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 .
Status of Claims
Amendment filed on 12/11/2025 is acknowledged.
Claims 1, 5, 8, 16-18 and 21 are amended.
Claims 4, 12 and 15 remain cancelled. Claims 2 and 25 is now cancelled.
Claims 1, 3, 5-11, 13-14 and 16-24 are pending and being examined on the merits herein.
Priority
The instant application, filed on 06/16/2022, is a 371 of PCT/EP2020/077736, filed on 10/02/2020, which claims foreign priority to European Patent Office 19218592.4, filed on 12/20/2019.
Information Disclosure Statement
The information disclosure statement (IDS) dated 12/11/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections/Rejections
All previous claim Objection(s) / Rejection(s) as set forth in the previous Office action (mailed 09/11/2025) that are not repeated and/or maintained in the instant Office action are withdrawn, in light of applicant’s amendment and remark filed on 12/11/2025.
Claim Interpretation
Claims/terms are interpreted as following.
Claim 1, the phrase “for the transmucosal administration of agomelatine” is interpreted as intended use or property of the system because it does not provide structural limitation to the system.
Claim 16 is interpreted as “process of making” limitation.
The agent “permeation enhancers” recited in claims 1 and 16 are interpreted specifically including the following agents, preferable or no preferable, as listed in instant specification [0191]-[0192]: diethylene glycol monoethyl ether (transcutol), dipropylene glycol, levulinic acid, lauryl lactate, lactic acid, dimethylethylene urea, N,N'-Dimethylpropyleneurea DMPU and N,N-Diethyl-meta-toluamide (DEET), 2-(2-Ethoxyethoxy)ethanol, 2,5- dimethylisosorbid (dottisol), propylene glycol monocaprylat, 2-Methoxy-4-(prop-2-en-1- yl)phenol, laurocapram, bile acid, bile acid salts, bile acid derivatives, acyl carnitines, sodium dodecylsulfate, dimethylsulfoxide, sodium laurylsulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid, and salicylates.
Claims 11, 13-14, 18 and 21-24 are interpreted as properties, or intended use, or “process of using” of the transmucosal therapeutic system, because they do not structurally contribute to the system.
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.
Claims 1, 3, 5-11, 13-14 and 16-24 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.
Claims 1 and 16 are amended to recite “does not comprise a permeation enhancer”. The term “permeation enhancer” in claims 1 and 16 is a relative term which renders the claim indefinite. The term “permeation enhancer” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. At what degree of enhancement in permeation would qualify the agent as a permeation enhancer is not defined by the claim or the instant specification. As instant specification (e.g., [0179]) indicates: “[I]t should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. E.g. a certain polymer can be a crystallization inhibitor but also a tackifier. Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer. The skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive”. The instant specification does not define permeation enhancer clearly, and it provides doubt of what agents are classified as permeation enhancers. A person with ordinary skills in the art would not be able to determine what components in the formulation would belong to permeation enhancer. The claims are indefinite.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1, 3, 5-11, 13-14, 16, and 18-24 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20160184246, 06/30/2016, IDS of 10/28/2022), in view of Finn et al. (US9597288,
03/21/2017, IDS of 04/28/2025) and Sesha et al. (WO2013063263, 05/02/2013, PTO-892).
Liu throughout the reference teaches compositions and methods for the transdermal drug delivery systems for agomelatine useful for treatment of depression (Abstract, [0002]).
Regarding instant claims 1, 3, 5, 7, 10 and 16, Liu teaches the transdermal drug delivery system can be transdermal/transmucosal drug delivery patches [0030-0031]. Liu indicates the transdermal drug delivery systems consist of a backing layer (reads on the backing layer of claim 1), a drug (agomelatine)-containing adhesive layer (reads on the agomelatine layer of claim 1), and a release liner, with regard to drug-in-polymer matrix embodiments illustrated in Fig. 1A, and reservoir-type systems in Fig. 1C [0039]. Liu claims the transdermal drug delivery system comprises agomelatine formulated in a polymer matrix that includes a pressure sensitive adhesive polymer with a backing. As exemplified in example 2 the transdermal agomelatine delivery system comprising 36 mg agomelatine and 2% hydroxyethyl cellulose (HEC) in gel reservoir (corresponding to agomelatine-containing layer), and includes an occlusive polyester/ ethylene vinyl acetate backing, a microporous polyethylene membrane, and peripheral adhesive for adhering the systems to the skin ([0111]; Claims 15, 16, 21).
Therefore, Liu teaches the transmucosal-therapeutic system in the form of a film for transmucosal administration of agomelatine comprising a mucoadhesive layer structure, and the mucoadhesive layer structure comprises a backing layer and an agomelatine-containing layer comprising agomelatine and a first dissolvable film-forming agent, wherein the dissolvable film-forming agent can be hydroxyethyl cellulose (corresponding to instant claims 1A), 1B)i) and 1B)ii) and claim 10).
Regarding the agomelatine and dissolvable film-forming agent amounts, Liu describes in specific embodiments, the drug-in-polymer matrix may comprise about 70% w/w acrylic polymer and about 30% silicone polymer, 10.5% w/w agomelatine in specific embodiments [0011]. In example 3, Liu presents polymer components comprising 72% acrylic polymer DuroTak 387-4287 (which includes hydroxyl groups, [0059]) and 28% w/w silicone polymer Bio-PSA 4402 (pressure-sensitive adhesive, [0082]), formulated with 10.5% w/w agomelatine of the drug-in-polymer matrix type system ([0112-0114], Claim 20) (overlapping with agomelatine amounts in instant claim 7). Liu indicates that the backing layer can be optional to the transdermal system [0012], therefore the polymer in the matrix relates to the polymer weight out of agomelatine-containing layer, resulting in polymer amount is at most 89.5% (calculated by 10.5% agomelatine being subtracted from the total weight, overlapping to first dissolvable film-forming agent amount in instant claims 1, 3, 16. Liu teaches that backing layer, protecting polymer matrix layer drug-containing layer, can comprise films of polyethylene, polyester, and other polymer materials well-known in the art [0032] without the drug, implying that polymer amount in the backing layer can be close to the total material in the backing layer, overlapping with second dissolvable film-forming agent amount ranges in instant claims 1, 5, 16.
