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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 24, 26, 38-40, and 46-47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (2020 Generation of uniform microparticles by microfluidic emulsification and solvent evaporation. Loughborough University. Thesis. https://doi.org/10.26174/thesis.lboro.12652184.v1).
Zhang discloses a step emulsification process via a multichannel microfluidic device for preparing microspheres (see abstract and page 120 last partial paragraph). This process is then employed to prepare sirolimus microspheres from a solution of sirolimus in a mixed solvent that is devoid of polymer and is dispersed in a solution of polyvinyl alcohol in water (see page 85). The result is called 100% sirolimus and contains non-spherical crystals and monodisperse, individually homogeneous microspheres (see figure 5.6). Here a solution of sirolimus in dichloromethane and isopropyl acetate is dispersed as droplets into a solution of poly(vinyl alcohol) in water via the process and results in microspheres sized at about 9.5 to 10.5 mm (page 87 last partial paragraph-page 88 and figures 5.1 and 5.5; instant claim 38). The microparticles/microspheres are washed to remove residual poly(vinyl alcohol) to avoid agglomeration (see page 57 first paragraph and page 70 first paragraph; instant claims 39-40 and 46). The produced microspheres meet the limitations of the instant microspheres having about 100 wt% sirolimus and the process performs the instantly recited method steps (see table 5-1 and page 85).The employed microfluidic chip has multiple junctions between the dispersed phase flow path and continuous phase flow path where the dispersed phase is pumped down into a cross flow of continuous phase (3D junction) (see figure 5.1; instant claims 26 and 47). Therefore claims 24, 26, 38-40, and 46-47 are anticipated by Zhang.
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.
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 24, 26, 31-33, 36, 38-41, and 46-47 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang.
Zhang discloses a step emulsification process via a multichannel microfluidic device for preparing microspheres (see abstract and page 120 last partial paragraph). This process is then employed to prepare sirolimus microspheres from a solution of sirolimus in a mixed solvent that is devoid of polymer and is dispersed in a solution of polyvinyl alcohol in water (see page 85). The result is called 100% sirolimus and contains non-spherical crystals and monodisperse, individually homogeneous microspheres (see figure 5.6). Here a solution of sirolimus in dichloromethane and isopropyl acetate is dispersed as droplets into a solution of poly(vinyl alcohol) in water via the process and results in microspheres sized at about 9.5 to 10.5 mm (page 87 last partial paragraph-page 88 and figures 5.1 and 5.5; instant claim 38). Zhang stresses the importance of washing the poly(vinyl alcohol) to avoid aggregation (see page 70 first paragraph). The microparticles/microspheres are washed to remove residual poly(vinyl alcohol) (see page 57 first paragraph; instant claims 39-40 and 46). A wash protocol is optimized/preferred for the microparticles that are prepared, where 6 to 7 washes or 8 washes are conducted by centrifuging, followed by the removal of the supernatant, the addition of 0.05 wt% aqueous polysorbate 20 (Tween® 20), and vortexing 5-10 seconds in each pass (see table 4-2, page 70, and page 76 last paragraph; instant claims 31-33, 36, 41). Washing is followed by freeze drying as the last step (see page 70). The employed microfluidic chip has multiple junctions between the dispersed phase flow path and continuous phase flow path where the dispersed phase is pumped down into a cross flow of continuous phase (3D junction) (see figure 5.1; instant claims 26 and 47). While Zhang does not explicitly state that a preferred washing procedure was employed, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ their preferred protocol when making the 100% sirolimus microspheres because of the importance Zhang places upon washing in the preparation protocol. Therefore claims 24, 26, 31-33, 36, 38-41, and 46-47 are obvious over Zhang.
Claims 24, 26, 31-34, 36, 38-41, and 46-47 are rejected under 35 U.S.C. 103 as being unpatentable Zhang as applied to claims 24, 26, 31-33, 36, 38-41, and 46-47above, and further in view of Brown B (WO 2009/129544 – previously cited).
