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
The Applicant’s reply filed on 1/13/26 is acknowledged. Claims 1, 11, 13, 15, 17, 19, 21, 23-30, 34, and 36-39 are pending. Claims 1, 11, 13, 15, 17, 19, 21, 23-27 and 29 have been withdrawn. Claims 28 and 34 have been amended. Claims 28, 30, 34 and 36-39 are under consideration.
Rejections Withdrawn
The rejection of Claims 28, 30, 32, 34, 36, 38 and 39 under 35 U.S.C. 103 as being unpatentable over Hassan et al. (US 2014/0093562; cited in IDS), as evidenced Alhazmi et al. (European Journal of Chemistry, 2017; cited in IDS), and in view of Yu et al. (US 5,360,615; cited in IDS) is withdrawn in view of the amended claim(s).
The rejection of Claims 37 under 35 U.S.C. 103 as being unpatentable over Hassan et al. (US 2014/0093562; cited in IDS), as evidenced Alhazmi et al. (European Journal of Chemistry, 2017; cited in IDS), and in view of Yu et al. (US 5,360,615; cited in IDS), as applied to claims 28, 30, 32, 34, 36, 38 and 39, and further in view of Gullapalli (Journal of Pharmaceutical Sciences, 2010; cited in IDS) is withdrawn in view of the amended claim(s).
Rejections Maintained and New Grounds of Rejections
Claim Objections
Claims 31-33 are objected to because of the following informalities: the claims do not include a status identifier, but will be treated as “canceled” because no text is present. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28, 30, 34 and 36-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28 recites the limitation "the potassium salt of naproxen" in line 7. There is insufficient antecedent basis for this limitation in the claim. The claim recites a reaction in terms of the reactants but does not recite a potassium salt of naproxen. This limitation was present in the previous claim set and has been removed. Claims 30, 34 and 36-39 are rejected as depending from and not clarifying claim 28.
In claim 28, is unclear which components and amounts thereof are required in the final pharmaceutical composition and what components and amounts thereof have already been reacted. The claim recites “…preparing a fill composition by mixing naproxen free acid and potassium hydroxide and dissolving in a solvent to react the naproxen free acid with the potassium hydroxide to obtain a reaction product…wherein the fill composition comprises the potassium salt of naproxen present at a concentration of from about 65 wt% to about 75 wt% based on a total combined weight of the naproxen free acid and the potassium salt of naproxen, and wherein the mini softgel capsule has a size of 8 to 14”. The recited range of 65 wt% to 75 wt% is unclear because it is unclear if all three components present in the fill composition (i.e. naproxen free acid, potassium hydroxide, and the potassium salt of naproxen), or is this calculated based on a pre-reaction amount? Accordingly, the metes and bounds of the claim are unclear. Claims 30, 34 and 36-39 are rejected as depending from and not clarifying claim 28.
Claim 30 recites “wherein a molar ratio of potassium hydroxide to naproxen free acid is about 0.55 to about 0.75”. It is unclear if this ratio refers to pre-reaction amounts or the final fill composition amounts.
Claim 39 recites “wherein a molar ratio of the potassium hydroxide to naproxen free acid is less than about 1”. It is unclear if this ratio refers to pre-reaction amounts or the final fill composition amounts.
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 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 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.
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 28, 30, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 5,360,615; cited in IDS) in view of Lopez et al. (US 2013/0011470; cited in IDS).
Yu et al. teach a solvent system for enhancing the solubility of an acidic, basic, or amphoteric pharmaceutical agent to produce a highly concentrated solution suitable for softgel filling, wherein the pharmaceutical agent is naproxen (e.g. abstract; Claims 1 and 8; Examples).
Yu et al. teach that the solvent system comprises polyethylene glycol, sodium hydroxide, and water, the polyethylene glycol acts to dissolve the free form of the acidic agent in monomer, dimer, trimer, etc. form; the sodium hydroxide is present in sufficient quantity to only partially form the sodium salt of the acidic pharmaceutical agent; and the small amount of water present acts to form a solvation sphere around the acid salt permitting it to go into solution in the polyethylene glycol (i.e. by mixing naproxen free acid and potassium hydroxide and dissolving in a solvent to react the naproxen free acid with the potassium hydroxide to obtain a reaction product) (e.g. column 7, lines 15-25). Yu et al. further teach that potassium hydroxide is the preferred form of hydroxide ion not only because it enhances the solubility of an acidic pharmaceutical agent to a greater extent than sodium hydroxide but also because it is less likely to result in precipitation over a wide variety of concentration ranges even at low temperatures (4° C.) as may occur during shipping (e.g. column 8, lines 16-39). Yu et al. further teach that the softgel has a minimum size of 7 for naproxen, and up to 20 (e.g. Table I). As 7 is the minimum and up to 20 is disclosed, it would have been obvious to have selected any of 7-20 as the size, including the subrange of 8-14. 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).
