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 .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on 22 December 2025 are acknowledged and have been fully considered. Claims 1-11 and 13-21 are pending. Claims 1-11 and 16-18 are under consideration in the instant office action. Claims 13-15 and 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 12 is canceled. Applicant’s claim amendments and arguments necessitated a new ground of rejections such as under 35 USC 103 as set forth below.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 22 December 2025 is noted and the submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the references. A signed copy is attached herein.
Election/Restrictions
Applicant argues that in addition, this application is US national phase of PCT/EP2020/077735. According to the international Search Report mailed on November 30, 2020, unity of invention is not lacking. But even assuming the RR was proper, which Applicant does not concede, Applicant requests that, upon allowance of the product claims of Group I, the method of treatment claims in Group II and method of manufacturing claims in Group III be rejoined, because: 1) the claims of Groups II depend directly or indirectly from product claim 1 of Group I; and 2) the claims of Group III contain all the elements of the product claims of Group I, and thus are eligible for rejoinder.
The examiner notes that and as indicated in the election/restriction requirement once an allowable product is identified process of making the allowable product and process of use utilizing the allowable product may be eligible for rejoinder.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Moot Arguments
Applicant’s arguments with respect to claim(s) 1-11 and 16-18 have been considered but are moot because of the new ground of rejections set forth below under 35 USC 103 addressing the new limitations added in the rejection.
New Rejections-Necessitated by Amendments
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-7, 9-10, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Kadbhane et al. (International Journal of ChemTech Research, 2017,10(10): 497-505, previously cited) in view of Myers et al. (US 2011/0033541, previously cited) and Bernardo et al. (WO 2020/014431, with effective filing date of July 11, 2019, newly cited).
Applicants’ claims
Applicants claim a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising the ingredients as recited.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Kadbhane et al. teach orally Fast dissolving film (OFDF) is a dosage form which placed in the oral cavity, quickly gets hydrated, sticks onto the site of application and then disintegrates to release the drug. Agomelatine is an antidepressant also used for mood disorders such as anxiety and obsessive compulsive disorder. Fast dissolving films of Agomelatine were prepared by solvent casting technique. HPMC E-15 was selected as polymer because of its good water solubility. Polyvinyl pyrrolidone K-30(PVP K-30) as superdisintegrant and polyvinyl alcohol as film forming agent. Mannitol as sweetener and saliva stimulating agent used in the formulation. The compatibility of the drug in the formulation was confirmed by FTIR studies. A various concentration of polymers was used in order to optimize API concentration of the new dosage form. The orally fast dissolving film was characterized for weight, thickness, folding endurance, tensile strength and dissolution using In-vitro experimentations. The effect of PVA and PVP K-30 on drug release profile and film forming properties was investigated. Estimation of drug content of films was performed and the results were satisfactory. In-vitro dissolution studies revealed higher drug release from formulation F6 batch (see abstract).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Kadbhane et al. do not specifically teach hydroxypropyl cellulose (HPC) as the dissolving film forming agent and the amount of HPC. Additionally, Kadbhane et al. do not specifically teach the incorporation of the ingredients recited in claim 16 and their respective amounts. These deficiencies are cured by the teachings of Myers et al.