Zhang renders obvious the limitations of instant claim 24, where the wash solution is a 0.05 wt% aqueous polysorbate 20. The microfluidic step emulsification process washes the microspheres, but does not detail the volume of wash liquid utilized.
Brown B teach a procedure for washing drug containing polymer microspheres that are generated in a production suspension (see example 5). The microspheres are washed several times (see paragraph 116). They centrifuge the suspension, remove the supernatant, followed by resuspending the microspheres in an equal volume of wash liquid (see paragraph 116; instant claim 34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to wash the microspheres in the process rendered obvious by Zhang via a known wash liquid volume employed for separating microparticles from a production suspension in light of Brown B. Specifically, the washing would entail adding an equal volume of wash solution for each wash cycle in the process. This modification would have been obvious because it was known to be effective in a similar emulsification process as detailed by Brown B. Therefore claims 24, 26, 31-34, 36, 38-41, and 46-47are obvious over Zhang in view of Brown B
Claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over McClain et al. (previously cited) in view of Coffman et al. (WO 2019/023392), Zhu et al. (previously cited), Zhang (CN 112791066 – English translation referenced for citations - henceforth Zhang B), and Vladisavijevic et al. (previously cited).
McClain et al. teach the inclusion of micronized sirolimus in implantable device coatings (see paragraphs 9 and 266). They teach the size of these particles to be 645 nm, 1.5 mm, 2.5 mm or other monodisperse, controlled sizes (see paragraph 9; instant claims 1 and 24). A particular method of production for these monodisperse particles is not detailed.
Coffman et al. teach of the production of particles of therapeutic agent made by dispersing a droplets of a solution of the therapeutic into a second liquid and evaporation of the first liquid to solidify the agent (see abstract). A variety of techniques include microfluidic droplet generation is detailed for forming droplets of the therapeutic agent solution (see page 12 lines 35-39). The solvent of the first solution may be an organic solvent where dichloromethane and isopropanol are envisioned (see page 13 line 3 and page 14 lines 5-13). They detail the first liquid may be formed into droplets within the second liquid in which the therapeutic agent is less soluble as well as the presence of a polymer stabilizer or surfactant in the second liquid when this liquid is water/aqueous (see page 16 lines 22-31, page 17 lines 1-13 26-36). An example is detailed where a drug is dissolved in an organic solvent in the absence of polymer, then dispersed as droplets in deionized water which are collected and dried (see example 59).
Zhu et al. teach that sirolimus (rapamycin) is a poorly water soluble drug (see page 738 second paragraph). They further detail the production of sirolimus containing microspheres via microfluidics as advantageous over more conventional methods because it produces more uniform microsphere populations in size and in composition (see page 738-page 739 first partial paragraph). They teach this benefit is particularly important for sirolimus that would benefit from the more precise control that microsphere delivery can provide, but requires product consistency in order to be able to reap their advantages (see page 738-page 739 first partial paragraph). The process of production employs a microfluidic oil-in-water emulsion preparation technique via a concentric capillary tube-within-capillary tube design (see page 740). A sirolimus containing solution in dichloromethane (DCM) is employed as a disperse phase solution while a solution of polyvinyl alcohol (PVA) as a stabilizer in water is employed as a continuous phase solution (see page 740; instant claims 2, 18, 20, 22, 38-40, and 46). Zhu et al. teach collecting droplets of the sirolimus containing solution within the PVA solution, evaporating the DCM, centrifuging and washing the microspheres four times in deionized water, and freeze drying the microspheres (see page 740; instant claims 1, 16, 24, 33, and 36). Zhu et al. teach that the rapamycin is in amorphous state in the microspheres (see page 746 first partial paragraph; instant claim 37).
