FINAL REJECTION
Receipt is acknowledged of Applicants' Amendments and Remarks, filed Dec. 30, 2025.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claims 2, 4, 12, 13, 15, 17, and 21 have been canceled.
Claim 1 has been amended to incorporate the limitations of canceled claim 2 and thus incorporates no new matter.
New claim 22 has been added.
Claims 8, 16, and 19 stand withdrawn as drawn to nonelected inventions and/or species.
Thus, claims 1, 3, 5-7, 9-11, 14, 18, 20, and 22 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
RESTRICTION & SPECIES ELECTION
In the reply filed Aug. 26, 2025, Applicant elected the invention of Group I (claims 1-11, 14, 18, and 19), drawn to compounds of formula (I); and the compound species of Example 56.
In the reply filed Dec. 30, 2025, Applicant submits that claims 8, 19, and 21 were part of elected Group I and read on the elected species, such that only claims 12, 13, and 15-17 (Groups II and III, drawn to methods of using the compounds) should be withdrawn from consideration (Remarks, p. 12).
As shown below, the elected compound species reads on formula (I) as recited by claims 1, 3, 5-7, 9-11, 14, 18, 20, and 22, wherein
y is 2, where one R1 is halogen (fluoro) and one R1 is deuterium;
z is 0, or R2 is hydrogen;
ring A is thiadiazole; x is 1, and Ra is halogen (chloro):
Elected compound (Example 56)
Formula (I), claim 1
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The elected compound does not read on claim 8, because it defines Raa and Rbb, which further limit Ra when Ra is –(CH2)nNRaaRbb. Because Ra of the elected compound species is halogen (chloro), not –(CH2)nNRaaRbb, the elected species does not read on claim 8.
The elected species also does not read on claim 19 (which depends from claim 10), because claim 19 further limits R3 when R3 is 3-6-membered heterocyclyl. Because the elected compound is chloro at R3, not 3-6 membered heterocyclyl, it does not read on claim 19.
Thus, claims 8 and 19 are properly withdrawn as drawn to non-elected species. Claim 16 is properly withdrawn as drawn to a non-elected invention. Claims 12, 13, 15, 17, and 21 have been canceled.
Therefore, claims 8, 16, and 19 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and/or species, there being no allowable generic or linking claim.
Claims 1, 3, 5-7, 9-11, 14, 18, 20, and 22 now represent all claims currently pending and under consideration.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Sep. 30, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim 11 stands rejected under 35 U.S.C. 103 as being unpatentable over Hoveyda et al. (USPN 9,422,299) in view of Hoveyda et al. (USPN 11,078,203).
The '299 patent exemplifies and claim compounds 1, 3, and 5 (Table 1; claim 12) as NK-3 receptor antagonists, having the structural formulae and IUPAC names as follows:
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Compound 1: (R)-(3,4-dichlorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]lpyrazin-7(8H)-yl)methanone
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Compound 3: (R)-(4-chlorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]-
triazolo-[4,3-a]pyrazin-7(8H)-yl)methanone
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Compound 5: (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]-triazolo[4,3-a]-
pyrazin-7(8H)-yl)methanone, a.k.a. fezolinetant (Veozah®).
Compounds 1 and 3 of the '299 patent are identical to the compounds of Examples 51 and 52 as recited by claim 11,
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except that the thiadiazole ring is substituted by methyl (CH3) rather than trideuteromethyl (CD3, a.k.a. methyl-d3).
However, exchanging hydrogen for deuterium is a common modification in medicinal chemistry which is known to often improve a compound's pharmacokinetic properties.
For example, the '203 patent claims deuterated fezolinetant (deuterated compound 5 of the '299 patent), having the structural formula and IUPAC name,
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(R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone, a.k.a. deuterated fezolinetant
wherein the three hydrogen atoms of the thiadiazole methyl group have been replaced by deuterium. I.e., the '299 patent claims fezolinetant (compound 5; claim 12), and the '203 patent claims deuterated fezolinetant (claim 1).
The '203 patent teaches that deuteration of fezolinetant provides an improved cytochrome P450 CYP profile – often responsible for metabolizing drugs – especially on isoforms CYP 2C9 and 2C19, while retaining the biological activity of fezolinetant, as well as its lipophilic efficiency. Deuterated fezolinetant also has improved in vivo half-life of the drug, compared to fezolinetant (col. 1, lines 49-61).
Therefore, it would have been predictable to one of ordinary skill in the art before the effective filing date to modify the 3,4-dichloro and 4-chloro compounds of the '299 patent by replacing the three thiadiazole methyl hydrogen atoms with deuterium to arrive at the compounds of claim 11 with a reasonable expectation of success, because the '203 patent teaches that making this modification to the 4-fluoro compound results in improved drug metabolism and improved in vivo half-life.
The rationale to modify the compounds of the '299 patent in view of the '203 patent is not derived from the Applicant but from the references themselves. The compounds of both patents are disclosed to have the same mechanism of action and biological activity as the claimed compounds, as NK-3 receptor antagonists. Thus, the '203 patent would lead a skilled artisan to reasonably expect that deuterating the same thiadiazole methyl group of closely similar compounds of the '299 patent would also improve their pharmacokinetic profile.
