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 .
Election/Restrictions
Applicant’s election without traverse of group I and the species where paclitaxel is the first therapeutic agent, sirolimus is the second therapeutic. Both therapeutic agents are located in each nanoparticle, and the nanoparticles have surface functionalization in the reply filed on is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 17-18, 20, and 29-46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
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.
The factual inquiries 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 1-2, 4, 8-11, 14, 19, 21-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. (CN 102657899 – English translation referenced for citations) in view of Rypacek et al. (US PGPub No. 2003/0219562) as evidenced by Pillai et al. (Colloids and Surfaces B: Biointerfaces 2015 136:1058-1066).
Yang et al. teach a stent with a coating that comprises polymer nanoparticles in which paclitaxel and rapamycin are encapsulated in each particle at a 1:1 mass ratio (see example 3; instant claims 1, 9-11, 14, and 21-22). The polymer is poly(lactide-co-glycolide) (PLGA) and the nanoparticles are made via oil-in-water emulsion with poly(vinyl alcohol) (PVA) in the aqueous phase.(see instant claims 2 The result of this technique is PVA on the surface of the nanoparticles; thereby yielding surface functionalized nanoparticles (see Pillai et al. page 1058 second column last partial paragraph-page 1059 first column second full paragraph; instant claim 4). Yang et al. further teach the PLGA to have a size of 100-200 nm (see paragraph 59; instant claims 8 and 26). In addition to the nanoparticles, the coating also includes a coupling agent in the aqueous phase that is a silane, titanate, or aluminate that bonds the nanoparticles to the stent surface (see paragraph 23 and example 3). A particular silane is not detailed.
Rypacek et al. teach a stent with a drug releasing coating that employs silane compounds to adhere a lactone (e.g., PLGA) containing coating to the stent surface (see abstract and paragraphs 20-24). The silane generating compounds are known as coupling agents and they expand the terminology to describe them as silane activating reagents (see paragraphs 113-135 and 228-229). Rypacek et al. go on to teach that the reagent self-condenses in water and forms a polymer that reacts with or interacts with hydroxyl groups on the surface of the stent as well as the lactone (see paragraphs 229-233 and figure 2). They exemplify 3-aminopropyl)triethoxysilane as the silane activating reagent (coupling agent) (see example 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select a silane coupling agent for the coated stent of Yang et al. because it is one of three options that they detail. More specifically, selecting a silane coupling agent/silane activating reagent of Rypacek et al., namely 3-aminopropyl)triethoxysilane, would have been obvious as the simple substitution of one known element fir anther in order to yield a predictable outcome. The result would be a silane polymer matrix in which the paclitaxel and rapamycin encapsulated and PVA surface functionalized PLGA nanoparticles are dispersed. Therefore claims 1-2, 4, 8-11, 14, 19, 21-23, and 26 are obvious over Yang et al. in view of Rypacek et al. as evidenced by Pillai et al.
Claims 1-2, 4-11, 14, 19, 21-23, and 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. as applied to claims 1-2, 4, 8-11, 14, 19, 21-23, and 26 above, and further in view of Chevalier et al. (European Polymer Journal 2017 95:348–357) as evidenced by Yamamoto et al. (JP 06276931 – English translation referenced for citations).
Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. render obvious the limitations of instant claims 1-2, 4, 8-11, 14, 19, 21-23, and 26. Paclitaxel and rapamycin are both known anti-proliferative compounds (see Rypacek et al. paragraph 83). While PVA is on the surface of the paclitaxel and rapamycin containing PLGA nanoparticles, poly(L-lysine) (PLL) is not discussed as also being present on the surface.
Chevalier et al. teach PLGA nanoparticles conferred with an improved ability to deliver their drug cargo into cells due to surface modification with a cationic charge (see abstract). Here the nanoparticles are provided with a combination of PVA and PLL on their surface to yield a cationic surface charge and cloak the anionic charge present otherwise (see page 349 third-fourth full paragraphs and figure 1). The nanoparticles have a cationic zeta potential and superior efficacy at delivery of the anti-proliferative effect of their cargo as compared to those without PLL (see page 355-356, figure 7, and table 3). PLL acts as cationic surfactant in water, therefore it also meets the instant limitations of a cationic surfactant (see Yamamoto et al. abstract and page 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the PLL along with the PVA already present on the surface of the nanoparticles of Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. to improve the efficacy of their anti-proliferative drug cargo. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Therefore claims 1-2, 4-11, 14, 19, 21-23, and 25-26 are obvious over Yang et al. in view of Rypacek et al. and Chevalier et al. as evidenced by Pillai et al. and Yamamoto et al.