Zhang B teaches the utility of mixed solvents to prepare microspheres composed of sirolimus in poly(lactide-co-glycolide) (PLGA) at a high load via emulsion of a solution of the sirolimus and PLGA in an aqueous poly(vinyl alcohol) phase (see abstract and paragraphs 8 and 12-20). They further detail washing and freeze drying the dispersed phase after evaporation of the dispersed phase solvent (see paragraphs 18-20). Zhang B highlights combinations of dichloromethane or ethyl acetate with benzyl alcohol, propylene carbonate or isopropanol as the dispersed phase solvent yielding high encapsulation (95%) efficiencies and loadings in excess of that made by Zhu et al. (see paragraphs 24 and 39, table 1 and example 2). A mixture of dichloromethane and isopropanol is also exemplified (see example 2).
Vladisavijevic et al. teach the production of polymer microspheres for drug delivery utilizing a microfluidic step emulsification procedure that generates an oil in water emulsion (see abstract and page 381 second column last full paragraph). The emulsification procedure employs a terraced collection of parallel arrays of microchannels with six 3D flow junctions in a silicon chip that provide the disperse phase in terraced microgrooves/microchannels and continuous phase in the cross-flow channels (see page 382 first column first full paragraph and figure 1; instant claims 1, 6, 8, and 26). They teach that the microfluidic device and procedure provide an improvement over other microfluidic microsphere production techniques due to the avoidance of problems that occur due the parallelization that is necessary when scaling up the production quantities via other microfluidic techniques (see page 381). In addition, Vladisavijevic et al. teach that the step emulsification process to be particularly good at producing monodisperse microspheres (see page 381). The disperse phase Vladisavijevic et al. employ is polylactide containing polymer blend in DCM and the continuous phase is an aqueous solution of PVA (see page 382 first column first partial paragraph; instant claims 2-3, 20, and 22). In the design 2 embodiment, Vladisavijevic et al. teach a terraced microfluidic device that has 10 sets of microgrooves with a depth of 4 mm (see page 382 first column second full paragraph, table 1, and figure 1; instant claims 9 and 28). The disperse phase is provided at 0.005 ml/h and the continuous phase is provided at 0.5 ml/h which resulted in droplets with a diameter of 14.1 mm and upon solvent evaporation resulted in microspheres of 4.9 mm in diameter that are suitable for injection (see page 382 second column first partial paragraph and page 389 first column first full paragraph). The ratio of the droplet to the microsphere diameter is 2.9. Vladisavijevic et al. teach the design 1 embodiment to have the same number of microgrooves, but sized with a depth of 5 mm (see table 1). Here the disperse phase is provided at 0.05 ml/h and the continuous phase is provided at 1 ml/h which resulted in droplets with a diameter of 25.5 mm and dried microspheres of 8.8 mm (see page 382 second column first partial paragraph and page 389 first column first full paragraph). The ratio of the droplet to the microsphere diameter is 2.9. They attribute the difference in size generated by the two device designs to the difference in equivalent diameter of the microchannels in the devices, thereby making droplet/particle size a result effective variable (see page 387 first column last partial paragraph-second column first partial paragraph). Vladisavijevic et al. detail that the microfluidic device is operated in the dripping regime (see page 386 first column first paragraph; instant claims 11 and 25).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the micronized sirolimus for the device of McClain et al. via the precipitation of an emulsion of sirolimus prepared in a step emulsification device as suggested by Vladisavijevic et al. because they are taught to generate the monodisperse particle sizes McClain et al. desire. and microfluidic processes are suggested by Zhu et al. for sirolimus. As a result, it would have been obvious to prepare a solution of sirolimus in DCM and isopropanol as the organic phase and PVA as the stabilizing surfactant in an aqueous phase because this solvent and aqueous phase were known to be suitable for generating high drug load sirolimus particles via emulsion in light of Zhang B. This preparation being devoid of polymer in the sirolimus solution would have been obvious to generate the sirolimus particles desired by McClain et al. and in light of Coffman et al. who identified microfluidic techniques of preparing oil-in-water emulsions to generate drug particles without a polymer carrier. Adjustment of the dimension of the terraces and channels in Vladisavijevic et al. to attain the needed uniform droplet size for particles sized as desired by McClain et al. would have been obvious in light of their teachings that these are result effective variables (see Vladisavijevic et al. page 390 first column first full paragraph). Further centrifuging, washing, and freeze drying the resultant particles as taught by Zhu et al. also would follow as the application of the same technique to a similar process in order to yield the same improvement (e.g. removal of excess continuous phase material). This process mirrors that of the instant example which produces “pure” drug particles (see instant example 5). The scope of the term “about” is not defined by the instant disclosure, therefore the particles rendered obvious by McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. which have sirolimus, potentially with some residual PVA on their surface, qualify as being about 100% sirolimus. Thus claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al.