Regarding agomelatine-containing layer does not comprise a permeation enhancer, Liu points out that “penetration enhancer” is an agent known to accelerate the delivery of the drug through the skin and these agents also have been referred to as accelerants, adjuvants, and sorption promoters, and are collectively referred to as “enhancers” [0063]. Liu points out that in accordance with some embodiments, the transdermal drug delivery systems described herein consist of a backing, a drug-containing composition (e.g., drug-in-solution reservoir, drug-in-gel reservoir, or drug-in-polymer matrix layer), and a release liner, as illustrated in FIG. 1A with regard to drug-in-polymer matrix embodiments, and as illustrated in FIG. 1C with regard to reservoir-type systems. In accordance with some embodiments, the transdermal drug delivery systems described herein consist of a backing, a drug-containing layer, a face adhesive, and a release liner, as illustrated in FIG. 1B [0039], without penetration enhancers. Sue continues with “in specific embodiments, the face adhesive is a silicone face adhesive comprising a silicone adhesive, such as a silicone pressure-sensitive adhesive and, optionally, one or more penetration enhancers” [0039]. Sue indicates later once again, in a drug-in-polymer matrix system, the drug is formulated in a polymer matrix, such as a pressure-sensitive adhesive polymer matrix, optionally with a penetration enhancer [0057]; and “as noted above, in some embodiments, the transdermal delivery system described include a penetration enhancer” [0062]. Therefore, Liu does not always add permeation enhancers to the drug delivery system. In light of claim interpretations of claims 1 and 16 as presented above, Liu exhibits embodiment examples 2 and 3 [0107]-[0114] comprising agomelatine polymer matrix without a permeation enhancer from the defined enhancer list as interpreted (corresponding to claims 1 and 16).
Regarding the system providing effective dose of agomelatine, Sue teaches that the system can provide a therapeutically effect amount of agomelatine is about 1-3 mg/day administered transdermally, based on the 5% bioavailability of the 25 mg/day and 50 mg/day oral doses, and those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease (corresponding to instant claims 1 and 16).
Regarding instant claim 6, Liu points out that the transdermal delivery systems described can be of any shape or size suitable for transdermal application [0097]. Liu illustrates the transdermal drug delivery systems in Fig. 1A-1C [0039], showing the size of the backing layer and the size of the agomelatine-containing layer are coextensive (Figure 1A, 1B).
Regarding instant claims 8, Liu indicates that the drug-containing polymer matrix can comprise tackifiers, plasticizers, crosslinking agents, enhancers, co-solvents, fillers, antioxidants, solubilizers, crystallization inhibitors, or other additives [0051].
Regarding instant claim 11, Liu measures agomelatine flux (or permeation) through human cadaver skin using a modified Franz-cell apparatus, using 0.1 mL solution per cm2, exhibiting maximum drug flux up to 17 µg/cm2/hr at 50-75% IPA, with drug flux falling off to 2-5 µg/cm2/hr at 90% IPA, when agomelatine is formulated at its saturation conditions (0.4 to >150 mg/ml) in different concentrations of aqueous IPA (aqueous isopropanol) (Page 9, [0108], Example 1) (range overlapping with those in instant claim 11). Liu also provides mucosal permeation rate of agomelatine on the skin of live swine for 24 hours from the transdermal drug delivery systems comprising 36 mg agomelatine in 0.9 ml aqueous IPA (50% v/v) and 2% hydroxyethyl cellulose with a 16 cm2 active surface area (Page 9, Example 2). Liu emphasizes that a therapeutically effective amount or therapeutic level can be adjusted by those skilled in the art in accordance with standard practices as needed to treat a specific subject and /or condition/disease [0028]. A therapeutically effect amount of agomelatine is about 1-3 mg/day administered transdermally, based on the 5% bioavailability of the 25 mg/day and 50 mg/day oral doses [0028], which translates into 1-3 mg/24-hr or about 0.3-1 mg/ 8 hours; while taking into account a reasonable size of transmucosal film for human or animal’s oral cavity, the permeation rate overlap with the ranges in instant claim 11.
Regarding instant claim 13, Liu specifies that the agomelatine transdermal drug delivery system can be applied once daily to the skin or mucosa of a subject in need of treating depression (Claim 25) including major depressive disorder [0104]. Liu further indicates that “subject” denotes any animal in need of drug therapy, including humans (corresponding to instant claim 13).
Regarding instant claim 14, Liu teaches that a subject may be suffering from or at risk of developing a condition that can be treated or prevented with agomelatine, or may be taking agomelatine for health maintenance purposes. In specific embodiments, the subject is a subject suffering from depression, including major depressive order [0027].
Regarding instant claim 16, Liu provides examples of preparation methods making the drug-in-polymer matrices known in the art. For example, the polymer matrix material can be applied to a backing layer and release liner by methods known in the art, and formed into sizes and shapes suitable for use [0098]. For example, after the polymer matrix is formed, it may be brought into contact with a support layer, such as a releaser liner layer or backing layer, in any manner known to those of skill in the art, techniques including such as calendar coating, hot melt coating, solution coating, etc. [0098]. Liu teaches that the drug can be added at any stage, a polymer matrix can be prepared by blending the components of the polymer matrix in the presence of a solvent, such as a volatile organic solvent, applying the wet blend of matrix material onto a support layer such as a backing layer or release liner, removing any remaining solvents (commonly known method to achieve this is drying), and laminating to a release liner or backing layer. [0099]. Liu indicates the backing layer can be adjacent the drug-containing composition and can comprise films of polymers [0032], with suitable polymers disclosed above. Moreover, Liu indicates that one or more additional polymer matrix layers, adhesive layer, backing layer, or release liner can be included in the transdermal drug delivery system [0056]. Therefore, Liu teaches the general process of manufacturing agomelatine-containing layer steps as recited in instant claim 16 A), and Liu points out that the process of manufacturing one or more polymer matrix layers including backing layer can be generally repetitive, thus teaching the general manufacturing process of a transmucosal therapeutic system as recited in instant claim 16 B), except the drying step.
Regarding instant claim 19, Liu teaches that only solubilized drug can be delivered transdermally, and crystallization reduces drug delivery and explains how enhancers can be formulated into the composition for delivery improvement [0038]. Liu describes that the polymer matrix in the transdermal delivery system comprises a pressure-sensitive adhesive polymer or a bio-adhesive polymer, with drug dissolved or dispersed [0051], and exemplifies that drug can be added at any stage, such as, in one embodiment, all polymer matrix components, including drug, are blended together; in another embodiment, the polymer matrix components other than drug are blended together, and then the drug is dissolved or dispersed therein [0099].
Regarding instant claim 20, Liu presents oleic acid and linoleic acid can be added in the system [0064].