RESPONSE TO ARGUMENTS
Applicant's arguments filed Dec. 30, 2025 have been fully considered but they are not persuasive. With respect to the rejection of claim 11 under 35 U.S.C. 103 as being unpatentable over Hoveyda et al. (USPN 9,422,299) in view of Hoveyda et al. (USPN 11,078,203), Applicant states that '[c]laim 11 has been amended to remove all compounds that do not comprise a "D" atom. The non-deuterated compounds corresponding to Examples 51 and 52 of the specification are no longer recited in amended claim 11. Accordingly, the basis for the rejection no longer applies" (Remarks, p. 13).
However, the deuterated compounds of Examples 51 and 52 are the subject of this rejection, and continue to be recited by amended claim 11 (see claims p. 7). Thus, the basis for the rejection continues to apply to compounds recited by claim 11.
NEW REJECTIONS
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.
Claims 1, 3, 5-7, 9, 14, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Hoveyda (WO 2019/012033, cited on PTO-892).
Hoveyda discloses that fezolinetant was developed as a selective NK-3 receptor antagonist and is useful in the treatment of sex-hormone dependent diseases (p. 1, lines 10-12). Fezolinetant has the structural formula shown below (at left).
Hoveyda exemplifies and claims deuterated fezolinetant, (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]trizolo[4,3-a]pyrazin-7(8H)-yl)methanone (claim 1), having the structural formula shown below (at right).
Fezolinetant (VEOZAH®)
Deuterated fezolinetant (Hoveyda)
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The deuterated compound of Hoveyda, or a pharmaceutically acceptable salt or solvate thereof, is disclosed and claimed in a pharmaceutical composition with at least one pharma-ceutically acceptable carrier, diluent, excipient and/or adjuvant (claim 2), and is especially useful for treating, e.g., hot flashes (hot flushes) (p. 11, lines 6-7; claim 5).
The compound of Hoveyda reads on formula (I) as recited by claim 1 to the extent that y is 1 and R1 is halogen (fluoro); z is 0 or R2 is hydrogen; ring A is 1,2,4-thiadizole; and x is 1.
The compound of Hoveyda differs from claimed formula (I) only in the position of the fluoro and CD3 substituents, as shown below:
Hoveyda
Deuterated Fezolinetant
Claimed compounds
Positional Isomer (CD3 ↔ F)
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Exchanging the positions of the fluoro and CD3 substituents yields the compound shown above (at right), which reads on claims 1, 3, 5-7, 9, 14, 20, and 22 wherein y is 1 and R1 is deuterated alkyl (CD3); z is 0 or R2 is hydrogen; ring A is 1,2,4-thiadizole; and x is 1 and Ra is halogen (fluoro).
The claimed compounds also have the same mechanism of action as the compound of Hoveyda, as NK-3 receptor antagonists, and are useful for treating the same diseases, e.g., hot flashes/flushes (specification p. 1, line 22 to p. 2, line 11).
Hoveyda discloses that deuteration of fezolinetant provides an improved CYP profile, especially on isoforms CYP 2C9 and 2C19. Deuterated fezolinetant retains the biological activity of fezolinetant as well as its lipophilic efficiency, and improves the in vivo half-life of the drug (p. 2, lines 5-14).
Because the compounds of Hoveyda are disclosed to have the same biological activity and to be useful for treating the same diseases, one of ordinary skill in the art could reasonably expect the claimed compounds to possess the same advantages and uses disclosed by Hoveyda.
It is well established that position isomers are prima facie obvious even in the absence of a teaching to modify. The isomer is expected to be preparable by the same method and to have generally the same properties. This expectation is then deemed the motivation for preparing the position isomers.
As recognized by MPEP § 2144.09, "[c]ompounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) . . . 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). Compounds which are positional isomers, differing only in the placement of substituents in a ring system, are not patentable absent a showing of unexpected properties. See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
Claim Objections
Claims 10 and 18 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.
Citation of Additional Prior Art
Additional references made of record are considered pertinent to applicant's disclosure:
Dean et al. (USPN 8,501,946, cited on PTO-892).
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Dean et al. disclose and claim compounds of formula (I), having the structural formula,
.
and exemplify compounds of formula (I), including, e.g., E169, E186-E188, E191-E203, and E205-E207, wherein ring A is thiazole or thiadiazole (claims 1-2). The compound of Example 188 (E188, col. 233) is representative:
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Dean et al. also exemplify the compounds of Examples 180-183 (E180-E183), wherein ring A is deuterium-substituted pyridine.
Dean et al. claim compounds of formula (I) wherein Ring A can be Het, which includes:
i) a 6-membered heteroaromatic monocyclic ring containing one, two or three ring-nitrogen atoms;
ii) a 5-membered heteroaromatic monocyclic ring containing one, two or three ring heteroatoms independently being N, O, or S; or
iii) a 9 or 10-membered heteroaromatic bicyclic ring containing one, two or three ring nitrogen atoms;
and wherein Het is optionally substituted with one or two substituents independently being C1-3-alkyl, fluorine, chlorine, OH, methoxy or deuterium.
The compounds of Dean et al. differ from the instant claims in that (1) they lack a methyl group at position 8 of the triazolopiperazinyl core; and (2) there is no teaching or suggestion to substitute the phenyl ring with deuterium at positions R1-R5.
Further, the compounds of Dean et al. are disclosed to have a different mechanism of action (P2X7 receptor antagonists) from the claimed compounds (NK-3 receptor antagonists); and are disclosed as useful to treat diseases that share little overlap with the claimed compounds.
Therefore, it would not have been predictable to one of ordinary skill in the art to make at least two changes to the compounds of Dean et al. to arrive at the claimed compounds with a reasonable expectation of success.
CONCLUSION
No claims are allowed.
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.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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