PEG)2-8 are showcased in the exemplified compounds 1-194 (for example, compounds 177-180, 50 and 123 below. For the full list, see Table 3, p 51-73, PD).
ANSARI teaches compounds 177-180 with the same moieties X and Y as the instant claim 12 by changing the PEG linker units from 2 to 6. The PEG linker
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is further extended to PEG7 (for example, compound 50) and PEG8 (for example, compound 123) with a different regulatory moiety X from that in compounds 177-180 and 50.
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Ascertaining the differences between the prior art and the claims at issue
In the instant claims, the compounds are “tethered” molecules with two parts: one part binds the defective DNA sequence, and the other part binds a regulatory protein in the nucleus. The DNA-binding part is typically a polyamide that recognizes the GAA repeat region in the minor groove of DNA (Y). The other end is a protein-binding “recruiting” moiety, including bromodomain-binding and other regulatory binding moiety (X). A linker (L) connects the two parts and is tuned in length and composition to position the regulatory protein near the target gene. The compounds are presented as pharmaceutical agents and as salts or compositions with excipients to increase or normalize FXN expression and thereby address symptoms of Friedreich’s ataxia.
ANSARI teaches the same pyrrole-imidazole polyamide moiety Y and the regulatory binding moiety X as those in the instant claims, as well as a various PEG linkers. ANSARI further teaches change of regulatory binding moiety X with different genes to be regulated and the length of the linker (L) is important since it brings the regulatory molecule in proximity to the target gene to modulate gene expression and have showcased various (PEG)2-8 and modified (PEG)2-8 are in the exemplified compounds 1-194 (for the full list, see Table 3, p 51-73, PD).
But, ANSARI doesn’t teach specific and/or modified moieties Y, X and linkers recited in the instant claims directly.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Regarding the instant claims, ANSARI teaches the pyrrole-imidazole polyamide moiety Y and the bicyclic pyrrolopyridone regulatory binding moiety X as well as a various pure PEG linkers of (PEG)2 to (PEG)8, and makes some instant claims obvious.
Regarding minor changes in chemical structures, like the minor changes in pyrrole-imidazole polyamide moieties Y, MPEP 2144.09 (I) and MPEP 2144.09 (II) provide guidance about chemical compounds with very close structural similarities and homology.
MPEP 2144.09 (I). A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c)
In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) (en banc) Structural similarity between a claimed compound and a prior-art compound can establish a prima facie case of obviousness, particularly where the compounds are expected to have similar properties or use. MPEP 2144.09 (II). Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). Closely related members of a homologous series may be obvious where the prior art would have suggested the neighboring compounds to a person of ordinary skill.
In the instant case, increasing or decreasing a beta amino acid unit in polyamide pyrrole-imidazole moieties X (such as in claims 11 and 8) and minor changes in adding a CH2 group (such as in claim 7) in a big molecule (X-L-Y) all fit this rationale as a small homologous variation. In addition, these changes are minimal in big molecules (X-L-Y) and they are not concurrent, and the resulted compounds and alternatives have similar properties and applications.
Regarding instant claim 5, both the moiety Y and the modified linker L are the same as those in ANSARI compound 211 (see below). Simply substituting moiety X in 211 with a different known moiety X in compounds 177-180, taught by ANSARI (paras [00178]-[00185], p 37-38, PD), would produce compound 4 of the instant claim 5.
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Regarding instant claim 7, the moiety Y is the same as that in ANSARI compound 177, a CH2 is inserted in between the amide NH and the phenyl ring in moiety X (as a homologous variation, MPEP 2144.09 (II)) the PEG linker is extended to PEG8 from PEG6 of compound 177 as taught in compound 123.
Regarding instant claim 8, the moiety X is the same, the moiety Y is a beta alanine unit shorter than that in ANSARI compounds 177-180, the PEG linker is PEG8 as in compound 123.
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Claim 7 Claim 8
Regarding instant claim 11, the moiety X is the same, the moiety Y is a beta alanine unit longer than those in compounds 177-180, the PEG linker is PEG8 in compound 123.
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Regarding claim 12, both the moieties Y and X are the same as those in compounds 177-180 and the linker is PEG5 (not shown here), which is in between compound 177 (PEG6) and compound 178 (PEG4).
Regarding claim 16, both the moieties Y and X are the same as those in compounds 177-180 and the linker is PEG8 (not shown here). It’s obvious by extending the PEG6 linker of compound 177 to PEG8 as taught in compound 123, or simply substituting moiety X in 123 with a different known moiety X in compounds 177-180 as taught by ANSARI (paras [00178]-[00185], p 37-38, PD).
Therefore, claims 1, 5, 7-8, 11-12 and 16 are obvious over ANSARI.
Regarding claim 21, ANSARI teaches a pharmaceutical composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier.
(para [0271], p 74; claim 69).
Regarding claims 22-26, ANSARI teaches a method of modulation of the expression of fxn comprising contacting fxn with a transcription modulator molecule (claim 70), a method of treatment of a disease caused by expression of a defective fxn comprising the administration of a therapeutically effective amount of a transcription modulator molecule to a patient in need thereof (claim 71) and said disease is Friedreich's ataxia (claim 72), and a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a transcription modulator molecule as disclosed herein, or a salt thereof, to a patient, wherein the effect is chosen from muscular atrophy, ataxia, fasciculation, and dementia(claim 74).
Thus, claims 21-26 are obvious over ANSARI.
Allowable Subject Matter
Claims 2, 6, 9-10, 13-15, 17-20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is an examiner's statement of reasons for allowance: With regard to the compounds of claims 2, 6, 9-10, 13-15 and 17-20, the prior art does not teach or suggest the modifications of the polyamide Y moiety (such as in claims 9-10) and the linker L (such as in claims 6 and 13) as well as the bicyclic moiety X (such as claims 2, 14-15, and 17-20).
These changes are in multiples places, or at unexpected positions. The modifications in claims 1 (partially), 2, 6, 9-10, 13-15, 17-20 are not anticipated by or obvious over the prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled "Comments on Statement of Reasons for Allowance."
Conclusion
Claims 2, 6, 9-10, 13-15, 17-20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 1, 3-5, 7-8, 11-12, 16 and 21-26 are rejected.
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/B.T./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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