Yu et al. teach that by selecting the proper ratio of the free pharmaceutical agent and its salt, the solubility of that agent can be maximized (e.g. column 6, lines 1-7), but are silent as to the concentration of the potassium salt of naproxen based on a total combined weight of the naproxen free acid and the potassium salt of naproxen. This is made up for by the teachings of Lopez et al.
Lopez et al. teach an NSAID formulation for encapsulation into a soft gel capsule with increased stability, concentration and bioavailability of the NSAID, wherein the preferred NSAID includes naproxen (e.g. abstract). The pH values of fill formulations may be adjusted without additional process steps. A process for increasing the achievable concentration of an NASAID pharmaceutical ingredient in a fill composition for dosage units is also provided. The highly concentrated NASAID formulation permits a reduction in the fill volume or dosage unit size or an increase in concentration of the NSAID in each dosage (e.g. abstract). Lopez et al. teach that the amount of naproxen in the formulation ranges from about 2% to about 25% by weight with the corresponding amount of naproxen salt in the formulation ranging from about 25% to about 2% by weight. The total amount of naproxen and naproxen sodium by weight in the formulation may depend on desired capsule size, but preferably range from about 22% to about 30% by weight (e.g. paragraph 0019). This results in a range of salt of naproxen present at a concentration from about 6-93 wt% based on a total combined weight of the naproxen free acid and the potassium salt of naproxen, which overlaps the claimed range. 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).
Regarding Claim 28, it would have been obvious to one of ordinary skill in the art at the time of the instant invention to vary the naproxen salt concentration through routine experimentation to arrive at the concentration of 65-75 wt% in order to optimize the resulting product. Yu et al. teach that by selecting the proper ratio of the free pharmaceutical agent and its salt, the solubility of that agent can be maximized (e.g. column 6, lines 1-7), but are silent as to the concentration of the potassium salt of naproxen based on a total combined weight of the naproxen free acid and the potassium salt of naproxen. It is obvious to optimize within prior art conditions or through routine experimentation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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).
In addition, it would have been obvious to one of ordinary skill in the art at the time of filing to select the concentration of potassium salt of naproxen based on a total combined weight of the naproxen free acid and the potassium salt of naproxen as disclosed by Lopez et al. for use in the process of Yu et al. It would have been obvious to one of ordinary skill in the art to combine the elements as claimed by known methods with no change in their respective functions, and the combination yielding nothing more than predictable results. One of ordinary skill in the art would have predicted success as both of Yu and Lopez are directed to highly concentrated compositions of naproxen and its salt. One of ordinary skill in the art would have been motivated to seek out additional guidance because Yu et al. disclose that by selecting the proper ratio of the free pharmaceutical agent and its salt, the solubility of that agent can be maximized, but do not provide a concentration range. Lopez et al. disclose a highly concentrated NASAID formulation permits a reduction in the fill volume or dosage unit size or an increase in concentration of the NSAID in each dosage (e.g. abstract).
Regarding Claim 30, Yu et al. teach a solubility enhancing amount of hydroxide ion, preferably 0.2-1.0 mole equivalents of hydroxide ion per mole equivalent of acid in an acidic pharmaceutical agent, which overlaps with the claimed range (e.g. column 4, lines 40-43). In addition, Yu et al. exemplify a pharmaceutical composition for highly concentrated naproxen comprising a softgel composition comprising naproxen free acid and potassium hydroxide in a molar ratio of potassium hydroxide to naproxen of 0.5 (i.e. “about 0.55”) (e.g. Example IV).
Regarding Claim 34, Yu et al. exemplify a highly concentrated solution (i.e. dissolved in) comprising polyethylene glycol 600 (e.g. Example IV), which as evidenced by the instant Specification in paragraph 0052, is low molecular weight.
