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 .
Current Status of 17/800,516
This Office action is responsive to the Applicant remarks and claims of 11/14/2025. Claims 1-34 and 36-51 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/CA2021/050275, international filing date 03/02/2021, which claims priority to U.S. Provisional Application No. 62/984,456, filed 03/03/2020.
Response to Amendments/Arguments
Applicants have amended claims 6-31, 34, and 39-49 to correct improper multiple dependency. These amendments render moot the previous objections to the claims and the objection is withdrawn.
Applicants' arguments have been fully considered but are not found persuasive. Applicants allege that there is no reason or motivation to select compound 3048 as a lead compound from the other compounds disclosed by Fader. Fader teaches a genus of compounds of Formula (I) and their use in the treatment/prevention of human cytomegalovirus (CMV) via inhibition of CMV DNA polymerase. The artisan would have reasonably selected an expressly exemplified, prepared species from the activity-directed genus as a lead compound. Compound 3048 is a synthesized and characterized species, making it enabled, and immediately accessible as a starting point for routine lead optimization while maintaining the core scaffold.
Applicants' characterization of Examples B and C as "merely prophetic" is unsupported. The reference provides specific preparation and characterization data for these compounds, demonstrating that the compounds were synthesized and tested in the assays (see Col 243, lines 14-17) rather than hypothetically proposed. The absence of comparative activity data does not render an example prophetic.
Applicants' arguments that there is no motivation to modify the compounds in a particular way to arrive at the instantly claimed compounds is similarly unpersuasive. Applicants highlight the fact that R4-R6 can each be selected from 20 different moieties, including R42 which can be selected from 12 different moieties. The variations at these positions therefore teach that these positions are amenable to variation while still maintaining the core scaffold required for the desired biological activity. This is precisely the teaching/motivation that would lead the artisan to perform standard SAR screening at these positions. Fader teaches that these positions are not essential to the desired biological activity. One such embodiment disclosed by Fader is a heterocycle that may be optionally substituted with 1-3 substituents each independently selected from a group which includes oxo. This disclosure therefore teaches the exact structures of the western ring of the instantly claimed compound and would have been an obvious modification to the core scaffold (Otsuka; Altana; MPEP § 2144.09). Sun was relied upon to further highlight why the artisan would be motivated to incorporate these moieties into the scaffold.
Applicants rely on hERG IC50 data to assert reduced cardiotoxicity risk. However, the reported data in Table 6 of the specification is limited to categorical values above or below 10mM and does not provide actual IC50 values, preventing determination of the magnitude of any alleged improvement relative to the prior art compounds. Additionally, while a 10mM cutoff is sometimes used as a screening classification for hERG inhibition, Applicants have not shown, nor does Danker et al. establish that >10mM is a clinically meaningful cardiotoxicity predictor.
The data of Table 6 is limited to 46 instantly claimed compounds, which represents only a small subset of the broad Markush genus encompassed by claim 1. Accordingly, the evidence is not commensurate in scope with the breadth of the claims and does not establish a substantial or unexpected difference sufficient to outweigh the strong prima facie case of obviousness.
Applicants arguments for the rejection of claims 1-5, 32, 33, 36, and 38 reiterate the above points that Fader and Sun fail to teach the instantly claimed compounds, and that the instant invention represents more than a predictable use of prior art elements. These arguments are unpersuasive for the same reasons outlined above.
Claim Rejections - 35 USC § 103
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 1-4, 6-31, 34, and 39-49 are rejected under 35 U.S.C. 103 as being unpatentable over Fader (US 9,315,499 B2, found in IDS submitted 11/09/2022) in view of Sun (Sun, S.; Jia, Q.; Zhang, Z. Applications of amide isosteres in medicinal chemistry. Bioorg. Med. Chem. Lett. 2019, 29, 2535– 2550, DOI: 10.1016/j.bmcl.2019.07.033 32).
