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 .
In view of the amendment, previous 112(b) rejection is hereby withdrawn.
In view of applicant’s argument, previous 103 rejections over Jenkins et al’806 in view of Schiraldi et al’243 and Lindsley et al (WO’783) are withdrawn and replaced by the new 103 rejection shown below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 5, 7, 9-11, 15-19 and 22-29 are rejected under 35 U.S.C. 103 as being unpatentable over Jenkins et al (US 2009/0252806 A1) in view of Schiraldi et al (4,713,243), Vaughn et al (WO 2008/028047 A2) and HOLM et al (US 2011/0263632 A1).
Jenkins teaches (claim 1) a nanoparticulate dispersion of tacrolimus comprising particles of tacrolimus having an effective average particle size of less than 2 mm and at least one surface stabilizer. Jenkins teaches ([0027]) that its nanoparticulate tacrolimus formulations are used for the prophylaxis of organ rejection, specifically in patients receiving allogenic liver or kidney transplants. Jenkins teaches (claim 4) that its nanoparticulate dispersion can be administered buccally as a controlled release formulation.
Jenkins does not teach instant mucoadhesive layer of claim 1. Schiraldi teaches (claims 1 and 7) a controlled-releasing medicament-containing extruded single or multi-layered thin film as shown below:
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Schiraldi teaches (col.1, lines 17-21, col.2, lines 14-23) that its bioadhesive extruded film is so thin and flexible when wet as to be unobtrusive to the patient after it has been properly positioned and placed in the mouth. Schiraldi also teaches that its film can be easily applied, has little or no mouthfeel, has good adhesion to the mucosal tissues and provides controlled release of the medicament and thus teaches that it is an effective and convenient intra-oral drug delivery system. Since Jenkins also teaches that its nanoparticulate tacrolimus dispersion can be administered buccally as a controlled release formulation, it would have been obvious to one skilled in the art to use Schiraldi’s bioadhesive extruded film to deliver Jenkins’s tacrolimus buccally with a reasonable expectation that such bioadhesive film would be easily applied, would have little mouthfeel and good adhesion to the mucosal tissue while effectively providing controlled release of the tacrolimus in an unobtrusive way.
With respect to instant tacrolimus contained in the mucoadhesive layer, Schiraldi teaches in claim 1 that the medicament is contained in the bioadhesive film, and the medicament may be incorporated into any or all of the layers (see col.2, lines 52-56). Thus, it would have been obvious to one skilled in the art to include Jenkins’s tacrolimus in the bioadhesive layer (instant mucoadhesive layer of claim 1) of Schiraldi’s bioadhesive extruded film with a reasonable expectation of success.
With respect to instant cellulose derivative, Schiraldi teaches (claim 1) that its bioadhesive layer also contains a hydroxypropyl cellulose (instant cellulose derivative of claims 1 and 5).
With respect to instant mucoadhesive polymer of claim 1, Jenkins in view of Schiraldi does not teach instant mucoadhesive polymer. Vaughn teaches (abstract, pg.5, lines 5-13) bioadhesive/mucoadhesive films that include a therapeutic agent and mixture of polyethylene oxide homopolymers having different molecular weights. Vaughn teaches (pg.3, 1st paragraph) that such bioadhesive film is smooth and non-tacky at room temperature, is mucoadhesive when moistened and placed in contact with a mucosal surface, and is formed using a hot-melt extrusion process. Vaughn teaches that the bioadhesive film results in controlled delivery of the therapeutic agent over a period of not less than 2 hours, 4 hours, 6 hours or 8 hours (see pg.3, lines 16-19). (i) Vaughn further teaches (pg.5, last paragraph – pg.6, 1st paragraph) that the PEO homopolymer (which Schiraldi teaches) may be combined with a secondary bioadhesive polymer to improve the bioadhesive properties of the film compositions, and as one of the examples for such bioadhesive polymer, Vaughn teaches a copolymer of methyl vinyl ether and maleic acid anhydride (instant mucoadhesive polymer of claim 1, which is (d) copolymers of methyl vinyl ether and maleic anhydride). Since Schiraldi’s bioadhesive layer already contains polyethylene oxide (PEO) homopolymer, it would have been obvious to one skilled in the art to further contain a secondary bioadhesive polymer such as a copolymer of methyl vinyl ether and maleic acid anhydride in Schiraldi’s bioadhesive layer with a reasonable expectation of further improving the bioadhesive properties of the bioadhesive extruded film. (ii) Alternatively, Vaughn also teaches (see pg.6, lines 10-13 and claims 7-8) using the combination of the mixture of polyethylene oxide homopolymers (as a primary matrix material) and one or more secondary hydrophilic or hydrophobic polymers. Among the examples for the hydrophilic polymers, Vaughn teaches (pg.3, last paragraph – pg.4, 1st paragraph) polyvinyl pyrrolidone (PVP), and among the examples for the hydrophobic polymers, Vaughn teaches (pg.4, 2nd paragraph) polyvinyl acetate. Since Schiraldi’s bioadhesive layer already contains polyethylene oxide homopolymer, it would have been obvious to one skilled in the art to further contain a secondary hydrophilic or hydrophobic polymer such as PVP or polyvinyl acetate (instant mucoadhesive polymer of claim 1, which is (e) polymers comprising polyvinyl acetate and/or polyvinylpyrrolidone) in Schiraldi’s bioadhesive layer with a reasonable expectation of further improving the bioadhesive properties of the bioadhesive extruded film and achieving a bioadhesive and mucoadhesive extruded film which is smooth and non-tacky at room temperature..
