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 .
Status of the Application
Claims 1-16 are pending in the application as of the response filed 06/08/2026. Claims 1-16 are examined herein.
The claim objections and objections to the specification of previous record are withdrawn in consideration of the amendments to the claims/specification.
The 35 U.S.C. § 112(a) rejection of previous record is withdrawn in consideration of the claim amendment to limit the scope of claims 15-16 to therapeutic treatment (supported by Para. [0027] of the instant specification) and Applicant remarks in pages 10-11 of the remarks dated 06/08/2026.
The 35 U.S.C. § 112(b) rejection of previous record is withdrawn in consideration of the claim amendments.
Applicant has properly invoked the 35 U.S.C. 102(b)(2)(C) exception over the prior art, Levell et al. (WO 2021/222761 A1, filing date of 30 April 2021, hereinafter Levell, in the IDS), by providing a statement that the subject application (US 18/289,467) and the subject matter disclosed in Levell, were, at the time of the invention of the subject case (US 18/289,467), commonly owned by Constellation Pharmaceuticals, Inc., as stated on pages 11-12 of the response dated 06/08/2024. Therefore, Levell is no longer available as prior art.
The 35 U.S.C. § 103 rejection of record over Levell in view of Ali is hereby withdrawn.
Applicant’s arguments regarding the nonstatutory double patenting rejection has been carefully considered but were not found to be persuasive.
In view of the pending claims, the nonstatutory double patenting rejection of record is maintained and updated to reflect any claim amendments. Applicant’s arguments are addressed below.
Double Patenting – Maintained and updated
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).
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).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-4, 6 and 8-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11-12, 14-15, 25, 28 and 30-31 of co-pending Application No 18/288,455 in view of Ali et al. (Input of Isosteric and Bioisosteric Approach in Drug Design, 2014, hereinafter Ali, of previous record).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to compounds having similar core structures.
The instant claims are drawn to compounds of general Formula I or a pharmaceutically acceptable salt thereof, with variables as defined in instant claim 1, a pharmaceutical composition and a method of treatment thereof.
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The claims of the reference ‘455 application are drawn to compounds of general Formula I or a pharmaceutically acceptable salt thereof, with variables as defined in claim 1 of the reference application, a pharmaceutical composition and a method of treatment thereof.
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The reference ‘455 application teaches the following species of compound in claim 28 (Pg. 36 of the claim set dated 05/19/2026), 2-((1S,2R)-1-(2-cyanopyridin-3-yl)-1-phenylpropan-2-yl)-5-hydroxy-N-(isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide, represented by the following structure.
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The above compound substantially overlaps the scope of a compound recited in instant claim 13.
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The compound of claim 28 of the reference ‘455 application differs from the instant compound of claim 13 with respect to the pyridinyl versus phenyl ring.
Ali teaches isosterism or bioisosterism is one of the approaches most frequently used in the design of new molecules (Pg. 150, first column, first paragraph). Ali teaches bioisosteres may be identified as any two compounds or structures that
show similar biological activities and share analogous topology, volume, electronic arrangements or physicochemical properties (Pg. 150, first column, first paragraph). Ali teaches the isosteric replacement approach is a practical and, possibly, better
substitute to the recent lead optimization techniques to improve its pharmacokinetic i.e. absorption, distribution, metabolism and excretion (ADME) or pharmacodynamic i.e. receptor, enzyme or channel level behavior (Pg. 150, first column, first paragraph). Ali teaches the benzene and pyridine rings are isosteres of each other (Pg. 153, Fig. 1; Pg. 158, Table 7).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of the reference ‘455 application and Ali, to replace the pyridinyl ring of the reference application with the phenyl ring as taught by Ali, to arrive at the instantly claimed compounds with a reasonable expectation of success. Looking into the specification of the reference ‘455 application for utility of the compounds, the compounds are taught to exhibit TREX1 inhibitory activity (specification Para. [0050] of the co-pending application). The instant compounds are taught to exhibit TREX1 inhibitory activity (Para. [0040] of the instant specification). The reference application teaches exemplary compounds that substantially overlap the scope of the instantly claimed compounds. Ali teaches the benzene and pyridine rings as biososteric ring equivalents. Ali teaches isosterism to be an important research tool in the design of new molecules, the reason being that isosteres show similar biological activities and share analogous topology, volume, electronic arrangements or physicochemical properties
According to MPEP 2144.09 (III), “Prior art structures do not have to be true homologs or isomers to render structurally similar compounds prima facie obvious. In re Payne, 606 F.2d 303, 203 USPQ 245 (CCPA 1979). See also In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (claimed and prior art compounds used in a method of treating depression would have been expected to have similar activity because the structural difference between the compounds involved a known bioisosteric replacement)”.