Claims 1-2, 4, 8-11, 14-15, 19, 21-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. as applied to claims 1-2, 4, 8-11, 14, 19, 21-23, and 26 above, and further in view of Yerlikaya et al. (Journal of Pharmaceutical Sciences 2013 102:3748-3761).
Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. render obvious the limitations of instant claims 1-2, 4, 8-11, 14, 19, 21-23, and 26. Paclitaxel and rapamycin are able to be in amorphous, semi-crystalline, or crystalline form; however the form in the PLGA particles is not detailed.
Yerlikaya et al. teach PLGA nanoparticles encapsulating paclitaxel (see abstract). The nanoparticles are made via much the same method as those of Yang et al. (see page 3749 first column last paragraph). Yerlikaya et al. go on to characterize the form of paclitaxel in the produced particles and note that it is amorphous (see page 3755 first column first full paragraph). They further detail that the form impacts the speed of dissolution, where amorphous forms release faster than crystalline, thereby permitting tuning of release kinetics (see page 3759 second column first full paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select an amorphous form for the paclitaxel in the PLGA nanoparticles of Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. This choice would have been obvious because it is likely the form they obtain during their production, in light of Yerlikaya et al., and was one of only three options for structural forms. It additionally would have been obvious in light of Yerlikaya et al. in order to permit tuning of the release kinetics as desired by the artisan of ordinary skill to meet design preferences. Therefore claims 1-2, 4, 8-11, 14-15, 19, 21-23, and 26 are obvious over Yang et al. in view of Rypacek et al. and Yerlikaya et al. as evidenced by Pillai et al.
Claims 1-2, 4, 8-14, 19, 21-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. as applied to claims 1-2, 4, 8-11, 14, 19, 21-23, and 26 above, and further in view of Toner et al. (US Patent No. 8,057,816).
Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. render obvious the limitations of instant claims 1-2, 4, 8-11, 14, 19, 21-23, and 26. Paclitaxel and rapamycin are present at a 1:1 mass ratio; however a variation of their relative proportions is not discussed.
Toner et al. teach medical devices, such as stents, that provide a combination of paclitaxel and rapamycin or an derivative to address undesired restenotic activity (see abstract, column 1 lines 36-44, column 23 lines 30-36, and claims 1 and 11). They detail a mass ratio of 7:10 to 0.1:10 as suitable for this purpose (see column 23 lines 36-50).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to apply the range of ratios of paclitaxel to rapamycin, detailed by Toner et al., on the stet of Yang et al. in view of Rypacek et al. as evidenced by Pillai et al. This modification would have been obvious because they were known to be useful for this drug combination. The result is a range that overlaps or embraces those instantly claimed, thereby rendering the claimed ranges obvious. “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)” (see MPEP 2144.05). Therefore claims 1-2, 4, 8-14, 19, 21-23, and 26 are obvious over Yang et al. in view of Rypacek et al. and Toner et al. as evidenced by Pillai et al.
Claims 1, 3-4, 7-11, 14, 16, 19, 21-22, 24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Weber (US PGPub No. 2006/0045901) in view of Ma et al. (Journal of Pharmaceutical and Biomedical Analysis 2011 54:807-811).
