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 .
DETAILED ACTION
This Office Action is responsive to Applicant’s Amendment and Remarks, field June 8, 2026. The amendment, filed June 8, 2026, is acknowledged, wherein claim 1 is amended, claims 3 – 8 and 27 – 33 are canceled, and claims 18 – 19, 25 – 26, and 34 are withdrawn.
Claims 1 – 2, 9 – 26, and 34 are pending in this application and claims 1 – 2, 9 – 17, and 20 – 24 are currently examined.
Priority
This application is a national stage application of PCT/CA2021/050725, filed May 28, 2021, which claims benefit of domestic application 63/031,023, filed May 28, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/08/2026 was filed after the mailing date of the previous Office Action on March 6, 2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
The objection of claim 1 in the previous Office Action, dated March 6, 2026, is withdrawn in view of the amended claim 1.
The following are maintained / modified grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed June 8, 2026, wherein claim 1 is amended. Previously cited references are used to establish the maintained / modified grounds of rejection.
Maintained / Modified 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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
Claims 1 – 2, 9 – 14, and 20 – 24 are rejected under 35 U.S.C. 103 as being unpatentable over Cote et al. (US2006/0004056A1, cited in the PTO-892 on September 19, 2025) in view of Southworth et al. (Cytokine, 2019, Vol. 113, page 68 – 73, cited in the PTO-892 on March 6, 2026), George et al. (PLOS ONE, 2018, Vol. 13, Issue 9, cited in the PTO-892 on March 6, 2026), and Moustafa et al. (Nucleosides, Nucleotides, and Nucleic Acids, 2013, Vol. 32, Issue 5, page 221 – 238, cited in the PTO-892 on March 6, 2026).
Cote et al. explicitly teaches the PDE4 inhibitor with the following structure (page 16, Example 6):
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which corresponds to the compound of Formula (I), wherein R1 is -C1-6alkyl substituted with 1 – 6 independent halogen; R2 is -C3-6cycloalkyl; R3, R4, R5, R6, and R7 are H; and Ar1 is 6-R8-3-pyridyl, wherein R8 is -C(R10)(R11)OH, wherein C10 and C11 are -C1-6alkyl; which reads on the limitations of claims 1 and 9 – 13 and aglycone portion of compound 10 of claim 16. Cote et al. teach the pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. Thus, Cote et al. teach a pharmaceutical composition comprising the PDE4 inhibitor and a pharmaceutically acceptable carrier, which reads on the limitations of claim 20. The pharmaceutical composition may also be in combination with one or more other therapeutically active compounds (para. [0088]), such as COX-2 selective inhibitors (para. [0098]). The unit dosage forms will generally contain between about 0.01 mg to about 1000 mg of the active ingredient (para. [0085]). The compound may be administered by controlled release means (para. [0087]). The pharmaceutical composition can be in a form for topical use, such as a cream (para. [0094]). The disclosure reads on the limitations “therapeutically effective amount” recited in claim 21, “sustained release formulation” of claim 22, “cream” of claim 23, and “selective COX-2 inhibitor” of claim 24.
However, Cote et al. do not teach that the modified PDE4 inhibitor has a β-D-glucuronide. Cote et al. also do not teach that the PDE4 inhibitor includes a β-D-glucuronide moiety attached at the 2-pyridone tautomeric oxygen position.
Southworth et al. teach that PDE4 inhibitors, including roflumilast, are associated with target-related side effects that make systemic PDE4 inhibition intolerable for some patients. Southworth et al. further teach that reducing systemic exposure is a recognized strategy for reducing such side effects (page 68, Left Col., para. 1; Right Col., para. 1 – 2). Thus, Southworth et al. provide the recognized problem and reason for modification, namely that PDE4 inhibitors may cause target-related side effects upon systemic exposure, and that reducing systemic exposure would be expected to reduce such side effects.
George et al. teach prodrugs for colon-restricted delivery (Title), wherein prodrug 11 has a structure of (page 8, Fig. 6):
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Oral dose of glucuronide analog 11 results in approximately equivalent amounts of active parent in both colon and plasma (page 8, para. 1), while no measurable plasma level of 11 is observed (page 9, para. 1). Thus, George et al. teach that conjugating a drug to a glucuronide moiety is a known prodrug approach for colon-restricted delivery, wherein oral administration of glucuronide analog 11 provides active parent in the colon while no measurable plasma level of the prodrug 11 is observed. Therefore, Geroge et al. teach that a glucuronide moiety may be used to reduce systemic exposure of the prodrug while still permitting release of the active parent.
