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 .
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 1-5 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.
Regarding claims 1 and 3, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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, 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.
Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Haeger (US 5,173,488) in view of Stella et al., (International Journal of Pharmaceutics, 2020).
Haeger teaches, “Injectable aqueous compositions comprising folic acid and leucovorin and their salts, optionally including benzyl alcohol, sodium chloride and agents for adjusting pH are stabilized and buffered in the range of 6 to 10 by adding a combination of tromethamine and monothioglycerol” (Abstract).
Haeger teaches a specific embodiment below:
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(col. 15, lines 15-30). Here, the amount of Leucovorin is 11 mg/mL; the amount of Sodium Chloride 5.6 mg/mL; water for injection is present; the pH is adjusted using hydrochloric acid and sodium hydroxide, as per claim 1. The amount of tromethamine is 1.5 mg/mL but can be adjusted to about 8 mg/mL, as claimed, insofar as Haeger teaches that the amount of tromethamine “can range from 0.1 to about 1.0%”, i.e., from 1mg/mL to 10mg/mL (col. 4, lines 55-57).
Concerning claim 2 and 4, Haeger teaches, “sodium chloride at a concentration from 0.45% to 0.65% w/v” (col. 3, lines 46-47), which is close enough to address the claimed amount of about 4mg/mL.
Concerning claim 3, Haeger teaches, “Water for Injection . . . is added to a stainless steel mixing tank” and “ingredients are sequentially added, mixed and dissolved in the following order: benzyl alcohol; sodium chloride; tromethamine; monothioglycerol; and calcium leucovorin. The pH is then adjusted to 8.1±0.1 with 5% hydrochloric acid and/or 1% sodium hydroxide. The batch is brought to a final volume of 20-30 liters with Water for Injection sparged with nitrogen” (col. 5, lines 53-66). Here the prior art makes obvious the sequential addition of ingredients followed by a final volume adjustment with Water for Injection.
Concerning claim 5, the formulation is filtered through “a 0.2 micrometer filtration cartridge” and transferred to containers, i.e. “It is fed from the surge bottle to filling needles which eject measured doses to conveyor fed ampules and vials” (col. 6, lines 1-20).
Haeger does not teach Betadex Sulfobutyl Ether Sodium (SBE-β-CD) or Hydroxy Propyl Beta Cyclodextrin (HP-β-CD) as a stabilizer and solubilizer.
Stella et al. teaches “some of the backstories behind the discovery and development of sulfobutylether-β-cyclodextrin as a novel parenterally safe solubilizer and stabilizer”, wherein the cyclodextrin “is known by its commercial name, Captisol®. Today it is in 13 FDA approved injectables and numerous clinical candidates” (Abstract). Furthermore, Captisol® is used “to meet solubility and chemical stability goals for the product” (p. 7, left column, 4th paragraph).
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)” (see MPEP 2144.07).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to add sulfobutylether-β-cyclodextrin to the compositions of Haeger et al. based on its art recognized suitability for its intended use as solubilizer/stabilizer in parenteral formulations, as well as, for the advantage of meeting solubility and chemical stability goals for the product. The artisan would have had a reasonable expectation of success with the combination insofar as the sulfobutylether-β-cyclodextrin is suitable for parenteral administration.
The prior art is silent concerning suitable amounts of sulfobutylether-β-cyclodextrin; however given its function as a solubilizer and stabilizer, it would have been obvious to optimize a range. Accordingly, "[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" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)).
Technological Background
The prior art made of record and considered pertinent to applicant's disclosure Brewster et al., (European Journal of Pharmaceutical Sciences, 2008). Brewster et al. is pertinent for teaching, “The current data assess the ability of hydrophilic cyclodextrins to solubilize compounds via stabilization of supersaturated drug solutions presumably by inhibition of nucleation and arresting crystal growth” (Abstract). In consideration of the stabilizing effect of HPβCD, the reference teaches, “This may suggest the mechanism other than simple complex formation are responsible for the stabilizing effects which may include inhibition of nucleation and crystal growth” (p. 100, left column, last paragraph).
Conclusion
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER E WEBB whose telephone number is (571)270-3287 and fax number is (571) 270-4287. The examiner can normally be reached from Mon-Fri 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612
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