Weber teaches a stent with a hydrophilic coating that includes nanoparticles in which a therapeutic agent(s) is encapsulated (see abstract and paragraph 22). The coating material is exemplified as PVA and the coating may be present as multiple layers containing different concentrations of the same therapeutic agent (see paragraphs 19 and 127; instant claims 3, 24, and 27). An example details the nanoparticles as encapsulating paclitaxel (see paragraphs 126-128). Weber teaches the nanoparticles to be multilayered particles that encapsulate the therapeutic agent in a core surrounded by layers of polymers that alternate positive or negative charge in a layer by layer fashion (see paragraphs 47 and 76; instant claims 1, 7, and 21). These nanoparticles therefore have a functionalized surface, given their positive or negative surface charge (see instant claims 4 and 6). They further teach the nanoparticles to have a size that ranges from 1 to 1000 nm (see paragraph 46; instant claim 8). Additionally, therapeutic agents envisioned in the nanoparticles include both paclitaxel and rapamycin (see paragraph 52; instant claims 9-11). Non-polymeric components are also envisioned in the nanoparticles, including fatty acids (see paragraph 90; instant claim 16). While combinations of therapeutic agents are envisioned, a mixture of paclitaxel and rapamycin is not explicitly detailed.
Ma et al. teach the combination of paclitaxel and rapamycin provided at a 1:1 mass ratio in a polymer coating on a stent (see abstract and page 808 second full paragraph). They note the known synergistic relationship between the two anti-proliferative compounds against tumor cells and recognized utility against restenosis that may also experience a similar synergistic impact (see page 807-page 808 first column first partial paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate rapamycin at 1:1 as taught by Ma et al. into the exemplified nanoparticles in the PVA coated stent of Weber to improve the efficacy of their anti-proliferative drug cargo. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The combination is additionally obvious because both compounds are anti-proliferative. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06). The application of the particle size and incorporation of a fatty acid in the nanoparticles would follow due to their suggestion by Weber. The result is a range of sizes that overlap those instantly claimed, thereby rendering the claimed ranges obvious (see MPEP 2144.05; instant claims 8 and 26). The application of two such PVA layers with different therapeutic concentrations would also follow from the suggestion of Weber. Therefore claims 1, 3-4, 7-11, 14, 16, 19, 21-22, 24, and 26-27 are obvious over Weber in view of Ma et al.
Claims 1, 3-4, 7-11, 14, 16, 19, 21-22, 24, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Weber in view of Ma et al. as applied to claims 1, 3-4, 7-11, 14, 16, 19, 21-22, 24, and 26-27 above, and further in view of Mohsin et al. (Materials Science and Engineering A 2011 528:925–930), Mohsin et al. (Journal of Applied Polymer Science 2011 122:3102-3109 – henceforth Mohsin B), and Dave (US PGPub No. 2007/0200268).
Weber in view of Ma et al. render obvious the limitations of instant claims 1, 3-4, 7-11, 14, 16, 19, 21-22, 24, and 26-27. The combination of teachings provide an embodiment with a two layered arrangement composed of PVA that contains polymer nanoparticles encapsulating paclitaxel and rapamycin. The presence of a sugar and glycerol in the outer layer is not detailed.
Mohsin er al. teach of the use of PVA in biomedical applications and the benefit of including glycerol as a plasticizer (see abstract and page 3102). Specifically, they detail that the inclusion of the plasticizer confers elasticity to films cast from PVA as indicated by the lowered elastic modulus (see page 3103 first column last partial paragraph-second column first partial paragraph and page 3106 second column first-second full paragraphs and table III).
Mohsin B also teach of the benefit of plasticized PVA for biomedical applications (see abstract and page 925). Here they teach sorbitol as an effective plasticizer that confers elasticity to films cast from PVA as indicated by the lowered elastic modulus (see page 926 first column third full paragraph, page 929, and table 3).
Dave teaches a stent that includes a polymer that may be present in a coating, where one or a mixture of plasticizers can be included (see abstract and paragraphs 56, 82, and 114). Sorbitol and glycerol are envisioned plasticizers (see paragraph 82).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate sorbitol and glycerol as plasticizers in the PVA layers of Weber in view of Ma et al. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. The inclusion of a combination of plasticizers is obvious in light of the suggestion of Dave and because they are employed for the same purpose. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06). The coating layers of Weber are films of PVA and would be expected to benefit from added elasticity, given that the stent expands during use. Therefore claims 1, 3-4, 7-11, 14, 16, 19, 21-24, and 26-28 are obvious over Weber in view of Ma et al., Mohsin et al. Mohsin B, and Dave.
Conclusion
No claim is allowed.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615