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 .
Applicant canceled claims 2-4, 6, 8, 12-14, 20 and 21.
In view of the amendment, previous 112(b) rejection on claim 7 is hereby withdrawn.
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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites that “the method comprises the use of the mucoadhesive layer of claim 1, wherein the method optionally comprises an attachment of the mucoadhesive layer in the body cavity of the patient.” The claim language as currently written is confusing and indefinite because it seems as if using the mucoadhesive layer of claim 1 and attaching the mucoadhesive layer in the body cavity of the patient are two independent steps (such scenario is not supported in the original disclosure, either).
Instant rejection can be overcome by changing claim 15 to recite --- . . . wherein the method comprises administering the mucoadhesive layer of claim 1 to the patient, wherein said administering optionally comprises attaching the mucoadhesive layer in the body cavity of the patient. --- (the support for such recitation is found on pg.9, 1st and 2nd paragraphs of present specification).
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, 22 and 24-27 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) and Lindsley et al (WO 2019/079783 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 mucoadhesive polymer, Schiraldi’s bioadhesive layer in its bioadhesive extruded film contains a homopolymer of ethylene oxide, which is instant mucoadhesive polymer (see Schiraldi’s claim 1 shown above).
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).
Thus, Jenkins in view of Schiraldi teaches instant mucoadhesive layer comprising tacrolimus, a mucoadhesive polymer and a cellulose derivative.
With respect to instant limitation “wherein the tacrolimus is in a molecularly dissolved non-nanoparticle form”, Jenkins in view of Schiraldi does not teach such limitation. Lindsley teaches (see [00222]) that in a solid solution, compounds are molecularly dissolved in a solid matrix. Spray-dried dispersions (SDD) are a type of solid solution which has been used to increase the bioavailability of BCS class 2 and BCS class 4 drugs. Lindsley also teaches ([00222]) that SDD provide long-term stability and manufacturability (“[f]or example, shelf lives of more than 2 years have been demonstrated with SDDs.”). SDD are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution. Since Tacrolimus is a BCS class 2 drug, it would be obvious to one skilled in the art to dissolve the tacrolimus and a polymer in an organic solvent and spray-dry the solution to form a solid solution with a reasonable expectation of increasing the bioavailability of tacrolimus and providing long term stability and manufacturability. Thus, Jenkins in view of Schiraldi and Lindsley teaches instant limitation “wherein the tacrolimus is in a molecularly dissolved 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 and Lindsley renders obvious instant claims 1, 5, 15 and 19.
With respect to instant claims 7 and 22, as discussed above, Schiraldi’s bioadhesive layer contains a homopolymer of ethylene oxide, which is instant mucoadhesive polymer. 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 and Lindsley 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 and Lindsley 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 and Lindsley 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 and Lindsley renders obvious instant claim 11.
With respect to instant claims 24 and 25, Schiraldi teaches (claim 1) that in its bioadhesive layer, the homopolymer of ethylene oxide (instant mucoadhesive polymer) can be present in the amount of 5-60 wt.%, which overlaps with instant range (2-17 wt.%) of claims 24 and 25 for the amount of the mucoadhesive polymer; 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; and 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. 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. Since Schiraldi’s ranges for the amounts of each of the components of claims 24 and 25 overlap with instant ranges, Schiraldi’s ranges render instant ranges 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). Thus, Jenkins in view of Schiraldi and Lindsley render obvious instant claims 24 and 25.
Claim(s) 23, 28 and 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) and Lindsley et al (WO 2019/079783 A1) as applied to claim 1 above, and further in view of Vaughn et al (WO 2008/028047 A2).
With respect to instant claim 23, Jenkins in view of Schiraldi and Lindsley does not teach instant mucoadhesive polymer of claim 23. 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 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. 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 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 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. Therefore, Jenkins in view of Schiraldi and Lindsley, and further in view of Vaughn renders obvious instant claim 23.
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 and Lindsley, and further in view of Vaughn renders instant claims 28 and 29.
Claims 16-18 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), Lindsley et al (WO 2019/079783 A1) and Vaughn et al (WO 2008/028047 A2).
With respect to instant step (i) of claim 16, as explained above, Jenkins in view of Schiraldi, Lindsley and Vaughn teaches instant tacrolimus which is in a molecularly dissolved non-nanoparticle form and instant polymer mixture containing a homopolymer of ethylene oxide, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyvinyl acetate or a copolymer of methyl vinyl ether and maleic anhydride. Thus, Jenkins in view of Schiraldi, Lindsley and Vaughn teaches instant step (i) of claim 16.
With respect 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, Lindsley and Vaughn renders obvious instant claim 16 (the steps (ii) and (v) are 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, Lindsley and Vaughn renders obvious instant claim 17.
With respect the 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 the 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, Lindsley and Vaughn renders obvious instant claim 18.
