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
Status of claims
The amendment filed on December 12, 2025 is acknowledged. Claims 2, 5, 8-15, 18, 21, 24-31, and 33-47 have been canceled. Claims 1, 3-4, 6-7, 16-17, 19-20, 22-23, and 32 are under examination in the instant office action.
Applicants' arguments, filed on December 12, 2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
The provisional rejection of Claims 1-47 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 24-52 of co-pending application 17/502562 is hereby withdrawn in view of the abandonment of the ‘562 application.
The provisional rejection of Claims 1-47 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-26 of co-pending application 19/056265 is hereby withdrawn in view of the abandonment of the ‘265 application.
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 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3-4, 6-7, 16-17, 19-20, 22-23, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0021284 (hereafter, Mégret; cited in the IDS filed on 6/15/2023) in view of US 8772306 (hereafter, Eller; cited in the IDS filed on 6/15/2023).
Mégret teaches modified release formulations of gamma-hydroxybutyrate (GHB; oxybate) that are administered only once at bed-time (nightly) with improved dissolution and pharmacokinetic profiles (abstract, [0017], and [0019]).
Mégret teaches that a method of treating a disorder treatable with gamma-hydroxybutyrate in a human subject in need thereof comprising orally administering a single bedtime daily dose to said human amounts of gamma-hydroxybutyrate equivalent to from 3.0 to 12.0 g of sodium oxybate in the modified release formulation ([0363]). Mégret further teaches that the therapeutically effective amount is most preferably equivalent from 4.5, 6.0, 7.5 or 9.0 g of sodium oxybate ([0363]). The dose amount is the same as those that are given absent co-administration of divalproex sodium GHB as evidenced by Eller (claim 8).
Mégret further teaches that the modified release formulation is effective to treat narcolepsy Type 1 or Type 2, wherein said treatment of narcolepsy is defined as reducing excessive daytime sleepiness or reducing the frequency of cataplectic attacks ([0363]). Mégret discloses that sleep-onset can be dramatic and fast, and patients are advised to be sitting in bed when consuming the dose ([0007]).
Mégret also teaches that the modified release formulations of gamma-hydroxybutyrate preferably have both immediate release and modified release portions wherein the release of gamma-hydroxybutyrate from the immediate release portion occurs almost immediately in 0.1N hydrochloric acid dissolution medium and the release from the modified portion is not triggered until a predetermined lag-time or the drug is subjected to a suitable dissolution medium such as a phosphate buffer pH 6.8 dissolution medium ([0029]).
In addition, Mégret discloses that sodium oxybate is marketed commercially in the United States as Xyrem®, which is formulated as an immediate release liquid solution that is taken once immediately before bed, and a second time approximately 2.5 to 4 hours later, in equal doses ([0007]). Mégret teaches that the requirement to take Xyrem® twice each night is a substantial inconvenience to narcolepsy patients and the patient must typically set an alarm to take the second dose, which can interrupt ongoing productive sleep ([0009]). Mégret teaches the modified release formulations yield a similar pharmacokinetic profile compared to an immediate release liquid solution of sodium oxybate administered twice nightly while potentially giving a reduced dose ([0022]). Mégret further discloses that the modified release formulations of gamma-hydroxybutyrate that allow once daily administration and reduced dose compared to the commercial treatment Xyrem® ([0023]).
Furthermore, Mégret discloses that the invention provides a modified release formulation of gamma-hydroxybutyrate, preferably comprising immediate release and modified release portions, wherein 4.5 g, 6 g, 7.5 g, and 9 g doses of the formulation have been shown to achieve a relative bioavailability (RBA) of greater than 80% when compared to an equal dose of an immediate release liquid solution of sodium oxybate administered in equally divided doses ([0038]). Mégret specifically discloses that a modified release composition of gamma-hydroxybutyrate according to the invention administered once approximately at the dose equivalent to 7.5 g of sodium oxybate results in a similar pharmacokinetic profile as an immediate release liquid solution of sodium oxybate (Xyrem ®) given in two separate equal doses of 4.5 g of sodium oxybate (total dose of 9.0 g) ([0028] and [0413]). The dose of the modified release formulation is about 20% less than that of the immediate release liquid solution (Xyrem ®).
Mégret does not specifically disclose concomitantly administering divalproex sodium.