Regarding instant claims 22-24, Liu addresses further that the agomelatine composition can be formulated for transdermal delivery to achieve drug delivery over a relatively short period of time (e.g., 12 hours or less), even if the transdermal delivery system is left in place on the subject's skin for a longer period of time (e.g., for one day). This permits the design of a "once daily" system for the delivery of agomelatine, such that subjects can apply a system once a day at the same time of day, usually in the evening (most conveniently it would be the time before going to bed), and leave the system in place until about the same time the following day, even though drug delivery is to be completed in less than one day [0037]. Liu discloses that the transmucosal agomelatine delivery system is applied to skin and mucosa including oral cavity and buccal cavity, as Liu explain that transdermal herein includes skin and mucosa, which includes oral, buccal, nasal, rectal and vaginal mucosa (e.g., [0030]). Therefore, Liu teaches that the mucoadhesive layer structure can be administered to human or animal patients in the evening to the mucosa of the oral cavity for treating major depression as needed and maintaining it in place until dissolved or about the same time the following day as discussed above.
Liu does not teach from 3 to 7 wt% of agomelatine amount in agomelatine-containing layer as recited in instant claims 1 and 16, or the first dissolvable film-forming agent is a hydroxypropyl cellulose, or a mixture of polymers selected from hydroxypropyl celluloses and ethyl cellulose in instant claims 1 and 16, and the backing layer comprises a second dissolvable film-forming agent which is a mixture of hydroxyethyl cellulose and hydroxypropyl cellulose as recited in instant claims 1, 5 and 16, and hydroxypropyl cellulose having a molecular weight of between 75,000 and 85,000 in instant claim 5. Liu also does not teach the area weight of agomelatine-containing layer or backing layer or transmucosal system as recited in instant claim 9. Liu does not explicitly teach in the manufacturing process of drying the first coating or drying the second coated coating as recited in instant claim 16. Liu does not teach the backing layer dissolving time as recited in instant claim 18, or mucoadhesive layer structure dissolving characters as recited in instant claim 21.
Finn throughout the reference teaches transmucosal bioerodable drug delivery devices including mucoadhesive polymeric diffusion environment that facilitates not only the absorption of the medicament across the mucosal membrane to which it is applied, but additionally, the permeability and/or motility of the medicament through the mucoadhesive polymeric diffusion environment to the mucosa (e.g., Abstract; Col. 1, lines 56-62; Col. 2, lines 63-67), and the method does not mention using enhancers for enhancing transmucosal uptake.
Finn indicates that the mucoadhesive polymeric diffusion environment is water-erodible (readily dissolvable, Col. 7, Lines 27-30) and can be made from first film-forming water-erodible polymers including hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, or a combination thereof (Col. 14, Lines 13-22). (corresponding to first dissolvable polymers in instant claims 1 and 16). Finn teaches that the barrier environment can be, e.g., a backing layer, adjacent to the mucoadhesive polymeric diffusion environment (Col. 15, Lines 4-7), and the backing layer is non-adhesive water-erodible layer that may include at least one water-erodible, film-forming polymer (Col. 15, Lines 35-37). Finn specifies that examples of the backing layer dissolvable film-forming polymer include, but not limited to, hydroxyethyl cellulose, hydroxypropyl cellulose (Col. 15, Lines 54-67), and ethyl cellulose, cellulose acetate phthalate and others (Col. 16, Lines 22-32). In Example 1, Finn exemplifies the backing layer comprising a mixture of hydroxypropyl cellulose and hydroxyethyl cellulose (Col. 19, Lines 60-63) (corresponding to backing layer polymer species in instant claims 1, 5 and 16). Finn also teaches that combinations of different polymers or similar polymers with definite molecular weight characteristics can be used in order to achieve preferred film forming capabilities, mechanical properties, and kinetics of dissolution (Col. 16, Lines 49-56).
Finn teaches that typically the bilayer thickness ranges from about 0.01 mm to about 1 mm, and more specifically, from about 0.05 mm to about 0.5 mm (Col. 17, Lines 64-67), the thickness of each layer can vary from about 10% to about 90% of the overall thickness of the device, and the preferred thickness of each layer can vary from about 0.005 mm to about 1.0 mm (Col. 17 line 66-Col. 18 line 4), with the drug-containing mucoadhesive polymeric diffusion environment or layer in a thickness of about 0.03-0.07 mm, or about 0.04-0.06 mm, or about 0.05 mm (Col. 18, Lines 6-15), backing layer thickness of about 0.05-0.35 mm, or about 0.1-0.3mm, or about 0.2 mm (Col. 18, Lines 21-27). Although Finn does not expressly show the area weight, taking the density hydroxypropyl cellulose around 0.5g/cm3 to calculate the weight when this dissolvable agent is casted into a film, 0.5 g/cm3 x (low 0.005 to high 0.35) mm thickness x 1m2 area (equals to 10,000 cm2) = 0.5 * 0.005 * 10,000 g/ m2 = 25 g/ m2 to 0.5*0.35*10,000 = 175 g/ m2. The thinness of the transmucosal film results in per square meter weight amounts of drug containing layer, backing layer, and the transmucosal system area weight overlap with those in instant claim 9.
Finn exemplifies the preparation of the transmucosal device in Example 1 (Col. 19-20), teaching that the layers are cast in series onto a St. Gobain polyester liner. First, the backing layer is cast using a knife-on-a blade coating method, then being cured in a continuous oven at about 65-95 C and dried (Col. 20, Lines 36-39). After two coating and drying iterations, an approximately 8 mil (203 to 213 micrometers) thick backing layer is obtained. Subsequently, the mucoadhesive polymeric diffusion environment was cast onto the backing layer, cured in an oven at about 65 to 95° C. and dried (Col. 20, Lines 40-44) (corresponding to drying step in instant claim 16).
Finn indicates that the backing layer will at least partially or substantially erode or dissolve before the substantial erosion of the mucoadhesive polymeric diffusion environment (Col. 15, lines 37-40), the dissolution or erosion of the water-erodible non-adhesive backing layer primarily controls the residence time of the device after application to the mucosa (Col. 15, lines 46-49), and that the device of the transmucosal drug delivery adhere to the mucosal surface in less than five seconds, and naturally erode in about twenty to thirty minutes, without any need to hold the device in place (Col. 18, lines 64-67) (corresponding to instant claims 18 and 21 with overlapping time ranges).
Sesha throughout the reference teaches pharmaceutical composition comprising therapeutically effective amount of agomelatine in formula (I) for treating pain and pain related disorders (e.g., Abstract, [0009]), without using penetration enhancers.
