DETAILED ACTION
This office action is in response to applicant’s filing dated January 9, 2026.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of claims
Claims 1 – 23 and 25 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of compound 272
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as a single elected species in the reply filed on January 9, 2026 is acknowledged. Upon performing the search of prior art Examiner detected compounds related to non-elected species. Hence, the election of species has been withdrawn and examination will proceed to the full scope of claims 1 – 23 and 25.
All claims 1 – 23 and 25 are under consideration in the present office action.
Priority
The present application is a 371 of PCT/US2021/053863, filed October 3, 2021, and claims the benefits of priority of U.S. Provisional Application No.
63/089,000, filed October 7, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/05/2024 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
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1 – 20 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Makings et al (US 8,642,609 B2, hereinafter Makings).
Regarding claims 1 – 7, 9, 11, 12, 14, 15, 17, 19, 20 and 25, drawn to a compound of Formula I:
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, such as compound of
Formula (Ia) ,
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,
Formula (Ib)
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,
Formula (Ic)
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or
Formula (Id)
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, where:
W is e.g. Ring A, where Ring A is -C3-6 cycloalkyl, -C5-10 aryl (e.g. phenyl), 5-10 membered heterocyclyl (e.g.
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or
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), and 5-10 membered heteroaryl; R1 is -halogen, -OH, -C1-6 alkyl, -NH2, C3-4 cycloalkyl, phenyl;
Y is e.g. Ring B and Ring B is -C5-10 cycloalkyl, -C5-6 aryl (e.g. phenyl), 4-10-membered heterocyclyl (e.g.
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), and 5-10-membered heteroaryl (e.g.
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,
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); R2 is -halogen, -OH, -C1-6 alkyl, -NH2, 4-10-membered heterocyclyl (e.g.
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or
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), 5-10-membered heteroaryl, -C3-10 cycloalkyl, phenyl;
X is hydrogen, halogen, -C1-6 alkyl;
Ring C is -C3-7 cycloalkyl, -C5-6 aryl (e.g. phenyl), 6-membered heterocyclyl, and 5-10 membered heteroaryl (e.g. pyrazole); R3 is hydrogen, halogen, -OH, -C1-6 alkyl, -NH2, 6-membered heterocyclyl. One of the exemplary compounds of Formula (I) is compound ex. 272
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. Instant claims are further drawn to a pharmaceutical composition, comprising compound of Formula (I), one or more additional therapeutic agent and pharmaceutically acceptable carrier. Said compounds and compositions are useful in the method for treating cystic fibrosis.
Makings teaches compounds of formula I:
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, such as compounds of formula I-A
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, I-B
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or I-C
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(column 15, lines 15 – 33), where:
RA is an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of RA are:
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,
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,
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,
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,
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,
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,
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, where q is 0, 1, 2, or 3, each occurrence of U-RU is hydrogen, F, Cl, Br, -NH2, -C1-C6 alkyl, 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur (columns 16 – 19, and 23);
R2 is hydrogen, halogen or -C1-6 alkyl;
R3 is optionally substituted phenyl, phenyloxy or T-Rz where T is a bond or -O- and Rz is an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur (column 7, lines 5 – 12 and 17 – 42);
L is G2 -B-G3 -Ar1, where G2 is -NR’- (e.g. -NH-), B is C1 alkylidene chain wherein methylene unit in the alkylidene chain is replaced with -SO2-; G3 is absent and Ar1 is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. For example Ar1 is
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(column 22, lines 30 – 35). Ar1 is optionally substituted with WRW, where m is 0-5, W is a bond or C1 alkylidene chain wherein methylene unit in the alkylidene chain is replaced with -NR- (R is hydrogen), and RW is hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur (column 8, lines 9 – 29).
Compounds, taught by Makings have the same pyrimidine core and structural elements, where variable RA is corresponding to variable Y of instantly clamed compounds, variable R2 of Makings is corresponding to variable X of instantly clamed compounds, variable R3 of Makings is corresponding to variable W of instantly clamed compounds and variable L of Makings is corresponding to fragment
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of instantly clamed compounds. Makings further teaches the pharmaceutically acceptable compositions, where compositions comprise compounds of formula I and pharmaceutically acceptable carrier. Said compositions optionally further comprise one or more additional therapeutic agents (e.g. CFTR modulator). The compounds and compositions, taught by Makings, are useful in the method for treating Cystic fibrosis (column 339, lines 32 –37 and 60 - 67).
Regarding limitations of claims 8 and 16, which recite ring A is phenyl optionally substituted with 1-3 methyl groups, or exemplary structures of Ring A, where Ring A is a heterocyclic saturated or unsaturated ring unsubstituted or substituted with methyl group(s) (e.g.