Claims 24-26, 28, 31, 33, 35-40, 46-47, 49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. as applied to claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 above, and further in view of Aboody et al. (previously cited).
McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. render obvious the limitations of instant claim 24. Zhu et al., within the modified teachings, detail washing the microspheres four times.
Aboody et al. teach the production of microparticles via oil-in-water emulsion of a dichloromethane solution in a water containing polyvinyl alcohol (see paragraph 211). Here six washing steps are conducted where the microparticles are centrifuged and resuspended in wash liquid a series of times (see paragraph 211; instant claim 31).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ six washing steps instead of four in the process rendered obvious by McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. This modification would have been obvious so as to further ensure removal of undesired preparatory materials from the final microspheres and because it was known to be a suitable number of washing times for similar microspheres made via emulsion as taught by Aboody et al. Therefore claims 24-26, 28, 31, 33, 35-40, 46-47, 49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Aboody et al.
Claims 24-26, 28, 32-33, 35-40, 46-47, 49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. as applied to claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 above, and further in view of Yuan et al. (previously cited).
McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. render obvious the limitations of instant claim 24. Zhu et al., within the modified teachings, detail washing the microspheres four times.
Yuan et al. teach the production of microparticles via oil-in-water emulsion of a dichloromethane solution in a water containing polyvinyl alcohol (see paragraphs 26 and 40-46). Here ten washing steps are conducted (see paragraph 46; instant claim 32).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ ten washing steps instead of four in the process rendered obvious by McClain et al. in view of Zhu et al., Coffman et al., and Vladisavijevic et al. This modification would have been obvious so as to further ensure removal of undesired preparatory materials from the final microspheres and because it was known to be a suitable number of washing times for similar microspheres made via emulsion as taught by Yuan et al. Therefore claims 24-26, 28, 32-33, 35-40, 46-47, 49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Yuan et al.
Claims 24-28, 33, 35-40, 46-49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. as applied to claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 above, and further in view of Kobayashi et al. (previously cited).
McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. render obvious the limitations of instant claim 24. The microfluidic step emulsification device of Vladisavijevic et al. has six 3D flow junctions and a ratio of continuous phase.
Kobayashi et al. teach a terraced microfluidic step emulsification device similar to that of Vladisavijevic et al. for producing monodisperse droplets and it also has seven 3D flow junctions (see abstract and figure 1; instant claims 27 and 48).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a seven 3D flow channel version of the device of Vladisavijevic et al. for the process rendered obvious by McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. This modification would have been obvious so as to have additional locations to generate microspheres in a larger quantity over a given time. Further, Kobayashi et al. detail that this number of junctions had been previously used in a similar emulsification process. Therefore claims 24-28, 33, 35-40, 46-49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Kobayashi et al.
Claims 24-26, 28, 33, 35-41, 46-47, 49, and 51 is rejected under 35 U.S.C. 103 as being unpatentable over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. as applied to claims 24-26, 28, 33, 35-40, 46-47, 49, and 51 above, and further in view of Bley et al. (previously cited).
McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic et al. render obvious the limitations of instant claim 24 where the microspheres are washed several times. The modified teachings do not detail the presence of polysorbate 20 (Tween® 20) in the wash solution.