Myers et al. teach oral dissolving films generally fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Fast dissolving films generally dissolve in about 1 second to about 30 seconds in the mouth. Moderate dissolving films generally dissolve in about 1 to about 30 minutes in the mouth, and slow dissolving films generally dissolve in more than 30 minutes in the mouth. Fast dissolving films may consist of low molecular weight hydrophilic polymers (i.e., polymers having a molecular weight between about 1,000 to 9,000, or polymers having a molecular weight up to 200,000). In contrast, slow dissolving films generally have high molecular weight polymers (i.e., having a molecular weight in the millions) (paragraph 0019). Moderate dissolving films tend to fall in between the fast and slow dissolving films. Moderate dissolving films dissolve rather quickly, but also have a good level of mucoadhesion. Moderate dissolving films are also flexible, quickly wettable, and are typically non-irritating to the user. For the instant invention, it is preferable to use films that fall between the categories of fast dissolving and moderate dissolving. Such moderate dissolving films provide a quick enough dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion level such that the film is not easily removable once it is placed in the oral cavity of the user (paragraph 0020). The film dosage composition preferably includes a polymeric carrier matrix. Any desired polymeric carrier matrix may be used, provided that it is orally dissolvable. Desirably, the dosage should have enough bioadhesion to not be easily removed and it should form a gel like structure when administered. The orally consumable films are preferably moderate-dissolving in the oral cavity and particularly suitable for delivery of actives, although both fast and sustained release compositions are also among the various embodiments contemplated (paragraph 0023). The films used in the pharmaceutical products may be produced by a combination of at least one polymer and a solvent, optionally including other fillers known in the art. The solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film may be prepared by utilizing a selected casting or deposition method and a controlled drying process (paragraph 0024). The polymer included in the films may be water-soluble, water-swellable, water-insoluble, or a combination of one or more either water-soluble, water-swellable or water-insoluble polymers. The polymer may include cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof For higher dosages, it may be desirable to incorporate a polymer that provides a high level of viscosity as compared to lower dosages (paragraph 0025). For instance, in some embodiments, the films may include polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof. Suitable water-soluble polymers include, without limitation, any of those provided above. In some embodiments, the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. In accordance with some embodiments, polyethylene oxide may range from about 20% to 100% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. In some embodiments, one or more water-swellable, water-insoluble and/or biodegradable polymers also may be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble or biodegradable polymers provided above may be employed. The second polymer component may be employed in amounts of about 0% to about 80% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight (paragraph 0032). A variety of optional components and fillers also may be added to the films. These may include, without limitation: surfactants; plasticizers; polyalcohols; anti-foaming agents, such as silicone-containing compounds, which promote a smoother film surface by releasing oxygen from the film; thermo-setting gels such as pectin, carageenan, and gelatin, which help in maintaining the dispersion of components; inclusion compounds, such as cyclodextrins and caged molecules; coloring agents; and flavors. In some embodiments, more than one active components may be included in the film (paragraph 0034). Additives may be included in the films. Examples of classes of additives include excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These additives may be added with the active ingredient(s) (paragraph 0035). There may further be added compounds to improve the texture properties of the starch material such as animal or vegetable fats, desirably in their hydrogenated form, especially those which are solid at room temperature. These fats desirably have a melting point of 50° C. or higher. Preferred are tri-glycerides with C12-, C14-, C16-, C18-, C20- and C22-fatty acids. These fats can be added alone without adding extenders or plasticizers and can be advantageously added alone or together with mono- and/or di-glycerides or phosphatides, especially lecithin. The mono- and di-glycerides are desirably derived from the types of fats described above, i.e. with C12-, C14-, C16-, C18-, C20- and C22-fatty acids (paragraph 0040). The total amounts used of the fats, mono-, di-glycerides and/or lecithins are up to about 5% and preferably within the range of about 0.5% to about 2% by weight of the total film composition (paragraph 0041). The use of active agents, sweeteners, and flavors in overlapping amounts as recited in claim 16 is taught in Table 5 of formulations 1-3).
Kadbhane et al. and Myers et al. do not specifically teach the agomelatine containing layer comprises from 0.1 to 2.0 mg/cm2 agomelatine as recited in claims 1 and 16. These deficiencies are cured by the teachings of Bernardo et al.