Further according to 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).”
Therefore, one of ordinary skill in the art would have been motivated to replace pyridinyl ring of the reference ‘455 application with a phenyl ring as taught by Ali, to arrive at the instantly claimed compounds, with a reasonable expectation of success that they would act as inhibitors of TREX1. The motivation being to improve its pharmacokinetic i.e. absorption, distribution, metabolism and excretion (ADME) or pharmacodynamic i.e. receptor, enzyme or channel level behavior (Ali, Pg. 150, first column, first paragraph).
Therefore, claims 1-5, 8, 11-12, 14-15, 25, 28 of the reference ‘455 application in view of Ali renders the instant compounds of claims 1-4, 6, 8-9 and 13 prima facie obvious. Claims 30-31 of the reference ‘455 application renders the instant pharmaceutical composition and method of treatment claims 14-16 prima facie obvious.
The instant claims 1-4, 6, 8-9 and 13-16 and claims 1-5, 8, 11-12, 14-15, 25, 28 and 30-31 of co-pending Application No 18/288,455 are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants argue on pages 12-13 of the response dated 06/08/2026, that “As explained by the Court, selection of a lead compound for optimization from the prior art is "guided by evidence of the compound's pertinent properties." See Eli Lilly, 471 F.3d at 1378; In re Lalu, 747 F.2d 703, 707 (Fed.Cir.1984). Such properties include positive attributes such as activity and potency, Altana, 566 F.3d at 1008; Eli Lilly, 471 F.3d at 1379; Yamanouchi, 231 F.3d at 1345; adverse effects such as toxicity, Takeda, 492 F.3d at 1358, and other relevant characteristics in evidence, see Eisai, 533 F.3d at 1358. This standard is not met”. Applicants argue “Out of all of the compounds disclosed in '455, the Examiner points to Compound 115 as allegedly supporting a prima facie case of obviousness. This finding, however, bypasses the first prong of the "two prong inquiry" required in the chemical arts, i.e., before asserting that claimed compound is obvious, one must first establish a compelling reason why one of skill in the art would have selected Compound '455 as a starting point for modification. No evidence is provided in this regard and the present double patenting rejection is improper for at least this reason.” Applicant concludes that the examiner uses impermissible hindsight and thus, a prima facie case of obviousness double patenting is not present.
Applicant's arguments have been fully considered but they are not persuasive.
The examiner respectfully notes that the referenced compound of the ‘455 application, 2-((1S,2R)-1-(2-cyanopyridin-3-yl)-1-phenylpropan-2-yl)-5-hydroxy-N-(isoxazol-4-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide, corresponds to Compound 155 (Pg. 289 of ‘455 application specification) and not Compound 115.
Regarding Applicant’s contention that there is no motivation to select Compound 155 of the reference ‘455 application, the examiner would like to bring Applicant’s attention to MPEP 2144.08 (d) which states that “Consider the properties and utilities of the structurally similar prior art species or subgenus. It is the properties and utilities that provide real world motivation for a person of ordinary skill to make species structurally similar to those in the prior art. Dillon, 919 F.2d at 697, 16 USPQ2d at 1905; In re Stemniski, 444 F.2d 581, 586, 170 USPQ 343, 348 (CCPA 1971).” In the instant case, the compounds of the instant invention and Compound 155 of the reference ‘455 application are taught to have the same utility, i.e., show activity as inhibitors of TREX1.
Further, considering the MPEP sections cited by Applicant, according to MPEP 2143(I)(B), Example 9, “The Federal Circuit in Eisai makes it clear that from the perspective of the law of obviousness, any known compound might possibly serve as a lead compound …Office personnel might also base an obviousness rejection on a known compound that pharmaceutical chemists would not select as a lead compound due to expense, handling issues, or other business considerations. However, there must be some reason for starting with that particular lead compound other than the mere fact that the "lead compound" exists”.