Fader teaches compounds of Formula (I)
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and identifies these compounds as inhibitors of human cytomegalovirus (CMV) DNA polymerase, pharmaceutical compositions containing the compounds, and methods of using these compounds in the treatment and prevention of CMV disease and/or infection (Col 1, lines 13-18). Fader teaches pharmaceutical compositions comprising the compounds and at least one other antiviral agent (Claim 16), and teaches a method of treating CMV disease/infection in a human being by administering the claimed compounds in combination with at least one other antiviral agent (Claim 19). Suitable antiviral agents include ganciclovir, valacylovir, valganciclovir, foscarnet, and letermovir (Col 15, lines 4-19).
Fader teaches that R4-R6 are
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428
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(Col 244) and that R42 is
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(Col 244-245). A species of Fader’s Formula (I) is compound 3048
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(Col 92, line 35). 3048 maps onto the instantly claimed compounds of Formula (I) and (II) of the instantly claimed compounds with the following substitutions: R1 is halogen, m is 1; R2 and R3 are H, n is 1; R4 and R5 together with the nitrogen to which they are attached form a substituted heterocycle; R6 is H; X is CR7, R7 is H; and R10 and R11 are C1 alkyl.
Fader’s 3048 differs from the instantly claimed compounds with regard to the position of the amide substituent and lacks a 2-pyrrolidone substituent attached to the bicyclic moiety of the compounds.
Although 3048 of Fader does not disclose the identical substitution pattern recited in the instant claims, Fader expressly teaches that positions R4-R6 are independently selected from a group which includes R42, where R42 includes optionally substituted heterocycles. The allowed optional substitutions include oxo and the term heterocycle is defined as including a saturated or unsaturated mono- or polycyclic-ring system including aromatic ring systems containing one or more heteroatoms selected from N, O or S(O)r (Col 7, lines 25-37). Thus, Fader, expressly contemplates placement of substituted heterocycles at the same position recited in the instant claims. Fader teaches that R4-R6 are independently variable and each may be selected from R42. The disclosure therefore does not limit the heterocycle to any particular position, nor does it indicate that biological activity depends on a specific substitution pattern at that site.
Based on Fader’s express teaching that substituted heterocycles may be incorporated at the R4-R6 positions, it would have been obvious for the artisan to select a substituted heterocycle as recited in the instant claims and position it at the claimed location as a matter of routine design choice. The selection of one of the expressly disclosed heterocyclic substituents at one of the expressly disclosed variable positions does not constitute hindsight reconstruction but rather represents the predictable selection of one of a finite number of identified, suitable substituents disclosed by the reference for incorporation into compounds of Formula (I).
Furthermore, Fader expressly teaches methods of treating/preventing human cytomegalovirus in human subjects by administering a compound of Formula (I) alone or in combination with additional antiviral agents. The instant method claims recite the same treatment of human CMV using the same compounds and same optional combination therapy. Accordingly, Fader teaches the same therapeutic methods of the instant claims. Because Fader teaches administering compounds of Formula (I) for the treatment of human CMB, and because the claimed compounds are obvious in view of the cited references, the claimed method of treatment would have been similarly obvious.
Moreover, Sun teaches that replacement of an amide group with a heterocyclic ring in a bioactive molecule can have many important effects on physiochemical and pharmacological properties and that these substitutions introduce structural rigidity that can lead to compounds with improved potency, selectivity, metabolic stability, and pharmacokinetic properties (pg. 2536 left column, final paragraph).
The artisan would have experience in the design, synthesis, and evaluation of small-molecules for therapeutic use. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
In view of Fader’s express teaching that substituted heterocycles may be incorporated at positions R4-R6 and Sun’s teaching that heterocyclic rings are known substitutes for amide functionalities to obtain beneficial physiochemical and pharmacological properties, it would have been obvious to the artisan to select a heterocyclic substituent at the claimed position as a matter of routine design choice.