Sesha teaches that the composition dosage form can be a bilayer form wherein one layer comprising therapeutically effective amount of agomelatine and second active ingredient palmitoylethanolamide (e.g., [0039]), and the composition is suitable for administration by many routes including transmucosal, buccal, transdermal, etc. (e.g., [0045]), for oral administration containing about 0.2-20 wt% of the active agent (e.g., [00105]), and in example 1 [00132], Sesha teaches agomelatine amount at 5.34% (calculated by 12.50/234) in the composition, and example 4 [00153] agomelatine presents drug-containing layer about 5% in the drug-containing release layer (calculated by 25/(375+130) ) (amounts overlapping with from 3 to 7 wt% agomelatine in instant claims 1 and 16).
Sesha teaches suitable binding agents, e.g., hydroxypropyl cellulose, hydroxyethyl cellulose ethylcellulose, and their mixtures can be used, and preferred are water-soluble materials having a weight average molecular weight of 25,000 to 3,000,000 (e.g., [0092]) (corresponding to dissolvable film-forming agents in instant claims 1 and 16, overlapping with molecular weight of hydroxypropyl cellulose molecular weight 75,000 and 85,000 as recited in instant claim 5).
It would have been prima facie obvious for one of ordinary skill in the art prior to the effective filing date of the claimed invention to incorporate the polymer species and agomelatine amount taught by Finn and Sesha into the transmucosal drug delivery system disclosed in Liu to arrive at current invention. Especially as Finn points out that combinations of different polymers or similar polymers with definite molecular weight characteristics can be used in order to achieve preferred film forming capabilities, mechanical properties, and kinetics of dissolution (e.g., Col. 16, Lines 49-52), it would have motivated scientists to select and experiment these polymers taught by Finn to achieve desirable features of the transmucosal drug delivery film. It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Artisans in the field would have reasonable expectations of success because using dissolvable film-forming polymers to replace the polymers in Liu’s structure would yield dissolvable transmucosal agomelatine drug delivery structure, as demonstrated in Finn of the dissolvable features of the polymers in transmucosal drug delivery. The claimed invention is a simple combination of reagents known to be obvious materials that all already taught in prior art and discussed above. The idea for combining them flows logically from them having been individually taught in the prior art. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Further regarding instant claim 16, in light of claim interpretation as presented above, claim 16 is interpreted as “process of making”. MPEP 2113. I. states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). As far as prior art teaches the product, for this instance, the drug delivery mucoadhesive layered structure, even if process of making the product is different from prior art, the patentability depends on the product itself. Let alone, prior art also teaches the process of making in this case.
Further regarding instant claims 11, 13-14, 18 and 21-24, they are interpreted as properties, or “intended use”, or “process of using” of the transmucosal therapeutic system, because they do not structurally contribute to the system. As far as prior art teaches the drug delivery layered structure system, these properties would be present, or be capable to achieve intended use, or be able to obtain the process of using as instantly claimed.
Moreover, MPEP 2145 II. states that “prima facie obviousness is not rebutted by merely recognizing additional advantages or latent properties present but not recognized in the prior art”, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). Furthermore, MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968).
Differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “a prima facie case of obviousness typically exists where the claimed ranges overlap or lie inside ranges disclosed by the prior art". In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). For this instance, the agomelatine amount, area weight of film layers, dissolving times of different layers, polymer molecular weight, and agomelatine permeation rate overlap with those in prior art. Regarding the first and second dissolvable film-forming agent amounts, they overlap with polymer amounts in Liu’s transdermal system, since Finn and Sesha combined teaching provides dissolvable polymer species, artisans in the field could simply swap the polymer species. As Liu teaches that those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease [0028] and Finn teaches that dissolution characteristics may be adjusted to modify the residence time and the release profile of a drug (Col. 16, lines 33-35), while Sesha indicates that water soluble polymers are preferable [0092], artisans in the field will take the opportunity to experiment and adjust component amounts and parameters to optimize the transmucosal device. MPEP §2144.05 (II) states, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than routine experimentation, because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition” See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US20160184246, 06/30/2016, IDS of 10/28/2022), in view of Finn et al. (US9597288, 03/21/2017, IDS of 04/28/2025) and Sesha et al. (WO2013063263, 05/02/2013, PTO-892) as applied to claims 1, 3, 5-11, 13-14, 16 and 18-24 above, and further in view of Singh et al. (US9089481, 06/28/2015).
Combined teaching of Liu, Finn and Sesha, as discussed in great detail as applied to claims 1, 3, 5-11, 13-14, 16 and 18-24 above, and incorporated herein, teaches an agomelatine transmucosal delivery system in layered mucoadhesive film that comprises a drug-containing layer comprising agomelatine at about 5%, at 10.5%, and 0.2-20% (overlapping with instant claim 17 B i) with a first dissolvable film-forming agent, e.g., hydroxypropyl cellulose (corresponding to first dissolvable polymer in instant claim 17); and a backing layer comprising a second dissolvable film-forming agent, which can be a mixture of hydroxyethyl cellulose, hydroxypropyl cellulose, and ethyl cellulose ; the polymer amount in drug-containing layer can be at 89.5% (overlapping with instant claim 17 B ii) and in backing layer up to 100% (corresponding to second dissolvable film-forming agent in instant claim 17), the area weight of the agomelatine-containing layer or backing layer can be roughly at 25 to 175 g/m2 (overlapping with area weight in instant claim 17) while thickness, size, and shape of film routinely adjustable and layer manufacturing process being repetitive known for the artisans with ordinary skills in the art as discussed above, and the system does not have to comprise a penetration enhancer (corresponding to no permeation enhancer as recited in instant claim 17) to provide a therapeutically effective dose of agomelatine when administered to a patient.
Liu further teaches other agents, e.g., enhancers or adjuvants [0063], include fatty acids oleic and linoleic acids [0064], can be used in an amount up to about 35% by dry weight of the polymer matrix, including up to 30% by weight, up to about 20% by weight, including 20% by weight, or up to about 10% by weight, up to 10% by weight, or up to 5% by weight, including up to 5% by weight, based on the dry weight of the polymer matrix [0067]. Since Liu also teaches backing layer can be similarly prepared as drug-containing layer without drug, as discussed above, therefore, Liu teaches fatty acid amount overlapping with from 5 to 15 wt% in instant claim 17 iii) of drug-containing layer and also in backing layer.
Combined teaching of Liu, Finn and Sesha fails to teach sweetener and flavoring agents with weight amount in the transmucosal drug delivery system as recited in instant claim 17.
Singh throughout the reference teaches a film-forming composition that can comprise a water soluble polymer, a blend of a hydrophilic polymer, and active ingredients (e.g., Abstract; Pg. 23, Claim 1), useful as dressings or protectants and for administering a wide variety of active agents to skin and mucosal tissue such as the mouth (Col. 1, Lines 21-26; Col. 4, Lines 38-43; Col. 16 -17; Claim 1).