Bernardo et al. teach an orally disintegrating film matrix (e.g., oral dissolvable film) that includes a rapidly dissolving binder, a film forming polymer, a moisture deterring polymer, and at least one of a first active ingredient and a second active ingredient. Also provided is a method of forming an orally disintegrating film matrix (e.g., oral dissolvable film) and kits that include the oral dissolvable film. Also provided is a method of delivering one or more active ingredients to a subject that include orally administering the oral dissolvable film (see abstract). An orally disintegrating film matrix comprising: rapidly dissolving hinder comprising polyvinyl alcohol (PVA) and polyvinyl alcohol (PVA)— polyethylene glycol (PEG) copolymer; and film forming polymer comprising hydroxypropyl methyl cellulose (HPMC); wherein, the orally disintegrating film matrix has a moisture content of less than 8 wt.%; and upon contact with the oral cavity, the orally disintegrating film matrix disintegrates within 60 seconds (see claim 1). The orally disintegrating film matrix of claim 1, further comprising a first active ingredient (see claim 3) . An orally disintegrating film matrix comprising: first active ingredient; rapidly dissolving binder comprising polyvinyl alcohol (PVA) and polyvinyl alcohol (PVA)— polyethylene glycol (PEG) copolymer; and film forming polymer comprising hydroxypropyl methyl cellulose (HPMC); wherein, the orally disintegrating film matrix has a moisture content of less than 8 wt.%, and upon contact with the oral cavity, the orally disintegrating film matrix disintegrates within 60 seconds (see claim 4) The term “active ingredient” is used to include any “drug,” “bioactive agent,” “preparation,” “medicament,” “therapeutic agent,” “physiological agent,” “nutraceutical,” or “pharmaceutical agent” and includes substances for use in the treatment of a disease or disorder (see page 13, lines 21-28). Buccal films provide for the transmucosal delivery of active ingredient. When the oral dissolvable film is a buccal film, the patient will typically wet the inside of the cheek or rinse the mouth with water to wet the area for placement of the buccal film. This may help the film stick and dissolve more easily. The buccal film can then be applied against the inside of the cheek (page 17, lines 17-21). The oral dissolvable films described herein are capable of accommodating a wide range of amounts of the active ingredient. The films are therefore capable of providing a relatively precise and accurate dosage amount (determined by the size of the film and concentration of the active in the slurry), regardless of whether the required dosage is high or low. For example, the oral dissolvable films described herein can include the active ingredient in up to about 10 mg/cm2 (page 18, lines 23-28). In specific embodiments, the orally disintegrating film matrix has a content uniformity, such that among two or more samples, the amount of second active ingredient ranges from 90% to 110%, with the standard deviation of less than or equal to 6%. In specific embodiments, the first active ingredient is present in 0.1 mg/cm2 to 10 mg/cm2 of the orally disintegrating film matrix. In specific embodiments, the first active ingredient is present in 4 ± 2.5 mg/cm2 of the orally disintegrating film matrix (page 49, lines 22-30 and page 50, lines 1-10).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Kadbhane et al. by substituting HPMC with hydroxypropyl cellulose as the film forming agent in amounts as recited because Myers et al. teach oral dissolving films generally fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Fast dissolving films generally dissolve in about 1 second to about 30 seconds in the mouth. Moderate dissolving films generally dissolve in about 1 to about 30 minutes in the mouth, and slow dissolving films generally dissolve in more than 30 minutes in the mouth. Fast dissolving films may consist of low molecular weight hydrophilic polymers (i.e., polymers having a molecular weight between about 1,000 to 9,000, or polymers having a molecular weight up to 200,000). In contrast, slow dissolving films generally have high molecular weight polymers (i.e., having a molecular weight in the millions) (paragraph 0019). Moderate dissolving films tend to fall in between the fast and slow dissolving films. Moderate dissolving films dissolve rather quickly, but also have a good level of mucoadhesion. Moderate dissolving films are also flexible, quickly wettable, and are typically non-irritating to the user. For the instant invention, it is preferable to use films that fall between the categories of fast dissolving and moderate dissolving. Such moderate dissolving films provide a quick enough dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion level such that the film is not easily removable once it is placed in the oral cavity of the user (paragraph 0020). The film dosage composition preferably includes a polymeric carrier matrix. One of ordinary skill in the art would have been motivated to do so because Myers et al. teach that any desired polymeric