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 .
It is to be noted that the effective filing date of the claimed invention is not June 14, 2021 (on which the foreign priority document was filed) but June 14, 2022 instead because the foreign priority document (EP21179203.1) does not support instant limitation of claims 1, 12 and 13 “buccally administering to the patient twice daily a mucoadhesive film . . .”.
THIS ACTION IS MADE FINAL. 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 § 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, 3, 5-7, 9-11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over HOLM et al (US 2011/0251231 A1) in view of Schiraldi et al (4,713,243), Vaughn et al (WO 2008/028047 A2) and Jenkins et al (US 2009/0252806 A1).
Holm teaches ([0012]) that tacrolimus is used for the prophylaxis of organ rejection in patients receiving allogenic liver or kidney transplants. Holm teaches ([0014]-[0015], [0049], [0050] and [0065]) that the bioavailability of tacrolimus is significantly increased (over that of the commercially available tacrolimus, Prograf) when it is administered to a mammal in a controlled (or modified) release composition. Holm teaches that the controlled release profile is obtained by providing a pharmaceutical composition comprising a solid solution of tacrolimus (instant molecularly dissolved non-nanoparticulate form of tacrolimus – see [0027] of Holm) in a hydrophilic or water-miscible vehicle (e.g., polyethylene oxide or hydroxypropyl cellulose – see claim 60, [0048] and [0157]-[0158]). Holm further teaches ([0167]) that its pharmaceutical composition can be administered buccally.
Holm does not teach instant mucoadhesive film 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 that when wet, it is 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 Holm also teaches that its solid solution of tacrolimus 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 Holm’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 “mucoadhesive layer comprising the tacrolimus in a molecularly dissolved non-nanoparticulate form”, Schiraldi teaches in claim 1 that the medicament is contained in the bioadhesive layer. Thus, it would have been obvious to one skilled in the art to include Holm’s solid solution of tacrolimus in the bioadhesive layer (instant mucoadhesive layer) of Schiraldi’s bioadhesive extruded film (instant mucoadhesive film) with a reasonable expectation of success. Thus, Holm in view of Schiraldi teaches or renders obvious instant “mucoadhesive layer comprising the tacrolimus in a molecularly dissolved non-nanoparticulate form”.
With respect to instant “30% to 70% hydroxypropyl cellulose”, as shown above, Schiraldi’s bioadhesive layer contains 40-95 wt.% of hydroxypropyl cellulose. Schiraldi’s range (40-95%) for the amount of hydroxypropyl cellulose overlaps with instant range (30-70%) for the amount of hydroxypropyl cellulose, 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, supra.
With respect to instant “5% to 40% by weight ethyl cellulose”, based on Schiraldi’s teaching in claim 1, it would have been obvious to one skilled in the art to use ethyl cellulose as the water-insoluble polymer with a reasonable expectation of success. Schiraldi’s range (0-10%) for the amount of water-insoluble polymer (ethyl cellulose) overlaps with instant range (5-40%) for the amount of ethyl cellulose, thus rendering instant range prima facie obvious. In re Wertheim, supra.
With respect to instant limitations “2% to 17% by weight of a mucoadhesive polymer” and “wherein the mucoadhesive polymer is selected from the group consisting of: a polymer comprising polyvinyl acetate or polyvinylpyrrolidone; a copolymer of methyl vinyl ether and maleic anhydride; and a combination of a polymer comprising polyvinyl acetate or polyvinylpyrrolidone, and a copolymer of methyl vinyl ether and maleic anhydride” as recited in claim 1, although the homopolymer of ethylene oxide contained in the bioadhesive layer of Schiraldi’s bioadhesive extruded film is a mucoadhesive polymer (see present specification, pg.19, lines 30-38), it does not teach those specific mucoadhesive polymers listed in instant claim 1. 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 examples for such secondary bioadhesive polymer, Vaughn teaches 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 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. Vaughn also teaches (pg.6, lines 3-6) that the secondary bioadhesive polymer (such as copolymer of methyl vinyl ether and maleic acid anhydride) can be present in the amount of greater than 5 wt.%. Such range overlaps with instant range of 2-17 wt.% for the amount of instant mucoadhesive polymer, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Schiraldi in view of Vaughn renders obvious instant 2-17 wt.% of instant mucoadhesive polymer, which is a copolymer of methyl vinyl ether and maleic anhydride. (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 secondary 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. Vaughn also teaches (col.6, lines 10-13) that the secondary hydrophilic or hydrophobic polymer can be present in the bioadhesive film in the amount of less than 20 wt.%. Such range overlaps with instant range 2-17 wt.% for the amount of instant mucoadhesive polymer, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Schiraldi in view of Vaughn renders obvious instant 2-17 wt.% of instant mucoadhesive polymer, which is polyvinyl acetate or polyvinylpyrrolidone.