Singh teaches that sweeteners suitable for the film include sucrose, fructose, aspartame, xylitol and saccharine. Preferably, the composition comprises sweeteners in an amount from about 0.001-5.0 wt % (Page 16, Col. 20, Lines 49-50) (overlapping with sweeteners from 0.1 to 2.0 wt% in instant claim 17). Singh specifies suitable flavorants include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils and oleoresins, as known in the art, as well as combinations thereof can be added to the composition (Page 16, Col. 20, Lines 34-44). Singh teaches the amount of flavorant employed is normally a matter of preference, subject to such factors as flavor type, individual flavor, and strength desired, Preferably, the composition comprises from about 0.1-5 wt % flavorant (Page 16, Col. 20, Lines 44-49) (overlapping with flavoring agent amount from 0.2 to 2.0 wt % in instant claim 17). Singh indicates a typical film thickness is from about 0.050-0.80 mm, preferably 0.25-0.50 mm, and points out that the thickness of the film is not critical, and can be varied according to the specific applications of the film (Page 19, Col. 25, Lines 32-39).
It would have been prima facie obvious for one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the transmucosal agomelatine delivery system taught by Liu, Finn and Sesha with additional sweeteners and flavoring agent taught by Singh to arrive at current invention. MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). Because transmucosal drug delivery in the mouth can be challenging to the patient if the composition contains bitter taste or other undesirable tastes or the patch is too thick to become uncomfortable on oral cavity, it would have motivated artisans in the field to add sweeteners and flavors to taste masking and to adjust the structure weight/thickness with a reasonable expectation of success. Selecting a known component to meet intended use is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). For this instance, since Liu teaches that drug-containing layer and backing layer preparation are repetitive and similar as discussed above, the same excipients and polymers used in one layer can be implemented the same way in another layer. Therefore, the sweeteners, flavoring agents can be contained in backing layer at same amount ranges as in drug-containing layer.
Differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “a prima facie case of obviousness typically exists where the claimed ranges overlap or lie inside ranges disclosed by the prior art". In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It would have been prima facie obvious for one of ordinary skill in the art to optimize the ingredient amount through nothing more than “routine experimentation.” A person of ordinary skill in the art would have found obvious to modify and optimize in ratios, levels, or percent of weight. See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-11, 13-14 and 16-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-21 of copending Application No. 17786235 (filed on 01/31/2023) in view of Liu et al. (US20160184246, IDS of 10/28/2022), Finn et al. (US9597288, 03/21/2017, IDS of 04/28/2025) and Sesha et al. (WO2013063263, 05/02/2013, PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
US’235 recites a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, with the mucoadhesive layer structure comprising an agomelatine-containing layer that comprises agomelatine from 0.1 to 2.0 mg/cm2 amount and a dissolvable film-forming agent with specified species of dissolvable film-forming agent, e.g., hydroxypropyl cellulose, in an amount of at least 75 wt %, or at least 85 wt % (Claim 1). US’235 indicates the dissolvable film-forming agent dissolving time from less than 5 minutes to less than 5 hours with many variable values, at 37 oC and 150 rpm, in water, in artificial or natural saliva, or in any other any other aqueous medium, if casted into a film having an area weight of from 30 to 100 g/m2, or of 50 g/m2 (Claim 2). It provides a long list of the dissolvable film-forming agent for selection including those mentioned in instant invention, and specifies the amount range of the dissolvable film-forming agent as well as the agomelatine amount ranges in the agomelatine-containing layer (Claims 3 and 4).
US’235 exhibits optional excipients that can be added to the agomelatine- containing layer, including fatty acids, sweeteners, flavoring agents, colorants, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffer reagents and further film-forming agents (Claim 5). US’235 indicates the agomelatine-containing layer comprises substantially no water or low amount of water, and the agomelatine-containing layer can be obtained by drying a coated coating composition comprising water or solvent (Claims 6 and 7). US’235 defines the area weight of agomelatine-containing layer of at least 25 g/m2, at least 35 g/m2, or at least 40 g/m2, or has an area weight of less than or equal to 300 g/m2, less than or equal to 250 g/m2, or less than or equal to 200 g/m2, or has an area weight of from 25 to 300 g/m2, from 35 to 250 g/m2, or from 40 to 200 g/m2 (Claim 8). US’235 points out that the mucoadhesive layer structure optionally comprise a cosmetic layer or does not comprise a backing layer (Claim 9). It indicates the mucoadhesive layer structure dissolving time as more than 30 seconds (the shortest) and less than 5 hours (the longest) with various durations (Claim 10).
US’235 describes mucosal permeation rate of agomelatine as measured with pig esophagus mucosa of from 10 pg/cm2-hr to 150 pg/cm2-hr after 1 hour, and/or wherein the transmucosal therapeutic system provides a cumulative release of agomelatine as measured with pig esophagus mucosa of at least 0.02 mg/cm2, at least 0.05 mg/cm2 or at least 0.1 mg/cm2, or less than or equal to 0.5 mg/cm2, less than or equal to 0.4 mg/cm2, or less than or equal to 0.3 mg/cm2, or of from 0.02 mg/cm2 to 0.5 mg/cm2, from 0.05 mg/cm2 to 0.4 mg/cm2, or from 0.1 mg/cm2 to 0.3 mg/cm2 over a time period of 8 hours (Claim 11). US’235 tells that the transmucosal therapeutic system is a method of treatment to a human patient of treating major depression, and the treatment is administered in the evening or at night-time before going to bed to the mucosa of the oral cavity (Claims 13, 14, 19-21).
US’235 describes the manufacture process of an agomelatine-containing layer comprising the steps of. i) combining at least agomelatine and a dissolvable film-forming agent in a solvent to obtain a coating composition; ii) coating the coating composition onto a release liner; and iii) drying the coated coating composition to form the agomelatine-containing layer (Claim 15). US’235 specifies the transmucosal therapeutic system comprising at least A) an agomelatine-containing layer comprising i) 3 to 10 wt % agomelatine-; ii) a dissolvable film-forming agent, and iii) from 5 to 15 wt-% of a fatty acid, iv) from 0.1 to 2 wt-% of one or more sweeteners, and v) from 0.2 to 2.0 wt-% of a flavoring agent wherein the dissolvable film-forming agent is selected from the group consisting of polyvinylpyrrolidone and hydroxypropyl cellulose, and the area weight of the agomelatine-containing layer ranges from 100 to 150 g/m2 (Claim 16). US’235 further indicates that the agomelatine-containing layer comprises agomelatine in dissolved or in dispersed form, or the agomelatine-containing layer is free of agomelatine crystals in the transmucosal therapeutic system according to claim 1 (Claim 17). US’235 provides the same long list of agents as seen in instant claim 20 for selection that can be included in the agomelatine-containing layer including groups of fatty acid, sweeteners, flavoring agents (Claim 18).