Bley et al. teach the production of microparticles via oil-in-water emulsion of a dichloromethane solution in a water containing polyvinyl alcohol (see paragraphs 175 and 177). A washing procedure for the microspheres is detailed where a 0.01 to 0.05 wt% aqueous polysorbate 20 solution is employed as the wash liquid to deter agglomeration (see paragraph 177; instant claim 41).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a 0.01 to 0.05 wt% aqueous polysorbate 20 as the wash solution for the microspheres in the process rendered obvious by McClain et al. in view of Coffman et al., Zhu et al., Zhang B, and Vladisavijevic 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, in light of Bley et al. The taught concentration range is narrow and embraces that instantly claimed, thereby rendering it obvious. Therefore claims 24-26, 28, 33, 35-41, 46-47, 49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Bley et al.
Claims 24-26, 28, 33-41, 46-47, 49, and 51 are rejected under 35 U.S.C. 103 as being unpatentable over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Bley et al. as applied to claims 24-26, 28, 33, 35-41, 46-47, 49, and 51 above, and further in view of Burke et al. (previously cited) and Brown B.
McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Bley et al. render obvious the limitations of instant claim 24, where the wash solution is a 0.05 wt% aqueous polysorbate 20. The microfluidic step emulsification process washes the microspheres, but does not detail the volume of wash liquid utilized or vortexing during the washing process.
Burke et al. teach the preparation of drug containing PLGA microspheres via an emulsion process (see paragraphs 173-179). The emulsion is centrifuged and decanted prior to the addition of wash liquid (see paragraph 179). The mixture is sonicated for 10 minutes, vortexed for 5 seconds, and centrifuged for each wash cycle (see paragraph 179; instant claim 34).
Brown B teach a procedure for washing drug containing polymer microspheres that are generated in a production suspension (see example 5). The microspheres are washed several times (see paragraph 116). They centrifuge the suspension, remove the supernatant, followed by resuspending the microspheres in an equal volume of wash liquid (see paragraph 116; instant claim 34).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to wash the microspheres in the process rendered obvious by McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., and Bley et al. via known wash procedures for separating microparticles from a production suspension in light of Brown B and Burke et al. Specifically, the washing would entail centrifuging the microparticle suspension, removing its supernatant, adding an equal volume of wash solution, and resuspending via vortex for 15 seconds for each wash cycle in the process. This modification would have been obvious because it was known to be effective in a similar emulsification process as detailed by Brown B and Burke et al. The teaching of 15 seconds meets the limitation of about 10 seconds because the term “about” has not been given a limiting definition that defines it otherwise (see instant claim 34). Therefore claims 24-26, 28, 33-41, 46-47, 49, and 51 are obvious over McClain et al. in view of Coffman et al., Zhu et al., Zhang B, Vladisavijevic et al., Bley et al., Brown B, and Burke et al.
Claims 24, 26, 31-33, 35-36, 38-41, 46-47, and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Liggins et al. (US PGPub No. 2008/0124400) in view of Zhang B and Zhang.
Liggins et al. teach high drug loaded polymer microspheres, where the polymer has monomers that may be selected from a grouping that includes lactic acid and glycolic acid and the drug may be sirolimus (rapamycin) (see abstract, paragraph 15 claims 1-6). PLGA is exemplified as the polymer (see example 3). The drug concentration is envisioned to be high such that it exceeds 75 wt% and is further envisioned to exceed 90 or 95 wt% (see paragraph 6 and claim 1). They additionally teach emulsification of a solution of drug and polymer into a non-solvent and evaporation of the dispersed phase solvent as a technique to prepare the microspheres (see paragraph 49, example 3, and table 12). Sirolimus is not exemplified in the microspheres.