Moustafa et al. teach that 2-pyridone has tautomeric structure that may undergo glycosylation at either position (page 224, Scheme 2):
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Thus, Moustafa et al. teach that 2-pyridone tautomeric system provides known heteroatom positions for glycosylation, including glycosylation through the pyridone nitrogen and/or the oxygen. Moustafa et al. therefore support that introduction of a sugar moiety onto a 2-pyridone-containing heterocycle is known and chemically feasible.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the PDE4 inhibitor as taught by Cote by attaching a β-D-glucuronide moiety to the 2-pyridone portion of the compound to form a colon-restricted prodrug in view of Southworth et al., George et al., and Moustafa et al. because Southworth et al. teach the recognized problem in the PDE4 inhibitor, which is that PDE4 inhibitors may cause target-related side effects upon systemic exposure, and that reducing systemic exposure would be expected to reduce such side effects, George et al. teach a known prodrug approach for colon-restricted delivery using a glucuronide moiety, wherein oral administration of glucuronide analog 11 provides active parent in the colon while no measurable plasma level of prodrug 11 is observed, and Moustafa et al. teach that 2-pyridone tautomeric systems may undergo glycosylation at available heteroatom positions, including through the pyridone nitrogen and/or oxygen, thereby demonstrating that introduction of a sugar moiety onto a 2-pyridone-containing heterocycle is known and chemically feasible. One would have been motivated to modify the PDE4 inhibitor as taught by Cote by attaching a β-D-glucuronide moiety to the 2-pyridone portion of the compound to form a colon-restricted prodrug in view of Southworth et al., George et al., and Moustafa et al. because Southworth et al. teach the recognized problem in the PDE4 inhibitor, which is that systemic exposure to PDE4 inhibitors may result in target-related side effects, and that reducing systemic exposure would be expected to reduce such side effects and George et al. teach a known solution to this type of problem by disclosing glucuronide-containing prodrugs for colon-restricted delivery, wherein oral administration of glucuronide analog 11 provides active parent in the colon while no measurable plasma level of prodrug 11 is observed. Thus, a person of ordinary skill in the art seeking to reduce systemic exposure of the PDE4 inhibitor of Cote et al. would have had reason to apply the glucuronide prodrug strategy in view of George et al. to the PDE4 inhibitor of Cote et al. to obtain the predictable result of reduced measurable systemic exposure of the prodrug while permitting release of the active parent in the colon. One of the ordinary skill in the art would have had a reasonable expectation of success to modify the PDE4 inhibitor as taught by Cote by attaching a β-D-glucuronide moiety to the 2-pyridone portion of the compound to form a colon-restricted prodrug in view of Southworth et al., George et al., and Moustafa et al. because Cote et al. teach the PDE4 inhibitor, Southworth et al. suggest that limiting systematic exposure will reduce the side effects, George et al. provide evidence that glucuronide prodrug may be orally administered to yield colon-restricted delivery characteristics and reduced measurable plasma levels of the prodrug, while still releasing the active parent drug, and Moustafa et al. teach that the 2-pyridone has tautomeric structure that may be modified by glycosylation, thereby, supporting the formation of the claimed compound.
Claims 15 – 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cote et al. (US2006/0004056A1, cited in the PTO-892 on September 19, 2025) in view of Southworth et al. (Cytokine, 2019, Vol. 113, page 68 – 73, cited in the PTO-892 on March 6, 2026), George et al. (PLOS ONE, 2018, Vol. 13, Issue 9, cited in the PTO-892 on March 6, 2026), and Moustafa et al. (Nucleosides, Nucleotides, and Nucleic Acids, 2013, Vol. 32, Issue 5, page 221 – 238, cited in the PTO-892 on March 6, 2026) as applied to claims 1 – 2, 9 – 14, and 20 – 24 above, and further in view of Graaf et al. (Biochemical Pharmacology, 2004, Vol. 68, Issue 11, page 2273 – 2281, cited in the PTO-892 on March 6, 2026).
Cote et al., Southworth et al., George et al., and Moustafa et al. teach the limitations discussed above. George et al. further teach that other glucoside analogs 9 and 10 (page 8, Fig. 6):
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also result in approximately equivalent amounts of active parent in both colon and plasma when administered orally. The plasma levels of prodrug 9 are ~100x less than active parent and no measurable plasma levels of 10 is observed (page 8, para. 1; page 9, para. 1).