US’235 does not recite the backing layer and its components, e.g., mixture of hydroxyethyl cellulose and hydroxypropyl cellulose, weight amount of the polymers, and hydroxypropyl cellulose molecular weight, or the manufacturing of the backing layer in the transmucosal therapeutic system of agomelatine delivery, or its features.
Liu, Finn and Sesha teaches a transmucosal therapeutic system of agomelatine delivery comprising a backing layer and an agomelatine-containing layer with the instantly claimed properties and features, and manufacture of the backing layer as disclosed in greater detail above.
It would have been prima farcie obvious for one of the ordinary skills in the art to have incorporated the backing layer taught by Liu, Finn and Sesha into the agomelatine transmucosal therapeutic system recited by US’235 to arrive at the instant invention. It would have been convenient to implement the backing layer with the method of manufacturing polymer matrix layer taught in Liu and apply similar film-forming agent known from US’235 to add the backing layer into the system. An ordinary skilled artisan would have had a reasonable expectation of success in adding the backing layer because Liu points out that the backing layer is adjacent the drug-containing composition, and when present, the backing layer protects the polymer matrix drug-containing layer from the environment and prevents loss of the drug and/or release of other components to the environment during use [0032]. Even though some amount or value numbers in US’235 or prior art differ from instant invention, they provide the opportunity for inventors to optimize through nothing more than “routine experimentation.” See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5-11, 13-14, and 16-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-2, 4, 9-11, 13-17, 19, 21 and 24 of copending Application No. 17786217 (filed on 06/16/2022), in view of Liu et al. (US20160184246, IDS of 10/28/2022), Finn et al. (US9597288, 03/21/2017, IDS of 04/28/2025), Sesha et al. (WO2013063263, 05/02/2013, PTO-892 and Singh et al. (US9089481, 06/28/2015). Although the claims at issue are not identical, they are not patentably distinct from each other.
US’217 claims a transdermal therapeutic system for agomelatine delivery, which does not comprise a permeation enhancer, comprising a self-adhesive layer structure that comprises a backing layer, an agomelatine-containing layer, and that the agomelatine-containing layer comprises agomelatine, a hydrophobic polymer, and at least 1 wt-% of a crystallization inhibitor. The crystallization inhibitor is selected from the group consisting of PVP and PVP-polyvinylacetate copolymer, and the hydrophobic polymer is a pressure- sensitive adhesives based on polysiloxanes (Claims 1 and 10). US’217 recites the agomelatine-containing layer in the transdermal system is of a microreservoir-type (Claim 2). US’217 indicates optional crystallization inhibitor amount ranges in the agomelatine-containing layer or the crystallization inhibitor is soluble polyvinylpyrrolidone (Claim 4). Both crystallization inhibitor and solubilizer correspond to a first dissolvable film-forming agent in instant application.
US’217 claims an inner phase having a composition comprising the agomelatine forms dispersed deposits in the outer phase in the agomelatine-containing layer (Claim 9). US’217 also provides permeation rate of agomelatine measurement values of the transdermal therapeutic system on human skin range between 0.5 ug/cm2-hr up to 25 ug/cm2-hr at different hours, or a cumulative permeation amount from 0.01 mg/cm2 to up to 0.2 mg/cm2 with many variable values within at hour 8 (Claim 11). US’217 recites the method of treatment administering the transdermal therapeutic system is for the human patient skin treating major depression and is applied onto skin for at least 2 hours to up to 24 hours with variations (Claims 13, 14, and 21).
US’217 discloses the manufacture of an agomelatine-containing layer comprising steps of combining at least agomelatine with the polymers in a solvent to obtain coating composition, then coating it onto a backing layer or a release liner, and drying the coated coating composition to form the drug-containing layer (Claim 15). US’217 further describes the self-adhesive layer structure comprising a backing layer and an agomelatine-containing layer. The agomelatine-containing layer (area weight ranges from 35 to 70 g/m2) can be 2 to 6 wt % agomelatine, 2-7 wt % PVP, 2-7 wt % of a permeation enhancer selected from levulinic acid and polyethlene glycol ethers, and a hydrophobic polymer; or 2 to 6 wt % agomelatine, 7-15 wt % PVP, and a hydrophobic polymer (Claim 16). It further defines the hydrophobic polymer weight range of the agomelatine-containing layer (Claim 17). It specifies that the agomelatine-containing layer is free of agomelatine crystals or it has the area weight of 25 g/m2, at least 35 g/m2, or at least 40 g/m2; or has an area weight of less than or equal to 150 g/m2, less than or equal to 120 g/m2, or less than or equal to 90 g/m2; or has an area weight of from 25 to 150 g/m2, from 35 to 120 g/m2, or from 40 to 90 g/m2 (Claim 19). US’217 recites that the duration times of the transdermal therapeutic system administered on human patient (Claim 21), and provides the agomelatine permeation cumulative rate (Claim 24).
US’217 does not disclose first dissolvable polymer as hydroxypropyl cellulose, or a mixture of one or more polymers selected from hydroxypropyl cellulose and ethyl cellulose in drug delivery system, or a second dissolvable polymer as hydroxypropyl cellulose and hydroxyethyl cellulose, or hydroxypropyl cellulose molecular weight, the first dissolvable film-forming agent area weight or layer dissolving time, or the relative size of the backing layer and the drug-containing layer. US’217 does not use pig esophagus mucosa test for permeation rate of agomelatine, and it does not indicate fatty acid, sweeteners or flavoring agents, neither does it indicate the system is administered to oral cavity mucosa in the evening or night before going to bed.
Liu, Finn, Sesha and Singh teaches a transmucosal therapeutic system of agomelatine delivery comprising backing layer and agomelatine-containing layer to be administered to oral cavity mucosa in the evening, containing a second dissolvable film-forming agent in the backing layer and optional fatty acid in the drug-containing layer, with detailed features and properties of the polymers as well as the layers as instantly claimed as disclosed in greater detail above.
It would have been prima farcie obvious for one of the ordinary skills in the art to have incorporated the excipients taught by Liu, Finn, Sesha and Singh into the transdermal therapeutic system disclosed by US’217 to arrive at instant invention. An ordinary skilled artisan would have had a reasonable expectation of success by swapping crystallization inhibiting and soluble polymers with the specific dissolvable polymers taught by prior art, and adding in sweeteners and flavors to the drug delivery system for oral cavity treatment, especially because sweeteners and flavoring agents can cover up or mask undesirable tastes of the transdermal drug delivery system. Even though some amount or value numbers in US’217 or prior art differ from instant invention, they provide the opportunity for inventors to optimize through nothing more than “routine experimentation.” See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). For different parameters or test results like permeation rates or dissolving times, "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants’ arguments and remarks filed on 12/11/2025 have been fully considered. New grounds of rejections are presented in this office action in light of applicant’s amendments.