With respect to instant backing layer which is impermeable to the tacrolimus present in the mucoadhesive layer, as shown above, in its claim 7, Schiraldi teaches 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 (see claim 8). Thus, Schiraldi teaches instant backing layer which is impermeable to the tacrolimus present in the mucoadhesive layer (see pg.5, lines 10-17 of present specification).
With respect to instant limitation “buccally administering to the patient twice daily a mucoadhesive film comprising about 1.5 mg to about 3.5 mg non-nanoparticulate tacrolimus per 1 cm2 of the mucoadhesive film” (as well as instant limitations of 2, 3 and 5), Holm does not teach such limitation. Holm only teaches ([0034], [0052]) that its inventive controlled release composition is intended to cover the release of tacrolimus that is appropriate to obtain a specific therapeutic or prophylactic response after being administered to a subject. As evidenced by Jenkins ([0202]-[0203]), 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 limitations as to twice daily buccal administration of about 1.5-3.5 mg of non-nanoparticulate tacrolimus per 1 cm2 of the mucoadhesive film (as in instant claims 1 and 2), the duration of administration being 60 minutes or 30 minutes twice daily (claim 3) and the time between the two administrations being about 4 hours (claim 5) 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) of Schiraldi’s bioadhesive extruded film (instant mucoadhesive film), the optimum length of the time of administration or the optimum time between the two administrations 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 both Holm ([0034], [0052]) and Jenkins ([0059]) teach that the tacrolimus should be administered in an amount to achieve a specific therapeutic, prophylactic response to a subject, and (ii) since both Holm ([0012]), Jenkins ([0027]) and applicant teach that tacrolimus is administered for the prophylaxis of organ rejection, specifically in patients receiving allogenic liver or kidney transplants, instant range (about 1.5-3.5 mg) for the amount of the non-nanoparticulate tacrolimus per 1 cm2 of the mucoadhesive film 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, Holm in view of Schiraldi, Vaughn and Jenkins renders obvious instant claims 1, 3 and 5.
With respect to instant claims 6 and 7, 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 6 and 7 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 6 (2-8 cm2) and claim 7 (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, Holm in view of Schiraldi, Vaughn and Jenkins renders obvious instant claims 6 and 7.
With respect to instant claim 9, Schiraldi teaches (claim 1 and col.4, lines 32-38) that its plasticizer which is used in the amount of 2-10% in the bioadhesive layer may be glycerin. The range taught by Schiraldi for the amount of the plasticizer (such as glycerin) overlaps with instant range 3-20%, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Holm in view of Schiraldi, Vaughn and Jenkins renders obvious instant claim 9.
With respect to instant claims 10-11, Schiraldi teaches (claims 1, 5 and 7) an multi-layer film laminate comprising a bioadhesive layer, a reservoir layer (instant intermediate layer of claim 11) and an outer protective membrane layer (instant backing layer). Schiraldi further teaches (claim 8) that the outer protective membrane layer consists essentially of a polymer matrix of a non-water soluble polymer such as ethyl cellulose. Thus, Holm in view of Schiraldi, Vaughn and Jenkins renders obvious instant claims 10-11.
With respect to instant claim 13, all the limitations of claim 13 were already discussed above (see the discussion relating to instant claims 1 and 10). Thus, Holm in view of Schiraldi, Vaughn and Jenkins renders obvious instant claim 13.
