DETAILED ACTION
This office action is in response to applicant’s filing dated June 4, 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, 25 and 72 – 75 are pending in the instant application. Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on June 4, 2026 are acknowledged. Acknowledgement is made of Applicant's amendment of claims 1-5, 7, 10, 13, and 16-18 and addition of new claims 72 – 75.
Claims 1 – 23, 25 and 72 – 75 are under consideration in the present office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/04/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objections and/or Rejections and Response to Arguments
Applicants' arguments, filed on June 4, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
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 – 17, 19, 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.
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 – 17, 19, 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.
Response to Arguments
Applicant argues:
- Amended claim 1 recites a compound selected from Formula I
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, wherein variables W and Y are defined as Ring A and Ring B, respectively. Makings discloses compounds with a pyrimidine core as seen in Formula I
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: in which each variable L, R2, R3, and G1 about the ring are disclosed broadly, having thousands of options. Makings does not set any "blaze marks" for a person of ordinary skill in the art to narrow the universe of each variable R2, R3, and G disclosed therein to arrive at Formula I of independent claim 1.
- Office has not established a prima facie case of obviousness as the Office provides no reason to select any of the examples in Makings as a "lead" compound. (See Eisai Co. Ltd. v. Dr. Reddy's Laboratories, Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008); Daiichi Sankyo Co. v. Matrix Laboratories Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010) (citations omitted)).
- To arrive at the core structural elements of Formula I of claim 1, a person of ordinary skill in the art would be required to make several selections from a large number options in a broad genus. Makings discloses over 400 compounds and the majority of which have a bicyclic ring with the pyrimidine core of Formula I and only 12 compounds lack the bicyclic ring. Most of these monocyclic pyrimidine compounds show lower activity compared to the compounds having a bicyclic ring. See Makings at Table 3. Therefore, a person of ordinary skill in the art would have no reason to pick a lead compound with a pyrimidine ring and not include the fused bicyclic ring present in the vast majority of the exemplified compounds.
- A prima facie finding of obviousness requires an objective reason or motivation to combine reference teachings. See M.P.E.P. § 2143.01(IV), citing Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993). Other than the mere disclosure of the claimed elements, the Office has failed to provide any rationale for picking the claimed elements from Makings and reengineering the core from a bicyclic system to a monocyclic system, other than sheer hindsight.
- In the rejection of claims 21-23 in view of Makings and Haseltine, Haseltine does not teach or suggest any of the compounds of the present application and fails to cure the deficiencies of Makings.
Examiner’s response:
Applicant's arguments have been fully considered but they are not persuasive because: as set forth above instant claims are extremely broad and disclose a compound of genus Formula I, where W and Y is a ring, where the ring is saturated or unsaturated, carbo- or heterocyclic with any possible identity, number and/or combination of heteroatoms. Each of rings W, Y and C are optionally substituted with literally any group known in organic chemistry. Makings teaches compounds of the same pyrimidine core, e.g.:
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, where all the substituents are equivalent to those encompassed by instantly claimed genus Formula I (see the rejection section above), where RA and R3 (variables equivalent to W and Y of instant genus Formula I) also represent a ring. The ring structures and their respective substituents disclosed in Makings are structurally equivalent to those defined in the description of the instant genus Formula I. Furthermore, given the broad scope of the structure of compound of Formula I, defined in instant claims, it clearly overlaps with Makings’ s genus disclosure, or at least render the structurally similar genus formula obvious to one of ordinary skill in the art.
Regarding the arguments about a “lead” compound, it is not persuasive because identification of a single lead compound is not necessary in every obviousness rejection of a chemical compound. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound (MPEP 2143.I.(B)).
Regarding the argument about structures of exemplary compounds taught by Makings, it is not persuasive because it is well-settled that 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). MPEP 2123 states: "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). 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).
Regarding the argument about motivation to combine and modify a refence teaching, it is not persuasive because the person of ordinary skills would have been motivated to modify prior art teachings, to make various structural analogs by selecting and combining known elements. Such a modification would be driven by a reasonable expectation of success that the resulting compounds would possess similar or improved chemical and biological properties. As states in MPEP 2143.I(B): “structural similarity can provide the necessary reason to modify prior art teachings. The Federal Circuit also addressed the kind of teaching that would be sufficient in the absence of an explicitly stated prior art-based motivation, explaining that an expectation of similar properties in light of the prior art can be sufficient, even without an explicit teaching that the compound will have a particular utility”.
Regarding Applicant’s argument that examiner’s conclusion of obviousness is based on hindsight reasoning, MPEP 2145.X(A) states: "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
Regarding the arguments about rejection of claims 21 – 23 over teachings of Makings in view of Haseltine, it is not persuasive because since instantly claimed compounds are considered obvious over teachings of Makings, 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. Especially since Makings suggested a pharmaceutical composition, comprising one or more additional therapeutic agent, such as CFTR modulator (see the rejection section above).
Therefore, Applicant’s arguments are not persuasive and the rejection of claims 1 – 17, 19, 20 and 25 as obvious over teachings of Makings, as well as the rejection of claims 21 – 23 as obvious over teachings of Makings and Haseltine is maintained.
Conclusion
Claims 1 – 17, 19 - 23 and 25 are rejected.
Claims 18 and 72 – 75 are free of art.
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.
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
/SAVITHA M RAO/Primary Examiner, Art Unit 1691
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