Response to Arguments
Applicant first argue that instant mucoadhesive films give unexpected result, as evidenced by, e.g., superior stability (instant Examples 7 and 8), non-irritation in the buccal mucosa (Example 9) and achieving blood levels suitable for effective administration (Example 10), even as compared to the Jenkins film (Jenkins’s Example 6), which was unsuccessful and unstable. Applicant argue that instant mucoadhesive films which comprise tacrolimus in a molecularly dissolved non-nanoparticulate form, and formulated at a dose of about 1.5 mg to about 3.5 mg per 1 cm² of the mucoadhesive layer are unexpectedly highly stable and can achieve clinically relevant blood levels of tacrolimus. Applicant further argue that instant mucoadhesive films surprisingly showed only 0.4% degradation after storage for 4 weeks at room temperature, in stark contrast to the micronized formulation having an order of magnitude more degradation products (paragraphs 3 and 4 of Horstkotte Declaration). Applicant point to Paragraph 5 of the Horstkotte Declaration which states the claimed mucoadhesive films achieved blood concentration levels that were comparable to oral administration of a commercial tacrolimus product and argue that this confirms instant mucoadhesive films' ability to buccally deliver a therapeutically effective amount of tacrolimus. Applicant argue that as described in Paragraphs 6-9 of the Horstkotte Declaration, instant mucoadhesive films considerably increased titres in vivo in pigs, in comparison to tacrolimus nanoparticles, which was unexpected and surprising. The Examiner disagrees. Putting aside the validity (such as whether the comparison was a fair one or not, whether the comparative data was commensurate in scope with the broadest claim) of comparative data shown in present specification for now, those advantages of using instant mucoadhesive layer (i.e., high stability and availability of tacrolimus in blood as well as non-irritation in the buccal mucosa) as asserted by applicant are nothing unexpected. As discussed above, Lindsley already teaches that spray-dried dispersions (SDD) (a type of solid solution) are used to increase the bioavailability of BCS class 2 and BCS class 4 drugs. Lindsley also teaches ([00222]) that SDD provide long-term stability (“[f]or example, shelf lives of more than 2 years have been demonstrated with SDDs.”). Since Tacrolimus is a BCS class 2 drug, one skilled in the art would have found it obvious to form a solid solution of Tacrolimus in the form of SDD with a reasonable expectation of increasing the bioavailability of tacrolimus and providing long term stability. Furthermore, Schiraldi already teaches (col.2, lines 14-18) that its inventive bioadhesive film provides very little or no mouthfeel. Thus, one skilled in the art reading Schiraldi would expect that such bioadhesive film would bring no irritation in the buccal mucosa. Thus, applicant’s arguments of “unexpected” and “surprising” results are not persuasive.
Applicant then argue that Jenkins is solely directed to nanoparticulate tacrolimus formulations, wherein tacrolimus is in the form of "micronized macrolide” and is entirely silent about molecularly dissolved non-nanoparticulate tacrolimus formulations, wherein tacrolimus is dissolved on a molecular level. Applicant argue that Schiraldi also does not teach or suggest tacrolimus in a molecularly dissolved non-nanoparticulate form. However, instant 103 rejection is not based on Jenkins in view of Schiraldi alone but instead based on Jenkins in view of Schiraldi and Lindsley. As already discussed above, Lindsley teaches that in a solid solution, compounds are molecularly dissolved in a solid matrix and teaches that spray-dried dispersions (SDD) are a type of solid solution which has been used to increase the bioavailability of BCS class 2 and BCS class 4 drugs (Lindsley also teaches ([00222]) that SDDs have demonstrated long-term stability and manufacturability). Since Tacrolimus is a BCS class 2 drug, it would be obvious to one skilled in the art to dissolve the tacrolimus and a polymer in an organic solvent and spray-dry the solution to form a solid solution with a reasonable expectation of increasing the bioavailability of tacrolimus and providing long-term stability and manufacturability. Thus, Jenkins in view of Schiraldi and Lindsley teaches instant limitation “wherein the tacrolimus is in a molecularly dissolved non-nanoparticle form”.
Applicant additionally argue that none of Jenkins and Schiraldi teaches or suggests a mucoadhesive film that includes about 1.5 to about 3.5 mg tacrolimus per 1 cm² area of the film and thus argue that the combination of Jenkins and Schiraldi fails to teach every limitation of the claims (Paragraph 12 of the Horstkotte Declaration). However, applicant’s such argument was already answered above in lengthy detail (see pg.6, last paragraph, pg.7 and pg. 8, 1st paragraph of this Office Action).
Applicant further argue that one skilled in the art could not have predicted that the combination of Jenkins and Schiraldi could result in mucoadhesive films with high stability and suitable for use in vivo to achieve clinically relevant blood levels of tacrolimus. Applicant argue that as discussed in the Horstkotte Declaration, Jenkins does not teach or suggest molecularly dissolved non-nanoparticulate tacrolimus formulations, nor does it teach or suggest tacrolimus formulations that would exhibit the stability and bioavailability demonstrated by the claimed invention. Applicant thus argue that one skilled in the art who develops molecularly dissolved non-nanoparticulate tacrolimus formulations would not have looked at Jenkins to start with and argue that even if said person were to review Jenkins, there is no reasonable expectation that formulating tacrolimus according to Jenkins would result in the claimed molecularly dissolved non-nanoparticulate tacrolimus formulation with high stability and availability. However, as already addressed above, instant 103 rejection is based on Jenkins in view of Schiraldi and Lindsley, and Lindsley teaches that in a solid solution, compounds are molecularly dissolved in a solid matrix to increase the bioavailability of BCS class 2 and BCS class 4 drugs, and which also teaches that SDDs (a type of solid solution) have demonstrated long-term stability and manufacturability. Since Tacrolimus is a BCS class 2 drug, it would be obvious to one skilled in the art to form a solid solution of tacrolimus with a reasonable expectation of increasing the bioavailability (availability) of tacrolimus and providing long-term stability. Thus, one skilled in the art looking at Jenkins in view of Schiraldi and Lindsley would have a reasonable expectation that formulating tacrolimus according to Lindsley’s teaching would result in the claimed molecularly dissolved non-nanoparticulate tacrolimus formulation with high stability and availability.
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
December 27, 2025