However, Cote et al., Southworth et al., George et al., and Moustafa et al. do not teach the modified PDE4 inhibitor with methyl glucuronate moiety:
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Graaf et al. teach a methyl ester of a glucuronide prodrug (Title). Graaf et al. disclose the prodrug referred to as DOX-mGA3. When administered in vivo, the methyl ester group of the prodrug is hydrolyzed by esterases/carboxylesterases to yield the corresponding glucuronide (-COOH), which is then activated by β-glucuronidase (page 2274, Right Col., para. 1; Figure 1):
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Graaf et al. hypothesize that slow release of DOX-GA3 after administration of DOX-mGA3 might result in improved pharmacokinetic of the glucuronide prodrug in vivo. Therefore, the use of the lipophilic DOX-mGA3, which can be considered a pro-prodrug, might allow lower doses to be administered to achieve the same therapeutic effect (page 2274, Right Col., para. 1). Furthermore, Graaf et al. provide a synthetic scheme showing the preparation of DOX-mGA3 (page 2275, Figure 2).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date to substitute the glucuronide moiety conjugated with PDE4 inhibitor as taught by Cote et al. and George et al. with the methyl ester of glucuronide in view of Graaf et al. because Graaf et al. teach that glucuronide prodrugs may be prepared as a methyl ester form and that the methyl ester is a known, predictable variant that is removable by esterases to yield the glucuronide, which is then be activated by β-glucuronidase. One would have been motivated to substitute the glucuronide moiety conjugated with PDE4 inhibitor as taught by Cote et al. and George et al. with the methyl ester of glucuronide in view of Graaf et al. because Graaf et al. teach that methyl ester of glucuronide is a known variant that will yield glucuronide in vivo and Graaf et al. also teach that the use of methyl ester of glucuronide allow lower doses to be administered to achieve the same therapeutic effect. One of ordinary skill in the art would have had a reasonable expectation of success to substitute the glucuronide moiety conjugated with PDE4 inhibitor as taught by Cote et al. and George et al. with the methyl ester of glucuronide in view of Graaf et al. because Graaf et al. teach and demonstrate that the methyl ester of glucuronide is enzymatically hydrolyzed by esterases to yield glucuronide and undergoes the activation by β-glucuronidase in vivo and Graaf et al. teach that the prodrug with methyl ester of glucuronide will allow lower dosage for the same therapeutic effect.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed June 8, 2026, have been fully considered and are found to be not persuasive.
Applicant argues that Cote et al. do not provide a teaching or suggestion to modify the pyridone ring of the disclosed PDE4 inhibitor. However, the argument is not persuasive. The rejection does not rely on Cote et al. alone to teach the modification of the pyridone ring. Cote et al. is relied upon for teaching the PDE4 inhibitor scaffold, including the 2-pyridone-containing compound corresponding to the claimed PDE4 inhibitor. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that Southworth et al. is directed to studies involving CHF6001 and corticosteroid 17-BMP in bronchoalveolar lavage cells from asthma patients, and that Southworth et al. discuss limiting systemic exposure in the context of inhalation or intratracheal administration. Applicant asserts that Southworth et al. do not provide a reason to modify the compounds of Cote et al. to arrive at the claimed colon-restricted glucuronide prodrugs. However, Southworth et al. is not relied upon for teaching colon delivery or for teaching the claimed glucuronide structure. Instead, Southworth et al. is relied upon for the recognized problem in the PDE4 inhibitor, which is the systemic exposure to PDE4 inhibitors that is associated with target-related side effects and that reducing systemic exposure would be expected to reduce such side effects. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that George et al. would not have led one of ordinary skill in the art to use glucuronide or glucoside prodrugs because George et al. identify cyclodextrin prodrugs as preferred or optimal. Applicant also points to the statement of George et al. that the pharmacodynamic effect in the colon is inferior to a systemically available positive control and that a suitable therapeutic index is not achieved for CSF1R inhibition using GI-restricted delivery in mice. However, the argument is not persuasive. George et al. is relied upon for teaching a colon-restricted prodrug strategy using glucuronide-containing prodrugs, including glucuronide analog 11. George et al. explicitly disclose glucuronide analog 11 and report that oral administration of glucuronide analog 11 provides active parent in the colon while no measurable plasma level of prodrug 11 is observed. The fact that George et al. identify cyclodextrin prodrugs as preferred in that particular study does not negate the teaching of George et al. that glucuronide prodrugs are tested and provided colon-restricted delivery characteristics. Further, the discussion of George et al. regarding insufficient therapeutic index is specific to the CSF1R target and the particular pharmacodynamic endpoint tested in mice, and does not teach that glucuronide prodrugs are unsuitable generally or that such prodrugs would not be useful for a different active agent, such as the PDE4 inhibitor taught by Cote et al.