Claims 1, 5, 32, 33, 36, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Fader and Sun in view of Silverman (Silverman, R. B., & Holladay, M. W. (2015). The Organic Chemistry of drug design and drug action (third edition). Academic Press.).
The teachings of Fader and Sun are discussed above and are incorporated by reference into this rejection. They teach the compounds of claim 1. Fader additionally teaches that the substitutions of R1 include halo, nitrile, (C1-6)alkyl, and (C1-6) haloalkyl. This anticipates R16 of (IIIA), (IIIB), and (IIIC) of instant claim 32, (IVA), (IVB), and (IVC) of instant claim 33, and the halogen and nitrile groups substituted in this position in all compounds of instant claims 36 and 38. (Fader Col 1, lines 61-62).
Fader teaches that R2 and R3 together with the N to which they are attached, are linked to form a heterocycle; wherein each heterocycle is optionally mono-, di-, or tri-substituted with R32 (Col 2, lines 7-10).
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are all heterocycles and are thus anticipated by Fader. Each instance of R32 is independently selected from halo, OH, -O-(C1-6)alkyl, and R33 where R33 is (C1-6)alkyl optionally mono- or di-substituted with OH (Col 2, lines 11-25). This anticipates the azetidine derivatives found in instant claims 32, 33, 36, and 38.
Fader teaches that position R5 can be selected from the group which includes R42 (Col 2, lines 29-37). Each R42 is selected from a group which includes heterocyclyl, wherein each heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: oxo, OH, -O-(C1-6)alkyl, and (C1-6)alkyl optionally mono- or di-substituted with OH, -O-(C1-6)alkyl, -NH2, -NH(C1-6)alkyl, -N((C1-6)alkyl)2, aryl, heterocyclyl or heteroaryl (Col 2, lines 38-60). These teachings anticipate the 2-pyrrolidone rings and their derivatives found in the compounds of instant claims 32 and 33. These teachings also anticipate the 2-pyrrolidone derivatives of compounds 1-4, 6, 8-12, 14, 15, 23, 27, 36, 39, 41, and 42 of instant claim 36 and compounds 33-35 of instant claim 38.
Fader does not teach that X can be N in the compound of instant formula (I) of claim 1. However, the substitution of -CH= for -N= are known ring equivalents and known isosteres as taught by Silverman (Table 2.9, entry 5b).
The artisan would have experience in the design, synthesis, and evaluation of small-molecules for therapeutic use. The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would be familiar with techniques to optimize potency, selectivity, and drug-like properties of promising compounds. The artisan would understand common medicinal chemistry principles such as bioisosteric replacement, scaffold modification, and functional group optimization to improve pharmacokinetic and pharmacodynamic properties.
The artisan would have been motivated to incorporate a nitrogen atom into the position corresponding to X in formula (I) of instant claim 1 based on the fact that -CH= and -N= are known, commonly used ring equivalents. The artisan would recognize that such substitutions are routinely employed during drug design to explore structure activity relationships while preserving the core molecular structure. The artisan would expect that this substitution would maintain the core structure of the molecule and confer comparable electronic and steric properties, retaining or potentially enhancing the compound’s pharmacological profile. This makes obvious instant claim 5.
Instant claims 32, 33, 36, and 38 are directed to general compound structures of Formula (I) as well as specific compounds encompassed by these structures. In all instances, the compounds recited in these claims include a nitrogen atom at the position corresponding to X in Formula (I). This substitution is discussed above and is considered obvious in light of known ring bioisosteres. The remaining structural features of these compounds are anticipated or rendered obvious by the teachings of Fader, as detailed in section 1 of this rejection. Accordingly, the only distinguishing feature is the presence of nitrogen at position X, which constitutes a routine and predictable substitution. Therefore, the claimed compounds do not present a patentable distinction over the prior art.
Conclusion
Claims 1-34, 36, and 38-49 are rejected.
Claim 37 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.
Claims 50 and 51 are objected to as being dependent upon a rejected base claim.
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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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625