carrier matrix may be used, provided that it is orally dissolvable. Desirably, the dosage should have enough bioadhesion to not be easily removed and it should form a gel like structure when administered. The orally consumable films are preferably moderate-dissolving in the oral cavity and particularly suitable for delivery of actives, although both fast and sustained release compositions are also among the various embodiments contemplated (paragraph 0023). The films used in the pharmaceutical products may be produced by a combination of at least one polymer and a solvent, optionally including other fillers known in the art. The solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film may be prepared by utilizing a selected casting or deposition method and a controlled drying process (paragraph 0024). The polymer included in the films may be water-soluble, water-swellable, water-insoluble, or a combination of one or more either water-soluble, water-swellable or water-insoluble polymers. The polymer may include cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof For higher dosages, it may be desirable to incorporate a polymer that provides a high level of viscosity as compared to lower dosages (paragraph 0025). For instance, in some embodiments, the films may include polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water-soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof. Suitable water-soluble polymers include, without limitation, any of those provided above. In some embodiments, the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. In accordance with some embodiments, polyethylene oxide may range from about 20% to 100% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. In some embodiments, one or more water-swellable, water-insoluble and/or biodegradable polymers also may be included in the polyethylene oxide-based film. Any of the water-swellable, water-insoluble or biodegradable polymers provided above may be employed. The second polymer component may be employed in amounts of about 0% to about 80% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight (paragraph 0032) The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). Additionally, it should be noticed that HPMC and HPC are functionally equivalent as demonstrated by Myers et al. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Kadbhane et al. and Myers et al. because both references teach film based active agent deliveries. Furthermore, in the case where the claimed amounts of active agents and other ingredients like polymers "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). It is within the purview of one of ordinary skill in the art to optimize the concentration or amounts of actives and other ingredients absent evidence to the contrary.
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Kadbhane et al. and Myers et al. by incorporating agomelatine in the agomelatine containing layer in amounts of 0.1 to 2.0 mg/cm2 because Bernardo et al. teach an orally disintegrating film matrix (e.g., oral dissolvable film) that includes a rapidly dissolving binder, a film forming polymer, a moisture deterring polymer, and at least one of a first active ingredient and a second active ingredient. Also provided is a method of forming an orally disintegrating film matrix (e.g., oral dissolvable film) and kits that include the oral dissolvable film. Also provided is a method of delivering one or more active ingredients to a subject that include orally administering the oral dissolvable film (see abstract). An orally disintegrating film matrix comprising: rapidly dissolving hinder comprising polyvinyl alcohol (PVA) and polyvinyl alcohol (PVA)— polyethylene glycol (PEG) copolymer; and film forming polymer comprising hydroxypropyl methyl cellulose (HPMC); wherein, the orally disintegrating film matrix has a moisture content of less than 8 wt.%; and upon contact with the oral cavity, the orally disintegrating film matrix disintegrates within 60 seconds (see claim 1). The orally disintegrating film matrix of claim 1, further comprising a first active ingredient (see claim 3) . An orally disintegrating film matrix comprising: first active ingredient; rapidly dissolving binder comprising polyvinyl alcohol (PVA) and polyvinyl alcohol (PVA)— polyethylene glycol (PEG) copolymer; and film forming polymer comprising hydroxypropyl methyl cellulose (HPMC); wherein, the orally disintegrating film matrix has a moisture content of less than 8 wt.