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 .
Priority
This application, filed 9 January, 2024, is a national stage application of PCT/US2022/036692, filed 11 July, 2022.
Election/Restrictions
Applicant’s election without traverse of Group I – directed to Compounds of Formula I and Species A-53, which reads upon Claims 1, 7, 12, 15, 25-26, 28, 38-39, 42 and 48 in the reply filed on 23 April, 2026 is acknowledged.
Upon Examination, the Species election was broadened from X1 is N, Y is NRc (Rc is H), Z1 is N, Z2 is CH, R1 is C3-C6 cycloalkyl (cyclopentoxy), Ring A is phenyl substituted at 4-position with C1-C6 alkyl (isobutyl), n is 1, and m is 0, to encompass the following:
X1 is N or CH;
Y is a bond, NRc (wherein Rc is H), or O;
Z1 and Z2 are each independently N or CH;
n is 1-2;
R1 is independently isopropyl, hydroxy, methoxy, cyclopentoxy, cyano, or two R1 are ortho to each other and taken together with the atoms to which they are attached form a fused 6-membered aromatic ring that is substituted with two methyl groups;
m is 0-1;
if m is 1, then R2 is methyl;
Ring A unsubstituted cyclopropyl, unsubstituted cyclohexyl, or phenyl substituted at the 4-position with C1-C6 alkyl or methoxy
Status of the Application
Receipt is acknowledged of Applicant's claimed invention, filed 4 August, 2026, in the matter of Application N° 18/577,851. Said documents have been entered on the record.
Claims 1, 7 and 48 are amended. Claims 2 and 5 are canceled. No new matter was introduced.
Thus, Claims 1, 7, 12, 15, 20, 25-26, 28, 38-39, 42, 47-48, 50-51, and 57-58 are pending.
Claims 47, 50-51 and 57-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 23 April, 2026.
Thus, Claims 1, 7, 12, 15, 20, 25-26, 28, 38-39, 42 and 48 represent all claims currently under consideration.
Response to Amendment/Arguments
Claims 2 and 5 have been canceled. Therefore, the rejections of these claims under 35 U.S.C. 112(d), 102(a)(1), and 103 are moot.
Applicant’s amendments are sufficient to overcome the previous objection and rejections of Claims under 35 U.S.C. 112(b) and 102(a)(1).
Applicant’s argument regarding the rejection under 35 U.S.C. 103 of Claims 1, 7, 12, 15, 25 and 38 over Zhao in view of Patani and LaVoie have been fully considered and are persuasive (Remarks, Pg 33-36). Accordingly, the rejection is withdrawn.
Applicant’s argument regarding the rejection under 35 U.S.C. 103 of Claims 1, 15, 20, 25-26, 38, and 42 over Mortlock and Keen in view of Hajduk and Sauer have been fully considered (Remarks, Pg 36-37). The rejection has been reconsidered in view of the amended claims and is superseded by the rejection set forth below, which further relies upon Ritchie and MacDonald for the teachings regarding variation in the number and position of heteroatoms within aromatic ring systems.
Below can be found new grounds of rejection necessitated by amendments.
Claim Objections
Claim 48 is objected to because of the following informalities: missing a period at the end of the sentence.
Appropriate correction is required.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 7, 12, 15, 25-26, 28, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Hashimoto and Robinson (EP 0 164 204 A1, of previous record), in view of Ritchie and MacDonald (European Journal of Medicinal Chemistry 124. 2016. 1057-1068).
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Regarding Claims 1, 12, 15, 25-26, 28 and 38-39, Hashimoto and Robinson teach pyrimidine compounds such as 5-(4-Methoxyphenyl)-N-(4-methoxyphenyl)pyrimidine-2-amine (‘204, Pg. 12, Example 6, also CAS RN 101987-02-4), shown top right, which significantly overlaps instant Formula I (as in instant Claim 1), shown bottom right, wherein X1 is N (as in instant Claim 38), m is 0 (as in instant Claim 39), Y is a bond, Z2 is CH, n is 1, R1 is methoxy (as in instant Claims 12 and 15), and Ring A is phenyl substituted at 4 with methoxy (as in instant Claims 25-26 and 28).
Hashimoto and Robinson’s Example 6 compound differs from the instant Formula 1 in that it exemplifies Z1 is CH, rather than the newly recited limitation Z1 is N.
However, Hashimoto and Robinson further teach the corresponding ring substituent may be selected from pyridinyl, pyrimidinyl, thiazolyl, pyrazinyl, pyridazinyl, imidazolyl and phenyl rings (‘204, Pg. 1, Lines 18-21). Thus, Hashimoto and Robinson expressly contemplate both the exemplified phenyl ring and its pyridinyl alternative (as in instant Claim 7), but do not specifically exemplify the presently claimed pyridinyl regioisomers wherein Z1 is N.
Ritchie and MacDonald (2016) teach replacement of benzene with nitrogen-containing heteroaromatic rings as a medicinal-chemistry strategy for modulating ADME-related properties and specifically evaluate the individual pyridine regioisomers as benzene replacements, demonstrating that the position of the introduced nitrogen affects properties including solubility and lipophilicity (2016, Pg 1057-1060; Fig.1 and Table 1).
It would therefore have been prima facie obvious to one of ordinary skill in the art before the effective filing date to select a pyridinyl ring as one of the finite number of heteroaromatic alternatives expressly taught by Hashimoto and Robinson, and to evaluate the individual pyridine regioisomers as taught by Ritchie and MacDonald, in order to modulate ADME-related properties such as solubility and lipophilicity. One of ordinary skill in the art would have had a reasonable expectation of success because Hashimoto and Robinson expressly identify pyridinyl as an alternative to phenyl at that position, while Ritchie and MacDonald demonstrate the use and evaluation of the individual pyridine regioisomers as benzene replacements.
