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
2. This Office Action is responsive to Applicant’s Remarks filed November 28, 2025. The Remarks, filed November 28, 2025, contain no amendment to the claims.
Claims 1 – 2, 9 – 26, and 34 are pending in this application, wherein claims 18 – 19, 25 – 26, and 34 are withdrawn, therefore claims 1 – 2, 9 – 17, and 20 – 24 are currently examined on the merits herein.
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.
Withdrawn Rejections
4. The rejection of claims 1 – 2, 9 – 17, and 20 – 24 in the previous Office Action, mailed September 19, 2025, under 35 U.S.C. 103 as being unpatentable over Cote et al. in view of Nikaido et al. and Lingam et al. has been considered and is withdrawn in view of Applicant’s Remarks regarding the combination of Nikaido et al. and Lingam et al. would only produce a more potent PDE4 inhibitor without mitigating the known undesirable side effects.
The following are modified / new grounds of rejection necessitated by Applicant’s Remarks, filed November 28, 2025, wherein no claims have been amended. Previously and newly cited references are used to establish the modified / new grounds of rejection.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, line 13, “,” immediately after “-C1-6alkyl” should be replaced by “or”.
Appropriate correction is required.
Modified / New 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, 16, and 20 – 24 are rejected under 35 U.S.C. 103 as being unpatentable over Cote et al. (US2006/0004056A1, cited in the previous Office Action mailed September 19, 2025) in view of Southworth et al. (Cytokine, 2019, Vol. 113, page 68 – 73, Reference included with PTO-892), George et al. (PLOS ONE, 2018, Vol. 13, Issue 9, Reference included with PTO-892), and Moustafa et al. (Nucleosides, Nucleotides, and Nucleic Acids, 2013, Vol. 32, Issue 5, page 221 – 238, Reference included with PTO-892).
a. Regarding claims 1 – 2, 9 – 14, 16, and 20 – 24, Cote et al. explicitly teaches the PDE4 inhibitor with the following structure (page 16, Example 6):
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Cote et al. teach the pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. 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]).
However, Cote et al. do not teach that the modified PDE4 inhibitor has a β-D-glucuronide.
Southworth et al. teach that PDE4 inhibitors, such as roflumilast, have target-related side effects that make it intolerable for some patients Southworth et al. suggest to develop novel PDE4 inhibitor to limit systemic exposure and the associated side effects (page 68, Left Col., para. 1; Right Col., para. 1 – 2).
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).
Moustafa et al. teach that 2-pyridone has tautomeric structure that may undergo glycosylation at either positions (page 224, Scheme 2):
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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 into a colon-restricted prodrug with glucuronide moiety in view of Southworth et al., George et al., and Moustafa et al. because Southworth et al. suggest that limiting systematic exposure will reduce the side effects, George et al. teach that the incorporation of glucuronide moiety to a drug will encourage colon delivery and minimize plasma concentration, and Moustafa et al. teach that 2-pyridone with tautomeric structure that may undergo glycosylation. One would have been motivated to modify the PDE4 inhibitor as taught by Cote into a colon-restricted prodrug with glucuronide moiety in view of Southworth et al., George et al., and Moustafa et al. because Southworth et al. teach that PDE4 inhibitors have target-related side effects that make it intolerable for some patients and limit systematic exposure would ameliorate the problem and George et al. teach that the incorporation of glucuronide moiety to a drug would minimize the plasma concentration, indicating the prodrug form reduces systematic exposure in the body. It would have been obvious for one of ordinary skill in the art to attach the β-D-glucuronide moiety to the 2-pyridone portion of the PDE4 inhibitor disclosed by Cote et al. because Moustafa et al. teach that 2-pyridone tautomeric structures may undergo glycosylation at either position, which demonstrates that the introduction of a sugar group onto such a tautomeric heterocycle is well-known in the art and the positions of the 2-pyridone for the glycosyl attachment has been recognized as known locations for glycosylation. Therefore, 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 into a colon-restricted prodrug with glucuronide moiety 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 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cote et al. (US2006/0004056A1, cited in the previous Office Action mailed September 19, 2025) in view of Southworth et al. (Cytokine, 2019, Vol. 113, page 68 – 73, Reference included with PTO-892), George et al. (PLOS ONE, 2018, Vol. 13, Issue 9, Reference included with PTO-892), and Moustafa et al. (Nucleosides, Nucleotides, and Nucleic Acids, 2013, Vol. 32, Issue 5, page 221 – 238, Reference included with PTO-892) as applied to claims 1 – 2, 9 – 14, 16, and 20 – 24 above, and further in view of Graaf et al. (Biochemical Pharmacology, 2004, Vol. 68, Issue 11, page 2273 – 2281, Reference included with PTO-892).
b. Regarding claims 15 and 17, the references 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, these references 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 November 28, 2025, have been fully considered and are found to be not persuasive.