Additionally, according to MPEP 2143(I)(B), Example 11, “Altana’s patent discussed a compound referred to as compound 12, which was one of eighteen compounds disclosed. The claimed compound pantoprazole was structurally similar to compound 12. The district court found that one of ordinary skill in the art would have selected compound 12 as a lead compound for modification, and the Federal Circuit affirmed … and experts had opined that one of ordinary skill in the art would have selected the eighteen compounds to pursue further investigation into their potential as proton pump inhibitors”.
In the instant case, the instant compound of claim 13 and Compound 155 of the reference ‘455 application are taught to exhibit TREX1 inhibitory activity with close structural similarity, differing only in the pyridinyl versus phenyl ring. The reference ‘455 application establishes that Compound 155 exhibits activity against the target of interest, i.e., TREX1 inhibitory activity. Based on examples 9 and 11 of MPEP 2143(I)(B) cited above, any of the compounds of the reference ‘455 application, would have qualified as lead compounds for further modification. Although Applicant contends that Compound 155 of the reference application is inferior to many other compounds (Tables 7 and 8 of ‘455 application), the examiner notes that the activity of Compound 155 is no different from the other compounds wherein certain stereoisomers exhibit superior activity than the other stereoisomers. For instance, Compound 155, D2E1 and Compound 155 D1E2 exhibit an IC50 of “A” and “B” respectively, towards hTREX1 inhibition.
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Therefore, Compound 155 constitutes a lead compound due to its close structural similarity and similar utility to the instant compounds. There is sufficient motivation/incentive for a person of ordinary skill in the art at the time the application was effectively filed, to further explore Compound 155 as a promising TREX1 inhibitory agent.
Regarding Applicant’s contention that the examiner uses impermissible hindsight, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Also, MPEP 2145 (X)(A), states that “However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness". In the instant case, the reference ‘455 application teaches closely structurally similar compounds having the same utility as the instant compounds and Ali provides motivation to make the pyridinyl to phenyl change (all taught before the effective filing date of the instant application). Therefore, the compound of instant claim 13 is rendered prima facie obvious.
Applicants have not demonstrated that the instant compound exhibits properties that are unexpectedly better than that of the closely structurally similar reference compound. Therefore, the examiner asserts that the choice of the lead compound to arrive at the instantly claimed compounds, as outlined above is proper. The nonstatutory double patenting rejection of record is maintained, in the absence of evidence to the contrary.
Allowable Subject Matter
The compounds of Formula I as in claim 1 are free of prior art. Except for the nonstatutory double patenting rejection, all claims would be allowable. Claims 5 and 7 are objected to for depending from a rejected base claim.
The following is a statement of reasons for the indication of allowable subject matter:
The instant application relates to a compound of general Formula I or a pharmaceutically acceptable salt thereof, with variables as defined in instant claim 1, a pharmaceutical composition and a method of treatment thereof.
The closest prior art of record is Gardberg et al. (WO 2020/118133 A1, 11 June 2020, hereinafter Gardberg, in the IDS) (Gardberg is commonly owned with partial co-inventors and qualifies as 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) prior art having a publication date of 11 June 2020 and an international filing date of 06 December 2019 respectively, both preceding the effective filing date of the instant invention, 05 May 2021). Gardberg teaches compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with TREX1 (Abstract; Para. [0015]).
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Gardberg teaches an exemplary compound, compound 80, (Para. [0089]) having the following structure.
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Compound 80 of Gardberg overlaps the core structure of instant Formula I, wherein
R1 is hydrogen;
R2 is C1 alkyl (methyl);
R3 is hydrogen;
R4 is C1 alkyl (methyl);
q is 0.
Compound 80 of Gardberg does not teach a second phenyl attached to the methylene group (highlighted above).
Although Gardberg teaches X may be (C1-C4)alkylene wherein (C1-C4)alkylene is optionally substituted with 1 to 2 groups selected from R4 as one option; R4 can be chosen to be phenyl as one option; Ring A can be phenyl as one option, there is too much picking and choosing to arrive at the -CH(Ph)2 group of the instant claims. Therefore, the instant compounds are novel and non-obvious variants of the compounds taught in the prior art.
Conclusion
Claims 1-4, 6 and 8-16 are rejected.
Claims 5 and 7 are objected to
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached 9:00-5:30 pm EDT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PADMAJA S RAO/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
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