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 § 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.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., EP 2982367B1 (International Publication Number WO 2014/163400 dated 09.10.2014) (hereinafter Lee), in view of Beyerinck et al. US 10,383,941 or Wang et al. CN 104224753 A, and further in view of Lee et al., US 7399486 (hereinafter Lee1).
Regarding claim 1, Lee teaches a sustained-release preparation for parenteral administration for donepezil [0007] having stable drug-releasing property for a long time by preparing donepezil as microspheres along with a biocompatible polymer and a controlled release agent. The biodegradable, biocompatible polymer is poly(lactide-co-glycolide), polylactide, polyglycolide, polycaprolactone,gelatin, hyaluronate or mixtures thereof; wherein the donepezil constitute an amount within the range recited in the claim of between 20% and 40% by weight (see table 2 [0048]. The reference generally teaches donepezil in an amount of 15% or more by weight of the microspheres [claim 1, 0008 and 0009]. Regarding instant claim 2, the reference teaches that the intrinsic viscosity of 0.5 to 1.9 dL/g; this range overlaps with the range recited in claim 2 [claim 2 and 0009]. Regarding instant claim 3, Lee states that the microspheres were sieved in sieves having 25 µm and 150 µm sizes [0022, 0027 and Examples 8 and 9]. Lee further teaches donepezil microspheres preparation method comprising the steps of: preparing a dispersion liquid by dissolving, in at least one type of solvent, donepezil or a pharmaceutically acceptable salt thereof, and a biodegradable, biocompatible polymer; forming microspheres by adding donepezil and biodegradable, biocompatible polymer solution in a hydrophilic polymer aqueous solution containing polyvinyl alcohol (a surfactant) [see Examples] (the continuous phase), agitating the same; and removing the solvent to obtain the microspheres, wherein the biodegradable, biocompatible polymer includes polylactide (see claim 12 and paragraphs [0012] and [0020]-[0022]). Regarding claim 10, the reference teaches using a sieve [0027]. Regarding instant claim 11, Lee teaches that the surfactant is polyvinyl alcohol. Regarding claim 5, the reference teaches that when 50 mg of the microspheres were completely dissolved in a mobile phase and filtrated with a 0.45 mm syringe filter to obtain a test solution, more than 80% of the drug loading could be achieved (see [0047-0048 and Table 2]). Note that the microsphere size disclosed in the reference is overlapping with the particle size recited in the claims and the microspheres are included in the same carrier, the artisan could have been capable of using the proper syringe and needle size for recovering microspheres in a similar percentage as recited in the claims through routine experimentation. Regarding instant claim 6, as discussed supra, the biocompatible polymer is poly(lactide-co-glycolide), polylactide or mixtures thereof (claim 1); since the reference suggests mixtures thereof, the microsphere composition may include two different lactides which consequently have different intrinsic viscosities. Regarding instant claim 8, the reference teaches donepezil dissolution rate which meets the required release in the claim (Table 3, Example 9-1); the only difference is the release in Day is 1 of 9.7% while the claim requires 0-8%. However, the difference of 1.7% is not significantly high; in addition, the law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. In such a situation, the applicant must show that the particular range of 1.7 less in the release of the first hour is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range.” In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). “[A] prima facie case of obviousness arises when the ranges of a claimed composition overlap the ranges disclosed in the prior art. Even without complete overlap of the claimed range and the prior art range, a minor difference shows a prima facie case of obviousness.” In re Harris, 409 F.3d 1339, 1341 (Fed. Cir. 2005). The Office has established an overlap between the claim ranges of all time periods and those of the cited prior art except for 1.7% less release in the first hour only, this would be sufficient to establish a prima facie case of obviousness. Applicant has to rebut the Office’s prima facie case of obviousness by a preponderance of the evidence.
The reference did not teach the span value of the microspheres recited currently in claim 1. However, microsphere of active agent having the claimed span value is desired and known in the art. See for example the teaching in Beyerinck at column 7, where Beyerinck teaches drug particle size that falls within the claimed range, and having a span value of less than 2.5. More specifically at column 18, Beyerinck teaches the desirability of having a homogenous particle size, or a narrow particle distribution which is also known to have a Span value. Beyerinck teaches a Span value of less than about 1.5 is known and desired in the art. Similarly, Wang teaches a composition comprising a sustained release microcapsule having average particle size ranges between 50 nm and 100 µm. see paragraph 0058. Wang further teaches a particle size distribution coefficient value or span value of less than 1.0. See paragraphs 0059 and 0103-0123.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to optimize the microsphere in Lee in view of the teaching of Beyerinck or Wang to obtain microsphere having uniform in size with the expectation to achieve a more stable and useful donepezil composition in the art. This is because Beyerinck or Wang teaches the advantageous of particle size uniformity in water-insoluble drug including more stable, high bioavailability and solubility.
Neither of the references teaches that the sustained release microspheres comprises two or more microspheres which comprise a polylactide having a different intrinsic viscosity.
Lee1 teaches a method for preparing mixed formulation of sustained release microspheres with different compositions by a continuous one-step process by continuously introducing the mixed fluids into a dryer from the two or more different fluids for preparation of sustained release microspheres containing a biodegradable polymer, a drug, an additive and a solvent with different types of contents or both of the components (abstract and claim 1). The reference teaches that the term “biodegradable polymer, as used in the reference, includes polylactide (PLA), polyglycolide (PGA) or their copolymer, poly(lactide-co-glycolide) (PLGA) among others (col. 4, lines 16-21 and claim 8). The two or more fluids of which the composition, quantity or both of one or more component are different from each other; and discloses that microspheres may be prepared by varying the type, concentration, etc. of the biodegradable polymer (see col. 2, lines 53-59, col. 3, lines 1-8 and col. 4, lines 5-15). Similarly, the reference teaches that the mixed formulation of sustained release microspheres with different compositions is prepared by a continuous one-step process by Suspending or emulsifying a drug to be encapsulated at same or different concentrations in Solutions of biodegradable polymers of different types or solutions of an identical biodegradable polymer of different concentrations (col. 5, lines 60-66). Thus, since different concentrations makes different viscosities, the limitation is properly met.
Thus, it would have been obvious to a person having ordinary skill in the art to modify the microspheres having sustained-release for donepezil and having stable drug-releasing property for a long time taught by Lee as modified by Wang by varying the type and concentration of the degradable polymer included in the microsphere and thus differ the intrinsic viscosity of the biodegradable polymer as taught by Lee 1 to modify the sustained-release for donepezil and having stable drug-releasing property for a long time disclosed in Lee as modified by Wang. Further, Lee, Wang and Lee1 are all in the same field of endeavor and pertain to sustained-release microspheres containing a drug and a lactides based polymer, and thus there is no particular difficulty in introducing the method of making microspheres comprising different types of degradable polymers such as lactides as disclosed in the Lee1 reference to the invention disclosed in Lee as modified by Beyerinck.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSAN T TRAN whose telephone number is (571)272-0606. The examiner can normally be reached Monday-Friday, 8:30 am-5:30 pm.
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/SUSAN T TRAN/Primary Examiner, Art Unit 1615
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