Claim(s) 12 is rejected under 35 U.S.C. 103 as being unpatentable over Holm et al (US 2009/0252806 A1) in view of Schiraldi et al (4,713,243), Vaughn et al (WO 2008/028047 A2), Jenkins et al (US 2009/0252806 A1) and Linn et al (US 2020/0281847 A1).
For the reasons already explained above in Paragraph 5, Holm in view of Schiraldi, Vaughn and Jenkins teaches or renders obvious instant invention of claim 12 except for instant intermediate layer comprising vinylpyrrolidone-vinyl acetate copolymer (although Schiraldi teaches a reservoir layer located between the bioadhesive layer and the outer protective-barrier membrane layer, Schiraldi does not teach instant intermediate layer containing vinylpyrrolidone-vinyl acetate copolymer). However, using an intermediate water-soluble adhesive layer to attach two non-adhesive layers without having to subject those two non-adhesive layers to additional heat and chemical loading is known in the art, as evidenced by Linn et al (abstract, [0008] and [0010]). Linn teaches ([0034] and [0010]) that such intermediate water-soluble adhesive layer contains at least one water soluble polymer, such as vinylpyrrolidone/vinyl acetate copolymer and a plasticizer. As discussed above in Paragraph 5, Schiraldi teaches an extruded multi-layered thin film having the bioadhesive layer, a reservoir layer and an outer protective-barrier membrane layer. Schiraldi teaches (col.6, lines 5-10) that after extruding the first layer, successive layers are extruded onto each other and laminated by passing them through heated stainless steel rollers. It would have been obvious to use Linn’s intermediate water-soluble adhesive layer containing vinylpyrrolidone/vinyl acetate copolymer and a plasticizer between the non-sticky layers of Schiraldi (the reservoir layer and the outer protective-barrier membrane layer) so as to attach them together without having to carry out additional heating steps. Such water-soluble adhesive layer located between Schiraldi’s reservoir layer and outer protective-barrier membrane layer would naturally be present between Schiraldi’s bioadhesive layer (instant mucoadhesive layer) and its outer protective-barrier membrane layer (instant backing layer). Thus, Holm in view of Schiraldi, Vaughn, Jenkins and Linn renders obvious instant claim 12.
Response to Arguments
With respect to instant 103 rejections over Holm in view of Schiraldi, Vaughn, and Jenkins, applicant argue that the claimed methods achieve clinically relevant blood levels of tacrolimus in vivo and exhibit a synergistic pharmacokinetic effect with twice-daily administration (see Example 12) and also argue that the claimed mucoadhesive films are unexpectedly stable (see Examples 7 and 8) and well-tolerated on the buccal mucosa without causing irritation (see Example 9). Applicant argue that although Holm mentions "buccal administration" once in a list of possible routes, it does not disclose any formulation suitable for buccal use and provides no teaching or suggestion that would motivate or guide a person of ordinary skill in the art to develop a mucoadhesive film because Holm is directed to modified-release oral dosage forms (e.g., capsules and tablets) comprising tacrolimus in a solid dispersion or solution and argue that moving away from Holm's oral dosage forms to a buccal mucoadhesive film would require abandoning Holm's principle of operation, including its delivery route, absorption pathway, and release mechanism. The Examiner disagrees. As stated by applicant, Holm clearly teaches that its pharmaceutical composition can be administered buccally, and also instant 103 rejection is not based on Holm alone. As already discussed above, Schiraldi teaches that its bioadhesive extruded film is so thin and flexible that when wet, it is unobtrusive to the patient and 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. Schiraldi thus teaches that the bioadhesive extruded film is an effective and convenient intra-oral drug delivery system. Thus, Schiraldi gives sufficient motivation to one skilled in the art to use its bioadhesive extruded film (a mucoadhesive film) to deliver Holm’s solid solution of tacrolimus buccally (with a reasonable expectation that such mucoadhesive film would effectively and conveniently provide controlled release of the tacrolimus in an unobtrusive way), especially since Holm already states that its solid solution of tacrolimus can be administered buccally as a controlled release formulation and also since Schiraldi gives sufficient detail on how to form such a mucoadhesive film.