Regarding Cote et al., Applicant argues that Dr. Mellon believed that the teachings of Cote et al. do not represent a valid starting point for the determination of obviousness because “in combination” disclosed by Cote et al. does not mean combining two compounds to for a new molecule. Applicant argues that Cote et al. do not represent a valid starting point because the compounds generated by Cotes already have a high potency. Applicant further argues that Cote et al. offers no solution to address the problem of the significant side effects.
Regarding Nikaido et al., Applicant argues that the combination of Cote et al. and Nikaido et al. only leads to a stronger and more potent PDE4 inhibitor and there is no teaching in Cote et al. or Nikaido et al. about addressing the problem of significant side effects. Based on the screening of inhibitory activity on cAMP phosphodiesterase disclosed by Nikaido et al., Applicant argues that there are compounds other than compounds 26 – 29 demonstrate strong inhibition. Therefore, not only has the skilled person many choices of cAMP phosphodiesterase inhibitory compounds, but the outcome of these choices would be uncertain as the IC50 values show variation and lack of predictability. Applicant argues that the experimentation conducted by Nikaido et al. is not particularly done for the PDE4 inhibitory activity because PDE enzyme preparations from beef heart did not contain a controlled mixture of enzyme in 1988. Furthermore, Applicant argues that Nikaido et al. should be consider as a whole for an obviousness analysis.
Regarding Lingam et al., Applicant argues that Lingam et al. do not cure the deficiencies of Cote et al. and Nikaido et al. because Lingam et al. state the best inhibitors are at least 5800-fold selective for PDE10a over other PDEs, showing that the structure-activity relationship differs vastly between phosphodiesterase enzymes, Lingam et al. identify glucuronide “26” as a metabolite of the best inhibitor “18b” and not the ester thereof, Lingam et al. did not determine the potency of this metabolite, thereby fails to provide any teaching regarding the alleged potency, and Lingam et al. did not use the metabolite as a prodrug.
However, these arguments are not moot because of the new grounds of rejection presented above. Regarding Cote et al., “in combination” disclosed is not meant for providing reasons, motivation, or suggestion for combining PDE4 inhibitor with the glucuronide moiety. The recitation is brought up for addressing claim 24. Regarding the arguments over Cote et al. in view of Nikaido et al. and Lingam et al., the arguments are moot because the new rejection is no longer rely on the combination of Cote et al., Nikaido et al. and Lingam et al. The new rejections are based on Cote et al., Southworth et al., George et al., and Moustafa et al. for claim 1 – 2, 9 – 14, 16, and 20 – 24 and based on Cote et al., Southworth et al., George et al., and Moustafa et al., and further in view of Graaf et al. for claims 15 and 17. Cote et al. teach the claimed PDE inhibitor and Southworth et al. provide the motivation to modify the PDE4 inhibitor. George et al. demonstrate that glucuronide moiety has been used in producing prodrugs that are colon-restricted and is able to minimize systematic exposure. Moustafa et al. teach that 2-pyridone tautomeric structures may undergo glycosylation at either position, which demonstrates that the introduction of a sugar group onto such a tautomeric heterocycle is well-known in the art and the positions of the 2-pyridone for the glycosyl attachment has been recognized as known locations for glycosylation. Finally, Graaf et al. teach that methyl ester of glucuronide is known in the art as a variant of glucuronide and the methyl ester group will convert to glucuronide in vivo. Therefore, the combination of these references render the claimed invention obvious.
Regarding unexpected results, Applicant argues that the claimed compounds have been found to exhibit biological activity as PDE4 inhibitors after being locally activated in the colon and the IC50 values of compounds IIIa and IIIb, which are the parent PDE4 inhibitors, are less than 10 nM, whereas the claimed compound 10 has an IC50 value of 164.2 nM. Applicant also argues that the there is a 30-fold improvement in tolerability for the prodrug compared to the parent compound IIIb in the emesis studies. However, the arguments are not persuasive. Applicant compares compound 10 to compound IIIb. This is not a proper comparison because compound 10 contains a stereocenter whereas compound IIIb is racemic. As different enantiomers of a chiral compound can exhibit materially different biological activity, potency, pharmacokinetics, and tolerability, a comparison between a single stereoisomer and a racemate does not allow proper determination of unexpected results. Moreover, Applicant’s Supplementary Tables 1 and 2 are directed to compound 10, which is the elected species. However, the claims are directed to the full scope of Formula (I), which encompasses many embodiments with different substituents. The result of inhibitory effects showing only one single compound is not commensurate in scope with the claims. Furthermore, George et al. disclose that colon-restricted delivery would reduce on-target or off-target side effects resulting from systemic exposure (page 18, para. 2). It is expected that the claimed prodrug will demonstrate improvement in tolerability.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE NON-FINAL.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693