Thus, Jenkins in view of Schiraldi and Vaughn teaches a mucoadhesive layer comprising tacrolimus, instant mucoadhesive polymer and instant cellulose derivative.
With respect to instant limitation “wherein the tacrolimus is in a molecularly dissolved non-nanoparticle form”, Jenkins in view of Schiraldi and Vaughn does not teach such limitation. Holm et al teaches (see abstract, [0001], [0014]) that tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or a solid solution at ambient temperature has improved bioavailability. Holm teaches ([0034]) that in a preferred embodiment, the active ingredient (tacrolimus) is fully dissolved in the vehicle to form a solid solution. Holm teaches ([0022]) that the solid solution denotes a drug or an active ingredient dissolved on a molecular level in an inert vehicle, carrier, diluent or matrix in a solid state. It would have been obvious to one skilled in the art to have Jenkin’s tacrolimus fully dissolved in a hydrophilic vehicle to form a solid solution so as to achieve improved bioavailability of tacrolimus. Thus, Jenkins in view of Schiraldi, Vaughn and Holm teaches instant limitation “wherein the tacrolimus is in a molecularly dissolved non-nanoparticle form” (since the tacrolimus is fully and molecularly dissolved in the vehicle to form a solid solution, it is in non-nanoparticle form).
With respect to instant limitation “wherein the mucoadhesive layer comprises about 1.5 mg to about 3.5 mg of the tacrolimus per 1 cm2 of the mucoadhesive layer”,
Jenkins teaches ([0202]-[0203]) that the tacrolimus should be administered in a therapeutically effective amount which can be determined empirically and that the dosage level of tacrolimus may be varied to obtain the amount that is effective based on the particular composition, method (i.e., route) of administration, the desired duration of treatment, and other factors. Jenkins further teaches ([0204]) that the dosage unit compositions may contain such amounts of submultiples thereof as may be used to make up the daily dose and that the specific dose level for any patient will depend on the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the agent; the duration of the treatment and like factors well known in medical arts. Thus, instant limitation as to the tacrolimus weight per area would have been obvious to one skilled in the art because determining the optimum effective amount for tacrolimus that is to be contained per 1 cm2 of the bioadhesive layer (instant mucoadhesive layer), and the optimum effective amount of the bioadhesive layer per square meter in Schiraldi’s bioadhesive extruded film (instant mucoadhesive film) that would provide the maximum benefit of tacrolimus in the prophylaxis of organ rejection for patients receiving allogenic liver or kidney transplants would be within a realm of one of ordinary skill in the art. Besides, (i) since Jenkins teaches that the tacrolimus should be administered in a “therapeutically effective amount”, which Jenkins defines ([0059]) as a drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment, and (ii) since both Jenkins ([0027]) and applicant (pg.9, lines 15-18) teach that macrolide (Tacrolimus) is administered for the prophylaxis of organ rejection, specifically in patients receiving allogenic liver or kidney transplants (i.e., since Jenkins teaches that the tacrolimus should be used in an amount that is therapeutically effective to prevent organ rejection, specifically in patients receiving allogenic liver or kidney transplants), instant range (about 1.5 mg to about 3.5 mg per 1 cm2 of the mucoadhesive layer) for the amount of tacrolimus would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980)). Thus, Jenkins’s teaching renders obvious instant limitation “wherein the mucoadhesive layer comprises about 1.5 mg to about 3.5 mg of the tacrolimus per 1 cm2 of the mucoadhesive layer”.
Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claims 1, 5, 15, 19 and 23.
With respect to instant claims 7 and 22, as discussed above, Schiraldi’s bioadhesive layer as modified by Vaughn’s teaching would contain a homopolymer of ethylene oxide and instant mucoadhesive polymer (either (d) copolymers of methyl vinyl ether and maleic anhydride, or (e) polymers comprising polyvinyl acetate and/or polyvinylpyrrolidone). As discussed above, Schiraldi also teaches that its bioadhesive layer contains hydroxypropyl cellulose and a plasticizer (see claim 1). Schiraldi further teaches (claim 1) that a water-insoluble polymer, such as ethyl cellulose, propyl cellulose, polyethylene and polypropylene, can be included in the bioadhesive layer. It would be obvious to one skilled in the art to further include ethyl cellulose as the water-insoluble polymer in the bioadhesive layer with a reasonable expectation of success. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claims 7 and 22.
With respect to instant claim 9, Schiraldi teaches (claim 7) that its extruded bioadhesive film that has a bioadhesive layer (instant mucoadhesive layer) can further contain an outer protective membrane, which consists of non-soluble, non-adhesive polymers that provide durability and protection and directs delivery of the drug to the treatment site (see col.3, lines 7-10). Thus, Schiraldi’s outer protective membrane teaches instant backing layer of claim 9 that is impermeable to the tacrolimus present in the mucoadhesive layer, and Schiraldi’s extruded bioadhesive film teaches instant mucoadhesive film of claim 9. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claim 9.
With respect to instant claims 10, 26 and 27, Schiraldi teaches (claims 7 and 8) that in addition to the bioadhesive layer, its controlled-releasing medicament-containing extruded multi-layered thin film also contains an outer protective-barrier membrane layer, which consists essentially of a polymer matrix of a non-water soluble polymer such as ethyl cellulose (instant cellulose derivative of claim 26). Schiraldi further teaches (see the table under Example 5) that the outer protective-barrier membrane layer can contain PEG-400, which teaches instant plasticizer (polyethylene glycol) of claim 10. Thus, Schiraldi teaches instant backing layer comprising ethyl cellulose and polyethylene glycol (instant plasticizer). Therefore, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claims 10, 26 and 27.
With respect to instant claim 11, Schiraldi teaches (claims 1, 5 and 7) a multi-layer film laminate comprising a bioadhesive layer, a reservoir layer (instant intermediate layer of claim 11) and an outer-protective barrier membrane layer. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claim 11.
With respect to instant claims 24 and 25, as already discussed above, Schiraldi in view of Vaughn renders obvious to further contain a secondary bioadhesive polymer, such as a copolymer of methyl vinyl ether and maleic acid anhydride, PVP or polyvinyl acetate (which are instant mucoadhesive polymers). Vaughn further teaches (pg.5, lines 29-33, pg.6, lines 3-6) that the secondary bioadhesive polymer (instant mucoadhesive polymer) may be used in the amount of 5 wt.% or greater. Such range overlaps with instant range (2-17 wt.%) of claims 24 and 25 for the amount of the mucoadhesive polymer, thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Schiraldi teaches that the hydroxypropyl cellulose can be present in the amount of 40-95 wt.%, which overlaps with instant range (30-70 wt.%) of claims 24 and 25 for the amount of hydroxypropyl cellulose, thus rendering instant range prima facie obvious. In re Wertheim, supra. Schiraldi teaches that the ethyl cellulose (Schiraldi’s water insoluble polymer of claim 1) can be present in the amount of 0-10 wt.% , which overlaps with instant range (5-40 wt.%) of claims 24 and 25 for the amount of ethyl cellulose, thus rendering instant range prima facie obvious. In re Wertheim, supra. Schiraldi further teaches (claim 1, col.4, lines 32-38) that its plasticizer used in the amount of 2-10 wt.% in the bioadhesive layer may be chosen from a polyhydric alcohol, such as glycerin (instant glycerol). It would be obvious to one skilled in the art to use glycerin as the plasticizer in Schiraldi’s bioadhesive layer with a reasonable expectation of success. The range 2-10 wt.% (as taught by Schiraldi) overlaps with instant range 3-20 wt.% for the amount of glycerol, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claims 24 and 25.