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or
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), Makings teaches variable R3, where R3 is an optionally substituted phenyl or R3 is T-Rz where T is a bond or -O- and Rz is an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Variable R3 corresponds to variable Ring A of instantly claimed structures. All the exemplary structures recited by claim 16 fall under above description of structure of variable R3 taught by Makings.
Although Makings does not explicitly teach phenyl or other ring is substituted with methyl, the term “optionally substituted” indicates that any substituent, including methyl, is allowed in this fragment of the molecular structure.
Regarding limitations of claim 10, which recites Ring C is phenyl substituted with NH2 or pyrazole substituted with methyl. Makings teaches variable Ar1, which corresponds to Ring C of instantly claimed structures. Makings teaches that Ar1 has a structure of phenyl substituted e.g. -NH2 (see the description above). Although Makings does not explicitly teach where Ar1 is a pyrazole substituted with methyl, however pyrazole substituted with methyl falls under the description of structure of Ar1 as 3-8 membered fully unsaturated monocyclic ring having 0-3 heteroatoms such as nitrogen, substituted with C1-C8 aliphatic group, since pyrazole substituted with methyl is a 5-membred heteroaromatic ring with two nitrogen atoms as ring members and methyl is a C1 alkyl group.
Regarding limitations of claim 13, which recites exemplary structures of variable R2, Makings teaches variable U-RU, which corresponds to variable R2 of instantly claimed structures, where U-RU is a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. All the structure shown in instant claim 13 fall under description of structure of variable U-RU taught by Makings.
Regarding limitations of claims 18, which recites exemplary compounds of Formula (I), although Makings does not explicitly teach the same exemplary structures, however, Makings teaches all the structural elements of the molecule of instantly claimed compounds.
Thus, since Makings teaches compounds, which compounds have the same core and all the structural elements as instantly claimed compounds, and where the compounds taught by Makings are useful for the same method (method of treating cystic fibrosis), it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to modify teachings of prior art and make various known compounds useful for the same method, to arrive at claimed compounds. The one of ordinary skills would be motivated to do so in search of an active agent with improved desired properties to treat Cystic fibrosis with the reasonable expectation of success.
Claims 21 - 23, are rejected under 35 U.S.C. 103 as being unpatentable over Makings et al (US 8,642,609 B2) as applied to claims 1 – 20 and 25 above, and further in view of Haseltine et al (WO 2019/018395 A1, hereinafter Haseltine).
Makings teaches all the limitations of claims 21 – 23 as discussed supra and are applied here in the same manner, except where the composition comprises tezacaftor and ivacaftor or the composition comprises tezacaftor and deutivacaftor.
However, Haseltine teaches compositions and methods of treating the CFTR-mediated disease cystic fibrosis comprising administering Compound I
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(CAS RN: 2216712-66-0, Elexacaftor) and at least one additional component (page 3, [0012]). The at least one additional active pharmaceutical ingredient is:
Compound II
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(CAS RN: 1152311-62-0, Tezacaftor);
Compound III
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(CASRN: 873054-44-5, Ivacaftor) or
Compound III-d
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(CAS RN: 1413431-07-8, Deutivacaftor) (pages 8 – 9, [0042]).
Haseltine further teaches pharmaceutical compositions where Compound I (Elexacaftor) and pharmaceutically acceptable salts thereof is administered in combination with Tezacaftor (Compounds II) or a pharmaceutically acceptable salt thereof and Ivacaftor (Compound III). Another variation of the pharmaceutical composition taught by Haseltine is where Compound I (Elexacaftor) and pharmaceutically acceptable salts thereof is administered in combination with Tezacaftor (Compounds II) or a pharmaceutically acceptable salt thereof and Deutivacaftor (Compound III-d) and pharmaceutically acceptable salts thereof page 11, [0045]).
Although instant claims do not recite Elexacaftor as one of the components of instantly claimed pharmaceutical composition, “comprising” claim language does not exclude additional, unrecited elements or steps.
Thus, since Makings teaches compounds and compositions thereof, which compounds and compositions are useful in the method of treatment of Cystic fibrosis, where the composition further comprises one or more additional therapeutic agent, such as CFTR modulator, and since Haseltine teaches pharmaceutical compositions, useful in the method of treatment of Cystic fibrosis, where the compositions comprise CFTR modulators Tezacaftor and Ivacaftor or the compositions comprise Tezacaftor and Deutivacaftor, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention to modify compositions of Haseltine by introducing compounds taught by Makings to arrive at a claimed pharmaceutical compositions. The one of ordinary skills would be motivated to do so in search of pharmaceutical composition effective in the method of treatment of Cystic fibrosis with the reasonable expectation of success.
Therefore, taking all together, taught by prior art, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Claims 1 – 23 and 25 are rejected. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691