Zhang B teaches sirolimus as a drug that is desirable in microsphere form to facilitate injection administration of high doses and to avoid low bioavailability of oral administration (see paragraphs 1-5). They teach the utility of employing mixed solvents to prepare microspheres composed of sirolimus in PLGA at a high load in excess of 45 wt% via emulsion in an aqueous poly(vinyl alcohol) phase (see abstract and paragraphs 8 and 12-20). They highlight combinations of dichloromethane or ethyl acetate with benzyl alcohol, propylene carbonate or isopropanol yielding high encapsulation (95%) efficiencies (see paragraphs 24 and 39, table 1 and example 2). A mixture of dichloromethane and isopropanol is also exemplified (see example 2).
Zhang teaches a step emulsification process via a multichannel microfluidic device for preparing microspheres of sirolimus (see abstract and page 120 last partial paragraph). They suggest the method to attain uniform microspheres to facilitate precision in controlled release to overcome the poor water solubility of sirolimus (see pages 1-2). This process is then employed to prepare sirolimus microspheres at various concentrations from 33 to 67% with PLGA (see pages 85, 88-92, figures and tables included). Here the dispersed phase is a solution in dichloromethane and isopropyl acetate dispersed as droplets into a solution of poly(vinyl alcohol) in water via the process and results in microspheres sized at about 7 to 10.5 mm, depending on the formulation (page 85 and 87 last partial paragraph-pages 88, 93 and figures 5.1- and 5.5; instant claim 38). Zhang teaches that the mixture of PLGA and sirolimus at higher sirolimus concentration tended to separate within the microspheres made from their mixed dichloromethane and isopropyl acetate solvents (see page 92 and figures 5.6-5.7). However, an increase in the ratio of continuous phase flowrate to disperse phase flowrate produced a more homogeneous mixture that increased with its increasing value which they test at 185, 384, and 406 (see page 94 last paragraph and figure 5.8). Thus this parameter is a result effective variable. Zhang further stresses the importance of washing the poly(vinyl alcohol) to avoid aggregation (see page 70 first paragraph). The microparticles/microspheres are washed to remove residual poly(vinyl alcohol) (see page 57 first paragraph; instant claims 39-40 and 46). A wash protocol is optimized/preferred for the microparticles that are prepared, where 6 to 7 washes or 8 washes are conducted by centrifuging, followed by the removal of the supernatant, the addition of 0.05 wt% aqueous polysorbate 20 (Tween® 20), and vortexing 5-10 seconds in each pass (see table 4-2, page 70, and page 76 last paragraph; instant claims 31-33, 36, 41). Washing is followed by freeze drying as the last step (see page 70). The employed microfluidic chip has multiple junctions between the dispersed phase flow path and continuous phase flow path, where the dispersed phase is pumped down into a cross flow of continuous phase (3D junction) (see figure 5.1; instant claims 26 and 47).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make sirolimus containing PLGA microspheres of Liggins et al. via the method/apparatus of Zhang. This choice would have been obvious because sirolimus is desirable in PLGA microspheres, as detailed by both Zhang and Zhang B, and so as to obtain a uniform population of the microspheres as the application of the same technique to a similar product in order to yield the same improvement. The teachings of Zhang and Zhang B provide solvent combinations that achieve high loading levels of sirolimus in PLGA recognized by the artisan of ordinary skill. The optimization of the ratio of continuous phase flowrate to dispersed phase flowrate would have been obvious as a matter of routine experimentation to attain homogeneous microspheres. The application of the preferred washing regimen of Zhang would then follow because they stress the importance of washing the microspheres. The scope of the term “about” is not defined by the instant disclosure, thus the recitation “about 100%” creates a range of sirolimus proportions in the microspheres. Liggins et al. yield overlapping teachings of greater than 90 wt% and greater than 95 wt% that render this range obvious (see MPEP 2144.05). Therefore the particles rendered obvious by Liggins et al. in view of Zhang B and Zhang qualify as being about 100% sirolimus. The microsphere size also overlaps with the instant range that is recited as “less than about 8 mm”, thereby rendering it obvious as well (see MPEP 2144.05; instant claim 51). Therefore claims 24, 26, 31-33, 35-36, 38-41, 46-47, and 50-51 are obvious over Liggins et al. in view of Zhang B and Zhang.