With respect to instant claims 28 and 29, Schiraldi teaches (col.3, lines 26-34) that depending on the desired delivery rate, the type of disorder to be treated, the area to be treated, and the medications being administered, it is possible to custom design the film. The final film product may be fabricated into flexible tapes of various thickness and width, spots of different sizes and shapes or other pre-determined forms. Under such guidelines, instant limitations of claims 28 and 29 would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, supra. Alternatively, Vaughn teaches (pg.21, 2nd paragraph) that bioadhesive films may have a contact surface area of at least 0.2 cm2, at least 0.5 cm2, at least 1.0 cm2, at least 2.0 cm2, at least 3.5 cm2, at least 5 cm2, at least 10cm2 or at least 20 cm2. Under such guidelines, instant ranges of claim 28 (2-8 cm2) and claim 29 (4.4-6 cm2) would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders instant claims 28 and 29.
With respect to instant claims 16-18, as explained above, Jenkins in view of Schiraldi, Vaughn and Holm teaches instant tacrolimus which is in a molecularly dissolved non-nanoparticle form and instant polymer mixture containing a homopolymer of ethylene oxide, hydroxypropyl cellulose (as taught by Schiraldi), ethyl cellulose (taught by Schiraldi), polyvinylpyrrolidone (as taught by Vaughn), polyvinyl acetate (taught by Vaughn) or a copolymer of methyl vinyl ether and maleic anhydride (as taught by Vaughn). Thus, Jenkins in view of Schiraldi, Vaughn and Holm teaches instant step (i) of claim 16. As to instant step (ii), Holm teaches ([0128]) that its solid dispersions (solid solutions) are prepared by the solvent method by dissolving a physical mixture of tacrolimus and a vehicle carrier (polymer such as PEG, PVP, PVP-PVA, PEO – see [0129]) in a common organic solvent (such as methanol, ethanol or acetone) followed by evaporation of the solvent. Thus, Holm teaches instant step (ii). As to instant steps (iii) and (iv) of claim 16, Schiraldi teaches (Example 1, col.4, lines 65-68, col.5, lines 1-3, lines 29-37, col.6, lines 6-10) that each of the three layers (i.e., a bioadhesive layer (instant mucoadhesive layer), an outer protective barrier membrane layer (instant backing layer) and a reservoir layer (instant intermediate layer)) of its controlled-releasing medicament-containing extruded multi-layered thin film are made separately. All the ingredients used except for the liquid plasticizer are placed in a V-blender with liquid addition capabilities. The ingredients which are all powders are blended for approximately 10-15 minutes while the liquid plasticizer is slowly added to the mix. Three separate powder blends are made, one for each layer. The powder blends are then extruded. Each layer is extruded separately with the first layer as a free film. Successive layers are extruded onto each other and laminated by passing them through heated stainless steel rollers. Thus, Schiraldi teaches the mixing and preparation steps (iii) and (iv) of claims 16. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claim 16 (the step (v) is optional in instant claim 16).
With respect to the step (a) of instant claim 17, as already discussed above, Schiraldi teaches a backing layer comprising ethyl cellulose and PEG-400. Thus, Schiraldi teaches instant step (a) providing a backing layer polymer mixture. With respect to the step (b) of instant claim 17, as discussed above, Schiraldi teaches that all the ingredients used except for the liquid plasticizer are placed in a V-blender with liquid addition capabilities. The ingredients which are all powders are blended for approximately 10-15 minutes while the liquid plasticizer is slowly added to the mix. Three separate powder blends are made, one for each layer. The powder blends are then extruded. Each layer is extruded separately. Thus, Schiraldi teaches instant step (b) of claim 17. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claim 17.
With respect to step (1) of instant claim 18, Schiraldi teaches (claim 8) that its reservoir layer consists essentially of a polymer matrix comprised of both a water-soluble or water-swellable polymer and a non-water soluble polymer. Therefore, Schiraldi teaches instant step (1) of claim 18. With respect to step (2) of instant claim 18, Schiraldi teaches that all the ingredients used except for the liquid plasticizer are placed in a V-blender with liquid addition capabilities. The ingredients which are all powders are blended for approximately 10-15 minutes while the liquid plasticizer is slowly added to the mix. Three separate powder blends are made, one for each layer. The powder blends are then extruded. Each layer is extruded separately. Thus, Schiraldi teaches instant step (2) of claim 18. Thus, Jenkins in view of Schiraldi, Vaughn and Holm renders obvious instant claim 18.