%, and upon contact with the oral cavity, the orally disintegrating film matrix disintegrates within 60 seconds (see claim 4) The term “active ingredient” is used to include any “drug,” “bioactive agent,” “preparation,” “medicament,” “therapeutic agent,” “physiological agent,” “nutraceutical,” or “pharmaceutical agent” and includes substances for use in the treatment of a disease or disorder (see page 13, lines 21-28).One of ordinary skill in the art would have been motivated to do so because Bernardo et al. teach that buccal films provide for the transmucosal delivery of active ingredient. When the oral dissolvable film is a buccal film, the patient will typically wet the inside of the cheek or rinse the mouth with water to wet the area for placement of the buccal film. This may help the film stick and dissolve more easily. The buccal film can then be applied against the inside of the cheek (page 17, lines 17-21). The oral dissolvable films described herein are capable of accommodating a wide range of amounts of the active ingredient. The films are therefore capable of providing a relatively precise and accurate dosage amount (determined by the size of the film and concentration of the active in the slurry), regardless of whether the required dosage is high or low. For example, the oral dissolvable films described herein can include the active ingredient in up to about 10 mg/cm2 (page 18, lines 23-28). In specific embodiments, the orally disintegrating film matrix has a content uniformity, such that among two or more samples, the amount of second active ingredient ranges from 90% to 110%, with the standard deviation of less than or equal to 6%. In specific embodiments, the first active ingredient is present in 0.1 mg/cm2 to 10 mg/cm2 of the orally disintegrating film matrix. In specific embodiments, the first active ingredient is present in 4 ± 2.5 mg/cm2 of the orally disintegrating film matrix (page 49, lines 22-30 and page 50, lines 1-10). Furthermore, in the case where the claimed amounts of agomelatine "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Kadbhane et al., Myers et al., and Bernardo et al. because the references teach oral dissolvable films for the delivery of active agents. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). It is within the purview of one of ordinary skill in the art to optimize the concentration or amounts of actives and other ingredients absent evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 2, 8, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kadbhane et al. (International Journal of ChemTech Research, 2017,10(10): 497-505, previously cited) in view of Myers et al. (US 2011/0033541, previously cited) and Bernardo et al. (WO 2020/014431, with effective filing date of July 11, 2019, newly cited) as applied to claims 1, 3-7, 9-10, and 17-18 above, and further in view of Krekeler (WO 2016/009001).
Applicants’ claims
Applicants claim a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising the ingredients as recited. Instant claim 2 recites when casted the film having an area weight of from 30-100 g/m2, or 50 g/m2 and other features. Instant claims 8 and 16 also recite similar area weights.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Kadbhane et al., Myers et al., and Bernardo et al. are described in detail above and are incorporated by reference herein.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Kadbhane et al., Myers et al., and Bernardo et al. do not specifically teach when casted the film having an area weight of from 30-100 g/m2, or 50 g/m2 as recited in claim 2 and the area weights recited in claims 8 and 16. These deficiencies are cured by the teachings of Krekeler.
Krekeler teaches an orodispersible film comprising a) a plant extract; and b) a film forming polymer wherein the film forming polymer has a number average molecular weight (Mn) ranging from 15000 Da (g/mol) to 30000 Da (g/mol) (see claim 1). The orodispersible film or the film forming suspension according to any of the preceding claims, wherein the film forming polymer is selected from cellulose, cellulose ester (such as cellulose acetate), cellulose ether (such as hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose) polyethylene oxide, polyvinyl pyrrolidone (e.g. PVP K-90), polyvinyl alcohol, pullulan, starch, modified starch, gelatin, pectin, alginate and combinations thereof (see claim 6). Typically the orodispersible film has a weight that ranges from 70 to 100 g/m2, preferably it is 80 g/m2 (paragraph 0058). The percentage amounts refer to the dry weight of the film forming suspension. Additionally, the suspension comprises water or a solvent system. Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system. Preferably, the amount of solvent other than water in the solvent system is from 0% (v/v) to 65% (v/v), preferably from 20% (v/v) to 40% (v/v), even more preferably from 25% (v/v) to 35% (v/v) of the solvent system. Hence in the preferred solvent system of water/ethanol, the amount of ethanol is from 0% (v/v) to 65% (v/v), preferably from 20% (v/v) to 40% (v/v), even more preferably from 25% (v/v) to 35% (v/v). The percentage amounts refer to the solvent system (paragraph 0078).