Applicant argues that one of ordinary skill in the art would not have combined Southworth et al. with George et al. because Southworth et al. concern lung-directed administration while George et al. concern colon-restricted delivery. Applicant asserts that the lung and colon are different in form and function, and therefore the references would not have been combined. However, the argument is not persuasive. The rejection does not require Southworth et al. and George et al. to involve the same tissue or route of administration. Southworth et al. is relied upon for the general PDE4-related problem of systemic exposure and associated side effects. George et al. is relied upon for a known prodrug solution that reduces measurable systemic exposure of the intact prodrug while permitting release of active parent in the colon. Both teachings are relevant to the same objective, which is reducing systemic exposure while maintaining therapeutic activity. Therefore, a person of ordinary skill in the art seeking to reduce systemic exposure of a PDE4 inhibitor would have had reason to consider known prodrug strategies, including the colon-restricted glucuronide prodrug strategy taught by George et al.
Applicant argues that Moustafa et al. is directed to glycosylation of a particular group of 2-pyridonesulfonamide compounds and that the pending claims exclude sulfonamide groups. Applicant therefore asserts that one of ordinary skill in the art would not have turned to Moustafa et al. to modify the compounds of Cote et al. However, the argument is not persuasive because Moustafa et al. is not relied upon for teaching a sulfonamide substituent or for teaching PDE4 inhibitory activity. Moustafa et al. is relied upon for the chemical teaching that 2-pyridone tautomeric systems may undergo glycosylation at available heteroatom positions, including the pyridone nitrogen and/or oxygen. The presence of sulfonamide substituents in the exemplified compound of Moustafa et al. does not negate the reference’s teaching regarding glycosylation of the 2-pyridone tautomeric heterocycle. Thus, Moustafa et al. support the chemical feasibility of attaching a sugar moiety to the 2-pyridone portion of the compound of Cote et al.
Applicant argues that the rejection is based on hindsight because, according to Applicant, only Applicant’s specification would have led one of ordinary skill in the art to combine the cited references to arrive at the claimed compounds. However, the argument is not persuasive. The rejection identifies teachings in the prior art corresponding to the claimed features and provides an articulated reason for the modification. Cote et al. teach the PDE4 inhibitor scaffold; Southworth et al. teach the desirability of reducing systemic exposure of PDE4 inhibitors to reduce side effects; George et al. teach glucuronide-containing prodrugs for colon-restricted delivery with no measurable plasma level of intact prodrug; and Moustafa et al. teach that 2-pyridone tautomeric systems may undergo glycosylation. Therefore, the rejection is based on the teachings of the applied references and the predictable application of known prodrug and glycosylation chemistry, not hindsight reconstruction.
Regarding claims 15 and 17, Applicant argues that Graaf et al. do not cure the deficiencies of Cote et al., Southworth et al., George et al., and Moustafa et al. Applicant appears to assert that because the base combination is allegedly improper, the additional reliance on Graaf et al. for claims 15 and 17 also fails. However, the argument is not persuasive. As discussed above, the combination of Cote et al., Southworth et al., George et al., and Moustafa et al. provides the PDE4 inhibitor scaffold, the reason to reduce systemic exposure, the colon-restricted glucuronide prodrug strategy, and the chemical feasibility of glycosylation at the 2-pyridone portion of the compound of Cote et al. Graaf et al. is relied upon only for the additional limitation, which is the methyl glucuronate feature. Graaf et al. teach a methyl ester of a glucuronide prodrug, DOX-mGA3, and teach that the methyl ester is hydrolyzed by esterases/carboxylesterases to yield the corresponding free glucuronide, which may then be activated by β-glucuronidase. Thus, Graaf et al. support that the methyl glucuronate moiety is a known, predictable ester variant of a glucuronide prodrug. Applicant’s argument regarding Graaf et al. is also unpersuasive because Graaf et al. need not teach colon-restricted delivery. George et al. is relied upon for the colon-restricted glucuronide prodrug strategy. Graaf et al. is relied upon for the simple substitution of the glucuronide carboxylic acid form with the known methyl ester form, i.e. -COOH to -COOCH3. Because Graaf et al. teach that the methyl ester is enzymatically hydrolyzed to regenerate the corresponding free glucuronide, a person of ordinary skill in the art would have reasonably expected the methyl glucuronate form to be compatible with the glucuronide-based prodrug strategy taught by George et al.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the maintained / modified 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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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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