Response to Arguments
First of all, applicant’s argument involving Lindsley et al (WO’783) is now moot as the previous 103 rejections over Jenkins et al’806 in view of Schiraldi et al’243 and Lindsley et al (WO’783) are withdrawn, and the Examiner is only addressing the rest of the arguments made by applicant.
Applicant first argue that the proposed combination of Jenkins, Schiraldi (and Lindsley) lacks technical coherence because the cited references disclose fundamentally different and technically incompatible formulation technologies and manufacturing approaches. Applicant argue that Schiraldi’s processing conditions including extrusion temperature of 125-185oC would likely compromise the amorphous character of spray dried dispersions through recrystallization or phase-separation and potentially cause degradation of tacrolimus. The Examiner disagrees, Holm (the newly cited reference) teaches ([0133]) that the solid dispersions or solid solutions may also be prepared through extrusion at elevated temperatures (melt extrusion). Furthermore, Ponnammal et al ("Orally Disintegrating Tablets Containing Melt Extruded Amorphous Solid Dispersion of Tacrolimus for Dissolution Enhancement", Pharmaceutics (2018), vol.10, 35. obtained from the website: https://doi.org/10.3390/pharmaceutics10010035 ) teaches (abstract) amorphous solid dispersion of tacrolimus prepared by hot-melt extrusion with 3 different hydrophilic polymers (polyvinylpyrrolidone vinyl acetate, SoluplusTR and HPC). The extrudates were found to be storage stable for 3 months with no recrystallization and showed higher dissolution rates, releasing 80% of the drug in 15 minutes compared to 5% drug release in 2 hours of the crystalline drug (without the hot-melt extrusion process). Ponnammal teaches (see pg.4, under section 2.5) that the tacrolimus and polymers were physically mixed to ensure homogeneity and extruded using a twin screw melt extruder having an extrusion temperature of 70oC-140oC and a die temperature of 135oC. The extrudates were then milled to produce a powdered solid. While Schiraldi gives examples of extruder temperatures that range from 100 to 185oC (see col.5, lines 45-55, lines 60-68; col.6, lines 1-5), Vaughn teaches (see pg.20, lines 7-20) that in a hot-melt extrusion process to produce films, the extruder zone and die can be set to any appropriate temperature typically between 50-140oC. Thus, it is the Examiner’s position that even if the spray-dried tacrolimus as taught by Holm undergoes Schiraldi’s hot-melt extrusion process (as modified by Vaughn) to form the bioadhesive layer, one skilled in the art would reasonably expect that the tacrolimus will still be in a molecularly dissolved state because the polymers in Schiraldi’s bioadhesive layer (PEO, HPC, and PVP as modified by Vaughn) are all hydrophilic polymers used as carriers to form the solid solution of tacrolimus through spray drying, and the temperature range (50-140oC) of the extrusion process is in the temperature range (70-140oC) of Ponnammal’s hot-melt extrusion.
As to applicant’s argument that none of the prior arts teaches any loading of tacrolimus expressed as mg/cm2, the Examiner believes that such argument was already addressed above in lengthy detail while discussing instant limitation “wherein the mucoadhesive layer comprises about 1.5 mg to about 3.5 mg of the tacrolimus per 1 cm2 of the mucoadhesive layer”. Additionally, although applicant present Jenkin’s Example 6 as an example of unpredictability of the art, the Examiner would like to point out that Jenkins provides nine different examples, each with different processing conditions and stabilizers, and that seven of those examples produced stable nanoparticle compositions. The Examiner believes that contrary to applicant’s assertion, Jenkins’s examples are indicative of routine optimization. Determining the optimum stabilizers and processing conditions must involve experimentation, and it is inevitable that some of those experiments will produce less than optimal results.
As to applicant’s argument of unexpected results (in terms of greater stability while achieving therapeutically relevant blood levels), such results are not unexpected in view of tacrolimus-specific teachings of Holm (tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or a solid solution at ambient temperature gives improved bioavailability) and Ponnammal (amorphous solid dispersion of tacrolimus are storage stable for 3 months and show greater dissolution than the crystalline drug).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
August 8, 2026
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