Applicant next argue that none of Holm, Schiraldi, Vaughn, or Jenkins teach or suggest administering a mucoadhesive film containing about 1.5 to about 3.5 mg tacrolimus per cm² twice daily. Applicant argue that the claimed dosing regimen is not a matter of routine optimization and that the Office's reliance on Jenkins's generic, route-agnostic statement regarding a "therapeutically effective amount" does not render the claimed specific dose and twice-daily regimen obvious. Applicant argue that since Jenkins provides no disclosure addressing buccal delivery or mucoadhesive film-based administration, it offers no predictive value or reasonable expectation that a twice- daily mucoadhesive film containing the claimed tacrolimus loading would achieve clinically relevant blood levels of tacrolimus. Applicant then argue that determining an effective buccal dosing regimen requires selecting and optimizing multiple interdependent variables, including polymer composition and ratios, tacrolimus loading per cm², film area, residence time, and dosing frequency and thus argue that identifying the claimed dosing regimen would require undue experimentation that the cited art does not guide or suggest. The Examiner disagrees. Holm in view of Schiraldi, Vaughn and Jenkins already teaches/renders obvious instant mucoadhesive film, and it is the Examiner’s position that determining the optimum dosage regimen for the taught mucoadhesive film containing the solid solution of tacrolimus required to achieve the therapeutic effect in the (human) patient would be a matter of routine experimentation for the skilled person as such routine tests do not require inventive skill (especially since tacrolimus is already a well-known drug).
Lastly, applicant argue unexpected results of the claimed invention. Applicant argue that present Example 12 shows that twice-daily administration of the claimed mucoadhesive film achieved clinically relevant and significantly higher tacrolimus blood concentrations than once-daily administration, even though the total daily dose was identical. Applicant argue that such findings demonstrate that the twice-daily regimen produces an unexpected pharmacokinetic synergy, unpredictable from the cited references. The Examiner disagrees. First of all, the Examiner considered only the comparison between Session 1 vs Session 2 (as shown in Table 18) because that comparison was the only one which was fair (where the residence time, film area, dose per animal and dose per film were kept the same between Session 1 vs Session 2, the only difference being whether the administration occurred once a day or twice a day (with 4 hours between the administration). After considering the comparison between Session 1 vs. Session 2, applicant’s argument of unexpected results of the twice-daily administration of the claimed mucoadhesive film was found to be unpersuasive for the following reasons: (i) First of all, the comparison made is not commensurate in scope because the residence time (60 min) and film area (6 cm2) employed in Session 1 and Session 2 represent the preferred embodiments of dependent claims 3 and 7, and the time between the two administrations (4 hours) taken in Session 2 represents the preferred embodiment of dependent claim 5. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See MPEP 716.02(d). (ii) Secondly, even though the average value for the AUC (h* ng/ml) was 21 for Session 1 and 35 for Session 2 (see Table 18), the detailed data shown in Table 19 for the AUC for Session 1 are: 21.13, 15.89, 40.88, 13.13 and 15.40 for the five pigs tested, which shows a huge variation between the pigs. Also, Table 20 shows the detailed data for the AUC for Session 2 to be: 32.65, 64.03, 37.47, 25.19 and 13.40 for the five pigs, which again shows a huge variation between the pigs. As calculated by the Examiner, the average AUC for Session 1 is 21.29 with a standard deviation of 11.34, and similarly, the average AUC for Session 2 is 34.45 with a standard deviation of 18.82. Based on this, the p value was calculated to be 0.1109 (which is higher than the standard threshold value (p value of ≤0.05) for statistical significance. Thus, the experimental results shown in Table 18 are not statistically significant, and thus, the Examiner disagrees with applicant’s argument that present Example 12 showed that twice-daily administration of the claimed mucoadhesive film achieved clinically relevant and significantly higher tacrolimus blood concentrations than once-daily administration, even though the total daily dose was identical.
For the reasons stated above, instant 103 rejections over Holm in view of Schiraldi, Vaughn and Jenkins still stand.
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
March 7, 2026