Claims 24-26, 28, 31-33, 35-36, 38-41, 46-47, and 49-51 are rejected under 35 U.S.C. 103 as being unpatentable over Liggins et al. in view of Zhang B and Zhang as applied to claims 24, 26, 31-33, 35-36, 38-41, 46-47, and 50-51 above, and further in view of Jhunjhunwala et al. and Vladisavijevic et al.
Liggins et al. in view of Zhang B and Zhang render obvious the limitations of instant claim 24. A terraced microgroove containing microfluidic chip is not explicitly detailed.
Jhunjhunwala et al. teach that it was desirable to delivery rapamycin to dendritic cells as an immunosuppressant (see page 191 second column last partial paragraph). The best size for biodegradable microparticle delivery of rapamycin to these cells is 1 to 10 m (see page 192 first column first full paragraph; instant claim 51). They go on to teach PLGA microspheres loaded with rapamycin (sirolimus) via an emulsification process (see page 192 first column second full paragraph).
Vladisavijevic et al. teach the production of polymer microspheres for drug delivery utilizing a microfluidic step emulsification procedure that generates an oil in water emulsion (see abstract and page 381 second column last full paragraph). The emulsification procedure employs a terraced collection of parallel arrays of microchannels with six 3D flow junctions in a silicon chip that provide the disperse phase in terraced microgrooves/microchannels and continuous phase in the cross-flow channels (see page 382 first column first full paragraph and figure 1; instant claims 26, 47, and 49). They teach that the microfluidic device and procedure provide an improvement over other microfluidic microsphere production techniques due to the avoidance of problems that occur due the parallelization that is necessary when scaling up the production quantities via other microfluidic techniques (see page 381). In addition, Vladisavijevic et al. teach that the step emulsification process to be particularly good at producing monodisperse microspheres (see page 381). The disperse phase Vladisavijevic et al. employ is a polylactide containing polymer blend in DCM and the continuous phase is an aqueous solution of PVA (see page 382 first column first partial paragraph). In the design 2 embodiment, Vladisavijevic et al. teach a terraced microfluidic device that has 10 sets of microgrooves with a depth of 4 m (see page 382 first column second full paragraph, table 1, and figure 1; instant claim 28). The disperse phase is provided at 0.005 ml/h and the continuous phase is provided at 0.5 ml/h which resulted in droplets with a diameter of 14.1m and upon solvent evaporation resulted in microspheres of 4.9 m in diameter that are suitable for injection (see page 382 second column first partial paragraph and page 389 first column first full paragraph). The ratio of the droplet to the microsphere diameter is 2.9. Vladisavijevic et al. teach the design 1 embodiment to have the same number of microgrooves, but sized with a depth of 5 m (see table 1). Here the disperse phase is provided at 0.05 ml/h and the continuous phase is provided at 1 ml/h which resulted in droplets with a diameter of 25.5m and dried microspheres of 8.8 m (less than about 8 m) (see page 382 second column first partial paragraph and page 389 first column first full paragraph; instant claim 51). The ratio of the droplet to the microsphere diameter is 2.9. They attribute the difference in size generated by the two device designs to the difference in equivalent diameter of the microchannels in the devices, thereby making droplet/particle size a result effective variable (see page 387 first column last partial paragraph-second column first partial paragraph). Vladisavijevic et al. detail that the microfluidic device is operated in the dripping regime (see page 386 first column first paragraph; instant claim 25).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make sirolimus microspheres of Liggins et al. in view of Zhang B and Zhang with the microfluidic device of Vladisavijevic et al. so as to make them monodisperse and size them within the 1 to 10 m range that is taught by Jhunjhunwala et al. so as to be useful for immunosuppression. This modification would have been obvious as the application of the same technique to a similar product in order to yield the same improvement. Given the ratio of the in-process droplet to the microsphere diameter is 2.9 when made as taught by Vladisavijevic et al., the corresponding in-process droplet size would be about 2.9 to 29 m. Microspheres on the lower end of the size range of Jhunjhunwala et al. are therefore attainable with the step emulsification apparatus/method of Vladisavijevic et al. and overlap with those instantly claimed; thereby rendering the instantly claimed diameter range obvious (see MPEP 2144.05; instant claim 51). Therefore claims 24-26, 28, 31-33, 35-36, 38-41, 46-47, and 49-51 are obvious over Liggins et al. in view of Zhang B, Zhang, Jhunjhunwala et al., and Vladisavijevic et al.