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Kadbhane et al., Myers et al., and Bernardo et al. by preparing the dissolvable films having area weights as recited in claims 2, 8, and 16 because Krekeler teaches an orodispersible film comprising a) a plant extract; and b) a film forming polymer wherein the film forming polymer has a number average molecular weight (Mn) ranging from 15000 Da (g/mol) to 30000 Da (g/mol) (see claim 1). The orodispersible film or the film forming suspension according to any of the preceding claims, wherein the film forming polymer is selected from cellulose, cellulose ester (such as cellulose acetate), cellulose ether (such as hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose) polyethylene oxide, polyvinyl pyrrolidone (e.g. PVP K-90), polyvinyl alcohol, pullulan, starch, modified starch, gelatin, pectin, alginate and combinations thereof (see claim 6). One of ordinary skill in the art would have been motivated to do so because Krekeler teach that this type of disperasable or dissolvable film has a weight that ranges from 70 to 100 g/m2, preferably it is 80 g/m2 (paragraph 0058). The percentage amounts refer to the dry weight of the film forming suspension. Additionally, the suspension comprises water or a solvent system. Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system. Preferably, the amount of solvent other than water in the solvent system is from 0% (v/v) to 65% (v/v), preferably from 20% (v/v) to 40% (v/v), even more preferably from 25% (v/v) to 35% (v/v) of the solvent system. Hence in the preferred solvent system of water/ethanol, the amount of ethanol is from 0% (v/v) to 65% (v/v), preferably from 20% (v/v) to 40% (v/v), even more preferably from 25% (v/v) to 35% (v/v). The percentage amounts refer to the solvent system (paragraph 0078). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). Additionally, it should be noticed that Krekeler teach the orodispersible or dissolvable films made from the same materials HPMC and HPC. "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Kadbhane et al., Myers et al., Bernardo et al., and Krekeler because all of the references teach orally dissolvable films for the delivery of active agents. Furthermore, in the case where the claimed amounts of active agents and other ingredients like polymers "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). It is within the purview of one of ordinary skill in the art to optimize the concentration or amounts of actives and other ingredients, area weights, etc., absent evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kadbhane et al. (International Journal of ChemTech Research, 2017,10(10): 497-505, previously cited) in view of Myers et al. (US 2011/0033541, previously cited) and Bernardo et al. (WO 2020/014431, with effective filing date of July 11, 2019, newly cited) as applied to claims 1, 3-7, 9-10, and 17-18 above, and further in view of Schobel et al. (US 2018/0200198).
Applicants’ claims
Applicants claim a transmucosal therapeutic system for the transmucosal administration of agomelatine comprising a mucoadhesive layer structure, said mucoadhesive layer structure comprising the ingredients as recited. Instant claim 11 recites permeation rates of the active agent from the film.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Kadbhane et al., Myers et al., and Bernardo et al. are described in detail above and are incorporated by reference herein.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Kadbhane et al., Myers et al., and Bernardo et al. do not specifically teach the permeation rates of active agent from the film as recited in claim 11. These deficiencies are cured by the teachings of Schobel et al.
Schobel et al. teach active ingredients, such as drugs or pharmaceuticals, are delivered to patients in deliberate fashion. Delivery of drugs or pharmaceuticals using film transdermally or transmucosally can require that the drug or pharmaceutical permeate or otherwise cross a biological membrane in an effective and efficient manne (paragraph 0003). A pharmaceutical composition, comprising: a polymeric matrix; a pharmaceutically active component in the polymeric matrix; and an adrenergic receptor interacter (see claim 1). The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a film further comprising a polymeric matrix, the pharmaceutically active component being contained in the polymeric matrix (see claim 6 and paragraph 0008). Oral dissolving films can fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Oral dissolving films can also include a combination of any of the above categories. Fast dissolving films can dissolve in about 1 second to about 30 seconds in the mouth, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderate dissolving films can dissolve in about 1 to about 30 minutes in the mouth including more than 1 minute, more than 5 minutes, more than 10 minutes, more than 20 minutes or less than 30 minutes, and slow dissolving films can dissolve in more than 30 minutes in the mouth. As a general trend, fast dissolving films can include (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight between about 1,000 to 9,000 daltons, or polymers having a molecular weight up to 200,000 daltons). In contrast, slow dissolving films generally include high molecular weight polymers (e.g., having a molecular weight in millions). Moderate dissolving films can tend to fall in between the fast and slow dissolving films (paragraph 0119). Permeation rates that are overlapping in range as the claimed rates in claim 11 are measured and documented in example 1 in mg/cm2 using different types of permeation enhancers.