Claims 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 5,360,615; cited in IDS) in view of Lopez et al. (US 2013/0011470; cited in IDS) as applied to claims 28, 30, 32, 34 and 35, and further in view of Gullapalli (Journal of Pharmaceutical Sciences, 2010; cited in IDS).
Regarding Claims 28, 30, and 34, the teachings of Yu et al. and Lopez et al. are described supra. Yu et al. teach softgel formulations of naproxen and potassium hydroxide, but are silent as to processing details including a rotary die encapsulation machine, drying, and moisture content. These deficiencies are made up for by the teachings of Gullapalli.
Gullapalli teaches softgel capsules and the manufacturing process for the production of softgels (e.g. abstract). Gullapalli teaches that the manufacturing process for the production of softgels is the rotary die process, using an encapsulation machine (e.g. page 4108, column 2; Figure 1), which is followed by a drying step (e.g. page 4111, column 1) and a final moisture content of 10-15% (e.g. page 4112, column 1).
Regarding Claims 36-38, it would have been obvious to one of ordinary skill in the art at the time of filing to look to the processing steps of Gullapalli for use with the compositions and methods of Yu et al. and Lopez et al. One of ordinary skill in the art would have predicted success as both Yu and Gullapalli are directed to softgel compositions, and one would have been motivated to seek out appropriate processing steps, as Yu et al. are silent.
Response to Arguments
Applicant's arguments filed 1/13/26 have been fully considered but they are not persuasive. Arguments relevant to the current grounds of rejection will be addressed below.
Applicant argues on page 7 that Example IV of Yu has a formulation including naproxen at 35.9% by weight with potassium hydroxide at 0.50 mole equivalents. While Yu et al. uses potassium hydroxide and polyethylene glycol 600, the molar ratio of 0.50 mole equivalents of potassium hydroxide to naproxen would not result in the claimed concentration range of about 65 wt% to about 75 wt% potassium salt of naproxen. Rather, a molar ratio of 0.50 would yield approximately 50 wt% potassium salt of naproxen based on the total combined weight of naproxen free acid and potassium salt, which falls outside the claimed range.
This is not found persuasive. First, as detailed in the rejection under 112(b), it is unclear what the concentration range of claim 28 is referring to or how it is calculated, based on the current claim language. Second, Yu et al. teach that by selecting the proper ratio of the free pharmaceutical agent and its salt, the solubility of that agent can be maximized (e.g. column 6, lines 1-7) and teach a solubility enhancing amount of hydroxide ion, preferably 0.2-1.0 mole equivalents of hydroxide ion per mole equivalent of acid in an acidic pharmaceutical agent, which overlaps with the claimed range (e.g. column 4, lines 40-43). Yu et al. further explain that an unexpected result was obtained when potassium hydroxide was substituted for sodium hydroxide in the preceding discussion. At equimolar concentrations of hydroxide ion, the solubility of ibuprofen, naproxen, indomethacin and acetaminophen was greater in the presence of potassium hydroxide than in the presence of sodium hydroxide. Moreover, much greater concentrations of potassium hydroxide than sodium hydroxide could be utilized to prepare the highly concentrated solutions of the acidic pharmaceutical agents in polyethylene glycol without precipitation occurring. For example, in the case of ibuprofen in PEG 400, precipitation occurs in the presence of 0.5 or more mole equivalents of sodium hydroxide, whereas no precipitation occurs in the presence of 1.0 mole equivalents of potassium hydroxide even at 4° C. (Table 4) (e.g. column 8, lines 16-39).
Applicant further argues that the present application explains that if a softgel pharmaceutical composition comprises less than about 55 wt% of naproxen salt based on the total combined weight of naproxen free acid and naproxen salt in the fill composition, the softgel may not be as efficacious in treating and/or preventing a target condition. ([0026] of the published application.) Yu's 0.50 mole equivalent ratio would produce a composition with approximately 50 wt% naproxen salt, which is below even this minimum threshold and well below the claimed range of 65-75 wt%.
This is not found persuasive. Applicant has not provided data for the Examiner to consider. The fact that the composition “may not be as efficacious in treating and/or preventing a target condition” does not overcome the Examiner’s finding of obviousness. The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
Conclusion
No claim is allowed.
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NICOLE PLOURDE BABSON whose telephone number is (571)272-3055. The examiner can normally be reached M-Th 8-4:30; F 8-12:30.
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/NICOLE P BABSON/ Primary Examiner, Art Unit 1619
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