The following are responses addressing the arguments involving art rejections over the prior art references that are used in current office action.
Applicant asserts that a skilled artisan would not have combined Liu with Finn because Liu and Finn deliver different actives with different objectives and by different delivery systems, e.g., Liu relates to a transdermal agomelatine delivery system with an enhancer, and by selecting and controlling the type and amount of enhancer, to achieve drug delivery over a relatively short period of time, e.g., 12 hours or less, while Finn relates to transmucosal device delivering fentanyl in less than 30 minutes.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, both Liu and Finn teaches transdermal drug delivery devices using similar dissolvable celluloses, as presented in office action above: Liu teaches dissolvable film-forming agent, e.g., hydroxyethyl cellulose, and Finn teaches hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose, etc., while Finn’s device is used to deliver different drugs other than agomelatine, e.g., fentanyl, fentanyl structure is a monocarboxylic acid amide (not a salt) and agomelatine is a member of acetamides. Therefore, they are generally similar transdermal drug delivery systems.
Regarding Liu uses an enhancer in the drug delivery system, as presented in this office action above, Liu does not have to use an enhancer in some embodiments. The permeation enhancer does not divide Liu and Finn into two totally different transdermal devices because an enhancer is just one agent in the system. Moreover, applicant does not provide clear definition of permeation enhancers, and the components used in instant invention, e.g., fatty acids oleic acid, linoleic acid, along with accelerants, adjuvants, and sorption promoters all are collectively referred to in Liu as penetration enhancers [0063-0064]. Thus, Liu and instant invention uses same permeation enhancing agents, or adjuvants, or excipients as the instant claimed adjuvants/excipients (e.g. instant claim 8). While based upon instant specification and in light of claim interpretation, Liu also does not use enhancer. Further, Finn device can optionally use enhancer (e.g., polyvinyl alcohol or polyvinyl pyrrolidone) (Col. 16, line 66). In conclusion, devices Liu and Finn are similar transdermal devices just like instant invention.
As Liu points out that the specific type(s) and relative amounts of polymer matrix components and penetration enhancer(s) can be selected and adjusted to control and modify the properties of the system, including the drug delivery profile ( e.g., pharmacokinetic profile) and physical properties ( e.g., adhesion, tackiness, wear, etc.) (e.g., [0060]), the drug delivery time duration difference between Liu and Finn, on the contrary to applicant’s assertion, provides artisans motivation to combine the teaching when shorter delivery time is desirable, especially using dissolvable polymers in the layered structure.
Applicant asserts that Liu requires enhancer, Finn also uses a permeation enhancer, which is excluded by the amended claims, and Finn does not teach the claimed amount of hydroxypropyl cellulose and hydroxyethyl cellulose.
In light of the amendment, over teachings from Liu, Finn and Sesha, new grounds of rejections are shown for transdermal layered film delivering agomelatine without enhancers. Please refer to the entire office action for detail. Regarding argument involving previous art rejections over Liu and Finn, evidence is shown that Liu or Finn does not have to include an enhancer in the system as copied below for reference:
Regarding agomelatine-containing layer does not comprise a permeation enhancer, Liu points out that “penetration enhancer” is an agent known to accelerate the delivery of the drug through the skin and these agents also have been referred to as accelerants, adjuvants, and sorption promoters, and are collectively referred to as “enhancers” [0063]. Liu points out that in accordance with some embodiments, the transdermal drug delivery systems described herein consist of a backing, a drug-containing composition (e.g., drug-in-solution reservoir, drug-in-gel reservoir, or drug-in-polymer matrix layer), and a release liner, as illustrated in FIG. 1A with regard to drug-in-polymer matrix embodiments, and as illustrated in FIG. 1C with regard to reservoir-type systems. In accordance with some embodiments, the transdermal drug delivery systems described herein consist of a backing, a drug-containing layer, a face adhesive, and a release liner, as illustrated in FIG. 1B [0039], without penetration enhancers. Sue continues with “in specific embodiments, the face adhesive is a silicone face adhesive comprising a silicone adhesive, such as a silicone pressure-sensitive adhesive and, optionally, one or more penetration enhancers” [0039]. Sue indicates later once again, in a drug-in-polymer matrix system, the drug is formulated in a polymer matrix, such as a pressure-sensitive adhesive polymer matrix, optionally with a penetration enhancer [0057]; and “as noted above, in some embodiments, the transdermal delivery system described include a penetration enhancer” [0062]. Therefore, Liu does not always add permeation enhancers to the drug delivery system. In light of claim interpretations of claims 1 and 16 as presented above, Liu exhibits embodiment examples 2 and 3 [0107]-[0114] comprising agomelatine polymer matrix without a permeation enhancer from the defined enhancer list as interpreted (corresponding to claims 1 and 16).
Applicant uses Liu’s examples 2 and 3 requiring a permeation enhancer isopropanol IPA, and Finn’s example 1 containing propylene glycol and vitamin E acetate to show Liu and Finn both require enhancers in the system. The teaching of reference is based on the entirety of the reference, not limited by examples, as stated in office action above: MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968).
Moreover, as discussed above, applicant does not clearly classify or define enhancers, and it appears that Liu shares agents present in instant claim set as enhancers, e.g., fatty acids linoleic acid and oleic acid. Therefore, based on prior art teaching, current invention uses enhancers too. In light of claim interpretation as presented, in order to clarify applicant’s term of enhancers, only the ones mentioned in instant specification are considered as enhancers. Based on the interpreted terminology according to instant specification, isopropanol, vitamin E, and propylene glycol are not enhancers.
Applicant asserts that applicant’s transmucosal therapeutic system exhibits an unexpected technical effect that the incorporation of the first and second dissolvable film-forming agents in the specified amounts as recited in claim 1 results in advantageous mucoadhesion and excellent dissolution behavior, as compared to other reference film-forming agents, e.g., PVA, Povidone K90, or other amounts.