Claims 24-28, 31-33, 35-36, 38-41, and 46-51 are rejected under 35 U.S.C. 103 as being unpatentable over Liggins et al. in view of Zhang B, Zhang, Jhunjhunwala et al., and Vladisavijevic et al. as applied to claims 24-26, 28, 31-33, 35-36, 38-41, 46-47, and 49-51 above, and further in view of Kobayashi et al.
Liggins et al. in view of Zhang B, Zhang, Jhunjhunwala et al., and Vladisavijevic et al. render obvious the limitations of instant claim 24. The microfluidic step emulsification device of Vladisavijevic et al. has six 3D flow junctions and a ratio of continuous phase.
Kobayashi et al. teach a terraced microfluidic step emulsification device similar to that of Vladisavijevic et al. for producing monodisperse droplets and it also has seven 3D flow junctions (see abstract and figure 1; instant claim 27).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a seven 3D flow channel version of the device of Vladisavijevic et al. for the process rendered obvious by Zhu et al. in view of Jhunjhunwala et al., Vladisavijevic et al., and Liggins et al. This modification would have been obvious so as to have additional locations to generate microspheres in a larger quantity over a given time. Further, Kobayashi et al. detail that this number of junctions had been previously used in a similar emulsification process. Therefore claims 24-26, 28, 33, 35-40, 46-49, and 51 are obvious over Liggins et al. in view of Zhang B, Zhang, Jhunjhunwala et al., Vladisavijevic et al., and Kobayashi et al.
Claims 24, 26, 31-36, 38-41, 46-47, and 50-51 are rejected under 35 U.S.C. 103 as being unpatentable over Liggins et al. in view of Zhang B and Zhang as applied to claims 24, 26, 31-33, 35-36, 38-41, 46-47, and 50-51 above, and further in view of Brown B.
Liggins et al. in view of Zhang B and Zhang render obvious the limitations of instant claim 24, where the wash solution is a 0.05 wt% aqueous polysorbate 20. The microfluidic step emulsification process washes the microspheres, but does not detail the volume of wash liquid utilized.
Brown B teach a procedure for washing drug containing polymer microspheres that are generated in a production suspension (see example 5). The microspheres are washed several times (see paragraph 116). They centrifuge the suspension, remove the supernatant, followed by resuspending the microspheres in an equal volume of wash liquid (see paragraph 116).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to wash the microspheres in the process rendered obvious by Liggins et al. in view of Zhang B and Zhang via a known wash liquid volume employed for separating microparticles from a production suspension in light of Brown B. Specifically, the washing would entail adding an equal volume of wash solution for each wash cycle in the process. This modification would have been obvious because it was known to be effective in a similar emulsification process as detailed by Brown B. Therefore claims 24-26, 28, 31-36, 38-41, 46-47, and 50-51 are obvious over Liggins et al. in view of Zhang B, Zhang, and Brown B
Response to Arguments
Applicant's arguments filed October 1, 2025 have been fully considered. In light of the amendment to the claims, the rejection under 35 USC 112(b) is hereby withdrawn as are those under 35 USC 103 over Zhu et al. as the primary reference under. The rejection under 35 USC 103 over McClain et al. in view of others is modified to address the new limitations in light of the amendment. New grounds of rejection are also made to address the new claims.
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 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.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615
/Robert A Wax/ Supervisory Patent Examiner, Art Unit 1615