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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/31/2026 has been entered.
Response to Arguments
Applicant's arguments filed 03/13/2026 have been fully considered but they are not persuasive.
Applicant argues that there is no teaching or suggestion that O-H cleavage in the -CH(OH)CO3Na moiety of GC376 is the rate-limiting step, or even a step, of the in vivo metabolic clearance reaction for GC376. The arguments hinge on the suggestion that deuteration can only be predictably applied to “clearance” of a drug. Conversion of a prodrug to its active form is a part of its metabolism. Note that the obviousness rejection of 02/11/2025 merely refers to metabolism and does not argue with respect to the “clearance” of the drug. A PHOSITA would not recognize altering “clearance” of an active drug as described by applicant as the only target for deuteration, particularly in the context of those drugs that undergo multiple transformations, i.e. prodrugs. That Liu et al. teaches “a lower clearance, higher maximum concentration, and a longer half-life” of an active drug does not preclude conversion of a prodrug to its active form as a reasonable target for deuteration. Furthermore, conversion of a prodrug to its active form can be reasonably considered as part of the “clearance” of the prodrug. Principles taught by Liu et al. would be recognized as applicable to the conversion of a prodrug to its active form – not just the metabolism of an active drug to its metabolites – and the prior art implicitly teaches via the conversion of the alcohol to an aldehyde that O-H bond cleavage is a step in such a process.
Kim et al. teaches “The high aqueous solubility and pH-dependent equilibria between the precursor carbonyl compound and bisulfite adduct were also envisaged to have a significant effect on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and on pharmacokinetics (PK). Solubility, as well as permeability and metabolic stability, affects oral bioavailability of a drug in vivo and also contributes to accurate and reliable in vitro assays. It is possible that a bisulfite adduct compound behaves as a prodrug of the precursor aldehyde, and this warrants further studies on its effects on pharmacokinetics and pharmacodynamics.” It is clear that this step is important to metabolism and a target for deuteration. While the rate-limiting step is not explicitly taught, a PHOSITA would recognize that conversion of the hydroxy to an aldehyde necessarily involves cleavage of the O-H bond. The hydroxymethane sulfonate as a whole is taught as metabolically labile and the hydroxy hydrogen is the only reasonable location for deuteration. Accordingly, deuteration of the hydroxy group would have been predicted to effect metabolism with a reasonable expectation of success.
Applicant cites unpredictable effects on oral bioavailability. A potential effect on oral bioavailability – particularly without a reasonable expectation of a negative impact – cannot be considered to teach away from deuteration. Previous arguments regarding the need for a reasonable expectation of success – not an absolute expectation of success – are further emphasized.
In summary, the prior art teaches deuteration of metabolically labile sites for altering pharmacokinetics and a metabolically labile site of GC376 is known. This fact pattern strongly supports a conclusion of obviousness of a GC376 analog wherein the known metabolically labile site is deuterated. While applicant’s arguments have been fully considered, they are insufficient in view of this fact pattern to shift the preponderance of the evidence toward a conclusion of nonobviousness for reasons above and those stated in previous actions. Accordingly, the rejection of claims 7 and 12-14 under 35 U.S.C. 103 is maintained.
Conclusion
Claims 7 and 12-14 are rejected.
Claims 1-5, 8-11 and 16-17 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JED A KUCHARCZK whose telephone number is (571)270-5206. The examiner can normally be reached Mon-Fri 7:30 to 5.
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/JED A KUCHARCZK/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623