However, it was known in the art that some patients receive concomitant-administration of GHB with divalproex sodium as evidenced by Eller. Eller teaches a method for treating a patient who is suffering from excessive daytime sleepiness, cataplexy, sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogic hallucinations, sleep arousal, insomnia, and nocturnal myoclonus with gamma-hydroxybutyrate (GHB) or a salt thereof, comprising: orally administering to the patient in need of treatment, an adjusted dosage amount of the salt of GHB when the patient is receiving a concomitant administration of valproate (col. 1, lines 24-32). Eller also teaches that valproic acid, which is called valproate or divalproex and used as sodium salt, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression (col 15, lines 19-35). Eller discloses administering two 3 g doses of Xyrem® (total daily dose of 6 g) and 1250 mg divalproex sodium extended-release tablets (col 22, lines 45-54). When the average weight of adults is 60 kg, the dosage amount of DVP is 21 mg/kg, which falls within the claimed range. In addition, Eller teaches that the amount of GHB is reduced by at least 5% or at least 10% to 30% and the effective dosage amount of the GHB is between 3 grams and 7 grams per day when the amount of GHB or salt thereof is reduced at least 10% to 30% when the patient is receiving a concomitant administration of valproate (claims 1, 4, 9, and 12). The GHB used in the method is commercially known as Xyrem® (col 2, lines 52-54 and col8, lines 37-45).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use GHB in the formulation of Mégret in place of Xyrem® for a patient who is also in need of divalproex sodium because of the following reasons. Eller already teaches co-administering divalproex with reduced daily dose amount of the commercially-available GHB such as Xyrem®. Mégret teaches that their modified release formulations of gamma-hydroxybutyrate can be administered only once at bed-time with improved dissolution and pharmacokinetic profiles and reduced daily dose compared to the commercial treatment Xyrem®. Thus, one of ordinary skill in the art would have been motivated to do so on the reasonable expectation that GHB in the modified release formulation of Mégret could be safely co-administered with divalproex sodium for those who are in need of both drugs as taught by Eller via easy and convenient once-nightly administration. Also, the skilled artisan would have been motivated to administer a full dosage amount of the modified release formulation of Mégret once a day without a dose reduction or with a dose reduction less than 5% because the skilled artisan would have reasoned that Mégret’s full daily dosage amount would be similar to that of adjusted or reduced daily dosage amount of Eller.
Response to Applicant’s arguments
Applicant argued that a person of ordinary skill in the art would not have reasonably expected that DVP could be administered concomitantly with GHB without having to decrease the dose of GHB. Applicant further argued that Eller never suggests it would be possible to avoid the unsafe effects of co-administering DVP with GHB by reformulating GHB and its sole solution is to reduce the dose of GHB or discontinue its use, thus Eller provides no reasonable expectation that DVP could be safely combined with GHB without reducing the dose of GHB. In addition, Applicant argued that Eller strongly teaches away from not reducing the dose of GHB when it is co-administered with DVP.
In response, the Examiner respectfully submits that the above rejection is based on a combination of references, not on Eller taken in a vacuum. As such, Applicants' arguments pertaining to Eller are not persuasive. 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).
In this case, Mégret discloses that the modified release formulations of gamma-hydroxybutyrate that allow once daily administration and reduced dose compared to the commercial treatment Xyrem® (see [0023]). Also, Mégret specifically discloses that a modified release composition of gamma-hydroxybutyrate according to their invention administered once approximately at the dose equivalent to 7.5 g of sodium oxybate results in a similar pharmacokinetic profile as an immediate release liquid solution of sodium oxybate (Xyrem ®) given in two separate equal doses of 4.5 g of sodium oxybate (total dose of 9.0 g) (see [0028] and [0413]). This means that a full dose amount of Mégret’s modified release formulation is 15% less than that of the immediate release liquid solution (Xyrem ®). Thus, one of ordinary skill in the art would have recognized that Mégret’s modified release formulation requires a dose amount, which is less than (e.g., about 15%) that of the immediate release liquid solution (Xyrem ®) for achieving similar pharmacokinetic profile of Xyrem ®. Because the skilled artisan would have reasoned that Mégret’s full daily dosage amount would be similar to that of reduced daily dosage amount disclosed in Eller (see col 18, lines 57-60) , it would have been obvious to one of ordinary skill in the art to administer a full dosage amount of the modified release formulation of Mégret once a day without a dose reduction. The skilled artisan would have been motivated to use the modified release formulation of Mégret on the reasonable expectation that GHB in the modified release formulation of Mégret could be safely co-administered with divalproex sodium for those who are in need of both drugs as taught by Eller via easy and convenient once-nightly administration and without dose-reduction. Also, Eller’s teaching about reducing the dose of GHB when co-administered with DVP is directed to only the immediate release liquid solution (Xyrem ®), which is typically administered twice a day (one dose prior to bed and another dose administered 1-2 hours later) (see column 19, para 1). Thus, one of ordinary skill in the art would not been taught away from not reducing the dose of GHB when DVP is co-administered with GHB in modified release formulation, which allows once daily administration and reduced dose compared to the commercial treatment Xyrem®. Instead, the skilled artisan would have been capable of arriving at suitable dosage amount for GHB in modified formulation for coadministration with DVP based on the teaching of the prior art.
As to claim 17 as amended, the instant claim 17 recites “the dosage of GHB is reduced by less than 5% in response to the concomitant administration of DVP”. For example, “less than 5%” encompasses 0% (no reduction) as well as 4.99%, which is very close 5% reduction taught by Eller. Further, Eller teaches that when valproate is concomitantly administered with GHB, the amount of GHB can be reduced at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the normal dose of GHB (see col 18, lines 54-57). Thus, the claimed range overlaps or very close to those of the prior art. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05 I. Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In addition, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
For foregoing reasons, Applicant’s arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611