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
Previous Rejections
Applicants' arguments, filed 06/01/26, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
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.
Claim(s) 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Cerdeira et al. (International Journal of Pharmaceutics, Vol. 443, 2013, pages 209-220) in view of Shen et al. (USP PG Pub. 2011/306539) and further in view of Baghel et al. ("Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs", Journal of Pharmaceutical Sciences 105, 9, 2016, pp. 2527-2544).
Cerdeira et al. discloses for very slightly water-soluble or practically water-insoluble drug substances, nanosuspensions are of great interest, as they can be formulated with up to 40% drug content in either aqueous or mixed aqueous-organic solvents, require only small amounts of non-toxic excipients, and may preserve drug stability better than other formulations (Patravale et al., 2004), see Introduction, column 1, first paragraph. Cerdeira et al. is drawn to the formation of micronazole and itraconazole nanosuspensions, as of Cerdeira, page 209, title and abstract. Cerdeira teaches the following method, as of page 210, right column, starting at bottom paragraph and going onto page 211, relevant text reproduced below:
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HPC refers to hydroxypropyl cellulose, which is a polymer, and SDS refers to sodium dodecyl sulfate, which is an anionic surfactant. As to the required step of suspending a pharmaceutically active substance in an aqueous solution of a polymer, as best understood by the examiner, the above-reproduced text suspends active substance in water dissolving hydroxypropyl cellulose. Cerdeira teaches drying, as of the above-reproduced spray drying process. As to the one or more surfactant, the above-reproduced text from Cerdeira appears to teach dissolving sodium dodecyl sulfate in water prior to drying. As such, the skilled artisan would have been motivated to have contacted the active agent with sodium dodecyl sulfate prior to the drying step. Cerdeira teaches milling, as of page 209, third line in abstract. Cerdeira teaches spray drying, as of the above-reproduced text. Cerdeira teaches the melting temperature of Itraconazole to be 168degrees Celsius, see page 210, left column, paragraph 4. Nanogrinding of drug substance is taught under section 2.2 on page 210. Thus, the art teaches formulation and drying of nanosuspensions, nanogrinding and drying process with active ingredients that have less than 10g/l of solubility along with polymer and surfactant.
The reference does not teach the claimed temperatures and time span and also the glass temperature determination with DSC exactly as claimed.
However, the reference does teach nano-dry-grinding and melting as discussed above. Therefore, it would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have manipulated the temperatures based on the guidance provided by Cerdeira et al. regarding nano-dry grinding and come to the claimed invention in combination with the guidance provided by Baghel et al. and Shen et al. as discussed below:
Shen et al. teaches a process for making particles for delivery of drug nanoparticles is disclosed herein. The process comprises the steps of (a) forming a suspension of drug nanoparticles by mixing a precipitant solution with an anti-solvent solution under micro-mixing environment, where the formed nanoparticles have a narrow particle size distribution; (b) providing an excipient to at least one of the precipitant solution, the anti-solvent solution and the suspension of drug nanoparticles, the excipient being selected to maintain said drug nanoparticles in a dispersed state when in liquid form; and (c) drying the suspension of drug nanoparticles containing the excipient therein to remove solvent therefrom, wherein removal of the solvent causes the excipient to solidify and thereby form micro-sized matrix particles, each micro-sized particle being comprised of drug nanoparticles dispersed in a solid matrix of the excipient, see abstract.
Shen et al. discloses a process for the production of nanoparticles containing cefuroxime axetil (Example 3). The active ingredient, with a melting point of 205°C, is dissolved together with sodium lauryl sulfate (SLS) and brought into contact with an anti-solvent containing lactose, hydroxypropylmethyl cellulose (HPMC) and SLS. The precipitated cefuroxime nanoparticles are spray dried at an inlet temperature of 150°C. Since HPMC has a glass transition temperature TG of 162°C, the spray drying temperature is in the claimed range from 20°C below to 30°C above the TG. The spray-dried particles have a D(90) of 768 nm (Table 5). Shen et al. teaches use of inert fillers, such as microcrystalline celluloses, lactose, dibasic calcium phosphates, saccharides, sorbitol’s, sucrose (sugar) , glucose (sugar) and/or mixtures of any of the foregoing in [0108].
The review article by Baghel et al. "Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs" by S. Baghel et al. in the Journal of Pharmaceutical Sciences 105, 9, 2016, pp. 2527-2544 describes the production of amorphous solid dispersions. Baghel et al. while teaching the process of making crystalline and amorphous nanoparticles, teaches that a material in a glassy state behaves like a brittle solid, but without crystalline structure and having only short range order. This transition is necessary because if the supercooled liquid state exists below the glass transition temperature, then a point comes whereby the crystals would have higher entropy compared to the supercooled liquid. The total entropy of the system would become negative before reaching absolute zero temperature, violating the third law of thermodynamics (entropy of perfect crystal is zero at 0 K). The glass transition is a second order thermodynamic transition characterized by a step change in the heat capacity which is also associated with change in derivative of extensive thermodynamic properties such as volume, enthalpy, and entropy. The amorphous state of a drug has a higher enthalpy, entropy, free energy, and volume as compared with the crystalline form which is responsible for its higher apparent solubility (as shown in Fig. 2), see page 3 second column, last paragraph. The reference teaches spray drying process on page 12.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have manipulated the nano-dry melting temperature and time span of the aqueous suspension as taught by Cerdeira et al. as modified by Shen et al. and Baghel et al. one of ordinary skilled would have been motivated to do so because nanoparticles are spray dried at an inlet temperature of 150°C. Since HPMC has a glass transition temperature TG of 162°C, the spray drying temperature is in the claimed range from 20°C below to 30°C above the TG. The spray-dried particles have a D(90) of 768 nm (Table 5) and Baghel et al teaches spray drying process and glass transition temperature based drying process as discussed above. Therefore, based on the guidance provided by Shen et al. and Baghel et al. depending upon the active ingredient and glass transition temperature of polymer used in the suspension, it would have been obvious to one of ordinary skill to have adjusted and manipulated the temperature and timespan for nano-dry melting process and come to the claimed invention.
Applicant’s arguments are moot in view of the rejections made above necessitated by claim amendments.
Action is final
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SNIGDHA MAEWALL whose telephone number is (571)272-6197. The examiner can normally be reached Monday thru Friday; 8:30 AM to 5PM.
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/SNIGDHA MAEWALL/ Primary Examiner, Art Unit 1612
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