Claims 1, 7, 12, 25-26, 28 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Grant (US 2002/0198219 A1, , of previous record), in view of Ritchie and MacDonald (European Journal of Medicinal Chemistry 124. 2016. 1057-1068).
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Grant teaches Compound 2 (‘219, Pg. 16, Table 4), shown top right, which significantly overlaps instant Formula I (as in instant Claim 1), shown bottom right, wherein X1 is CH (as in instant Claim 38), m is 0, Y is a bond, Z1 is CH, Z2 is CH, n is 1, R1 is hydroxy (as in instant Claim 12), and Ring A is phenyl substituted at 4 with methoxy (as in instant Claims 25-26 and 28).
Grant’s Compound 2 differs from the instant Formula 1 in that it exemplifies Z1 is CH, rather than the newly recited limitation Z1 is N.
However, Grant further teaches the substituent corresponding to the Z1-Z2-containing ring of instant Formula I may be selected from, inter alia, phenyl and pyridinyl rings (‘219, Pg. 3, Para 0035-0037). Thus, while exemplified Compound 2 contains phenyl at this position, Grant expressly contemplates pyridinyl (i.e., Z1 is N, as in instant Claims 1 and 7) as an alternative within its disclosed genus.
Ritchie and MacDonald (2016), as set forth above and incorporated herein, teach replacement of benzene with nitrogen-containing heteroaromatic rings as a medicinal-chemistry strategy for modulating ADME-related properties and specifically evaluate the individual pyridine regioisomers as benzene replacements, demonstrating that the position of the introduced nitrogen affects properties including solubility and lipophilicity (2016, Pg 1057-1060; Fig.1 and Table 1).
It would therefore have been prima facie obvious to one of ordinary skill in the art before the effective filing date to select a pyridinyl ring from among the alternatives expressly taught by Grant, and to evaluate the individual pyridine regioisomers as taught by Ritchie and MacDonald, in order to modulate ADME-related properties such as solubility and lipophilicity. One of ordinary skill in the art would have had a reasonable expectation of success because Grant expressly teaches both phenyl and pyridinyl at that position, while Ritchie and MacDonald demonstrate the use and evaluation of the individual pyridine regioisomers as benzene replacements.
Claims 1, 15, 20, 25-26, 38, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Mortlock and Keen (WO 01/21597 A1, of previous record), in view of Hajduk and Sauer (J. Med. Chem. 2008, 51, 553–564, of previous record) and further in view of Ritchie and MacDonald (European Journal of Medicinal Chemistry 124. 2016. 1057-1068).
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Mortlock and Keen teach 2,5-Pyridinediamine, N2-cyclohexyl-N5-(6,7-dimethoxy-4-quinazolinyl), (as evidenced by CAS RN 331803-84-0, CAPLUS), shown top right, which significantly overlaps instant Formula I (as in instant Claim 1), shown bottom right, wherein X1 is CH (as in instant Claim 38), Y is NRc and Rc is H (as in instant Claim 42), Z1 is N, n is 2, both R1, which are ortho to each other and form a substituted fused 6-member aromatic ring (as in instant Claims 15 and 20), m is 0, and Ring A is an unsubstituted cyclohexyl (as in instant Claims 25-26)
Mortlock and Keen fail to exemplify the two substituents of the fused ring as methyl (as in instant Claim 20), but rather as methoxy, and further exemplify the heteroaromatic ring wherein Z1 and Z2 are each N, rather than the newly recited alternative wherein Z1 is N and Z2 is CH or CR1.
However, Hajduk and Sauer teach common phenyl substitutions patterns, including dimethoxy and dimethyl analogues (2008, Pg. 557, Table 3), and that “the frequencies of achieving 10-fold gains in potency for dimethyl substitutions are generally higher than that observed for dimethoxy substitutions (2008, Pg. 556, Para 2).
Furthermore, Ritchie and MacDonald (2016), as set forth above and incorporated herein, teach the systemic replacement and evaluation of aromatic rings having differing numbers and positions of nitrogen atoms as a medicinal-chemistry strategy for modulating ADME-related properties. Ritchie and MacDonald specifically evaluate pyridine regioisomers containing one ring nitrogen together with diazine ring systems containing two ring nitrogens, including pyrimidine, pyridazine, and pyrazine, and demonstrate that ring identity and nitrogen arrangement affect properties including solubility and lipophilicity (2016, Pg 1057-1067; Figures 2-4 and 6, and Tables 2 and 5).
It would therefore have been prima facie obvious to one of ordinary skill in the art at the time of the invention to evaluate the corresponding one-nitrogen heteroaromatic analog of the diazine-containing compound of Mortlock and Keen, as taught by Ritchie and MacDonald, in order to modulate ADME-related properties such as solubility and lipophilicity. It would have been obvious to replace the dimethoxy substituents with dimethyl substituents as taught by Hajduk and Sauer, which demonstrate that dimethyl- and dimethoxy-substituted phenyl analogues were recognized medicinal chemistry modifications having comparable potency distributions. One or ordinary skill in the art would have had a reasonable expectation of success in preparing and evaluating such analogs in view of the express teachings of Ritchie and MacDonald and Hajduk and Sauer.
Allowable Subject Matter
Claim 48 is 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, and to overcome the minor informality objected to above (i.e. a missing period).
Conclusion
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.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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