MPEP 716.02(d) states "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). Applicant points to the unexpected results generated from examples 9c, e, f and 11a-i containing about 5% agomelatine in specification (Table 12.1) with polymers in agomelatine-containing layer, Ex. 9c containing HPC GF and HPC EF total 81%, Ex. 9c having HPC EF and EC N50NF total 80.7%, Ex. 9f having HPC LF 80.8%; Ex. 11a having HPC EF 80.8%, Ex. 11b having PVA 81.0%, Ex. 11c having Providone K90 80.9%, Ex. 11d having HPC GF and HPC EF total 81%, Ex. 11e having HPC EF and EC N50NF 31.6%, Ex. 11f having HPC LF 80.8%, Ex. 11h having Povidone 80.9%, Ex. 11i having PVA 81.0%. In backing layer Ex. 9c, 9e, 9f, 11a, 11b, 11c having 29.4% HPC EF and 58.6% HEC, while Ex. 11d-i having 54.5% HPC EF and 23.4% Eudragit L100.
These amount points in experiments do not commensurate with the claimed scope ranges in claim 1. Because the claimed ranges in claim 1 as agomelatine from 3 to 7%, but the data sets only show agomelatine about 5% (4.98%, 4.99%, and 5%); at least 70% and less than or equal to 98% of the first dissolvable film-forming agent is claimed, while the data only show amount points about 81%; at least 75% of the second dissolvable film-forming agent, while the data only represent total 88% or 78.9%.
Furthermore, claim 1 recites hydroxypropyl cellulose, ethyl cellulose, hydroxylethyl cellulose can be any of these celluloses with different MW polymers. The data only using a couple of types of the polymers with specific molecular weights in HF, GF, LF, and EF grades, and therefore, the data is not enough to show for the entire claimed scope of any MW hydroxypropyl and/or with hydroxyethyl cellulose or ethyl cellulose.
Applicant draws unexpected results from the experiments that are not compared directly to the closest prior art. Experiments show that drug-containing layer containing hydroxypropyl cellulose (e.g., experiment 11a) is compared to having PVA (e.g., experiment 11b and 11 i) or Povidone K90 (e.g., experiment 11c and 11h), wherein experiments 11b and 11i product coiled up, and 11c and 11h exhibited unacceptable adhesion behavior. However, the polymers PVA and Povidone K90 are not the polymers presented in office action in the closest prior art as presented above. Specifically, Finn teaches hydroxypropyl cellulose and hydroxyethyl cellulose which are relevant to the art rejection as presented, and Liu teaches the agomelatine delivery device with polymer amounts in the drug containing layer as well as backing layer with no mentioning of PVA or Povidone K90. The experiments are not comparing to the closest prior art.
Moreover, the conclusion of unexpected results is not established as significant, because the results of adhesive and/or dissolution profiles are not statistically assessed. Adhesive behavior being acceptable or unacceptable, excellent, moderate or good, as well as the dissolution time appear to be unconclusive based on Table 12.1. Taking Ex. 11a and Ex. 11b as an example, Ex. 11a contains HPC as in claim 1, and Ex. 11b having PVA and Ex. 11c having Povidone K90 in the drug containing layer, and all three experiments have the same backing layer as claim 1, the evaluation mucoadhesion indicates 11a has initial excellent and over time good result, while 11c also shows the same mucoadhesion result as 11a. Further, as applicant points out that Ex. 11b coiled up, however, as specification [0413] indicates “ both samples of Example 11b coiled up about 1 minute after application, and did no more adhere to the mucosa. After 3 minutes, the samples uncoiled itself and adhered again”. Therefore, the conclusion of using HPC is critical over Povidone K90 in drug containing layer is not convincing based on mucoadhesion data.
In addition, Ex. 11a shows dissolution time 5.3 hr, 6 hr as system complete, while 11b also shows 5 hr, 5.5hr system complete; meanwhile “-“ indicating no observation for Ex. 11a regarding AL and BL dissolution times, therefore, Ex. 11b data of AL and BL do not have direct comparison to Ex. 11a; therefore, based on the system completion times, whether 5.3 hr, 6 hr in Ex. 11a vs. 5 hr, 5.5 hr in Ex. 11b is significantly different is in doubtful.
Moreover, because Liu, Finn and Sesha teaches the specific polymers with amounts as instantly claimed in claim 1, it would have been expected to have the polymers to dissolve at certain rate depending on Finn’s teaching that hydroxypropyl cellulose and hydroxyethyl cellulose polymers are readily dissolvable, and are routinely used in transmucosal formulations. The results in instant specification showing experiments containing such polymers and amounts as recited in claim 1, e.g., Experiments 9c, 9e, 9f, and 11a, would have been expected, and it is obvious that the results affirm the drug delivery device created based upon prior art teaching can achieve such outcome.
In summary, the unexpected results thus are not unexpected over prior art.
Applicant asserts that POSA would not have combined Singh with Liu and Finn in Claim 17 rejection because Singh discloses a hydrogel composition for dental care focusing on whitening, not delivering a therapeutic agent.
As presented in office action Singh cures the teaching deficiency of Liu, Finn and Sesha, as shown in the new grounds of rejection in light of amendment, specifically relevant to applicant’s assertion, Singh teaches transmucosal delivery system in the form of film for administering wide variety of active ingredients, the most relevant parts copied below:
Singh throughout the reference teaches a film-forming composition that can comprise a water soluble polymer, a blend of a hydrophilic polymer, and active ingredients (e.g., Abstract; Pg. 23, Claim 1), useful as dressings or protectants and for administering a wide variety of active agents to skin and mucosal tissue such as the mouth (Col. 1, Lines 21-26; Col. 4, Lines 38-43; Col. 16 -17; Claim 1).
It would have been prima facie obvious for one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the transmucosal agomelatine delivery system taught by Liu, Finn and Sesha with additional sweeteners and flavoring agent taught by Singh to arrive at current invention. MPEP 2144.01 points out "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). Because transmucosal drug delivery in the mouth can be challenging to the patient if the composition contains bitter taste or other undesirable tastes or the patch is too thick to become uncomfortable on oral cavity, it would have motivated artisans in the field to add sweeteners and flavors to taste masking and to adjust the structure weight/thickness with a reasonable expectation of success. Selecting a known component to meet intended use is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
In conclusion, applicant’s argument is not persuasive. Prior art teaches the current invention.
Please refer to the entire office action as a complete response to remarks/arguments.
A request to hold non-statutory double patenting rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP §714.02 and 37 CFR 1.111(b)). Also, the cancellations of claims 4 and 15 do not traverse the other claims being provisionally rejected on the grounds of non-statutory obviousness rejection, as presented in this office action above. Thus, the double patenting rejection(s) of record has/have been maintained as no further action regarding these rejections has been taken by Applicants at this time.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DONGXIU ZHANG SPIERING whose telephone number is (703)756-4796. The examiner can normally be reached 7:30am-5:00pm (Except for Fridays).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, SUE X. LIU can be reached at (571)272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DX.Z./Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616