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Kadbhane et al., Myers et al., and Bernardo et al. by achieving permeation rates from the film for the active agent as recited in claim 11 because Schobel et al. teach active ingredients, such as drugs or pharmaceuticals, are delivered to patients in deliberate fashion. Delivery of drugs or pharmaceuticals using film transdermally or transmucosally can require that the drug or pharmaceutical permeate or otherwise cross a biological membrane in an effective and efficient manne (paragraph 0003). A pharmaceutical composition, comprising: a polymeric matrix; a pharmaceutically active component in the polymeric matrix; and an adrenergic receptor interacter (see claim 1). The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a film further comprising a polymeric matrix, the pharmaceutically active component being contained in the polymeric matrix (see claim 6 and paragraph 0008). Oral dissolving films can fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Oral dissolving films can also include a combination of any of the above categories. Fast dissolving films can dissolve in about 1 second to about 30 seconds in the mouth, including more than 1 second, more than 5 seconds, more than 10 seconds, more than 20 seconds, and less than 30 seconds. Moderate dissolving films can dissolve in about 1 to about 30 minutes in the mouth including more than 1 minute, more than 5 minutes, more than 10 minutes, more than 20 minutes or less than 30 minutes, and slow dissolving films can dissolve in more than 30 minutes in the mouth. As a general trend, fast dissolving films can include (or consist of) low molecular weight hydrophilic polymers (e.g., polymers having a molecular weight between about 1,000 to 9,000 daltons, or polymers having a molecular weight up to 200,000 daltons). In contrast, slow dissolving films generally include high molecular weight polymers (e.g., having a molecular weight in millions). Moderate dissolving films can tend to fall in between the fast and slow dissolving films (paragraph 0119). Permeation rates that are overlapping in range as the claimed rates in claim 11 are measured and documented in example 1 in mg/cm2 using different types of permeation enhancers. One of ordinary skill would have been motivated to achieve desirable permeation rates as recited in claim 11 because Schobel et al. teach that mucosal surfaces, such as the oral mucosa, are a convenient route for delivering drugs to the body due to the fact that they are highly vascularized and permeable, providing increased bioavailability and rapid onset of action because it does not pass through the digestive system and thereby avoids first pass metabolism. In particular, the buccal and sublingual tissues offer advantageous sites for drug delivery because they are highly permeable regions of the oral mucosa, allowing drugs diffusing from the oral mucosa to have direct access to systemic circulation. This also offers increased convenience and therefore increased compliance in patients. For certain drugs, or pharmaceutically active components, a permeation enhancer can help to overcome the mucosal barrier and improve permeability. Permeation enhancers reversibly modulate the penetrability of the barrier layer in favor of drug absorption. Permeation enhancers facilitate transport of molecules through the epithelium. Absorption profiles and their rates can be controlled and modulated by a variety of parameters, such as but not limited to film size, drug loading, enhancer type/loading, polymer matrix release rate and mucosal residence time (paragraph 077). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (Claims to a printing ink comprising a solvent having the vapor pressure characteristics of butyl carbitol so that the ink would not dry at room temperature but would dry quickly upon heating were held invalid over a reference teaching a printing ink made with a different solvent that was nonvolatile at room temperature but highly volatile when heated in view of an article which taught the desired boiling point and vapor pressure characteristics of a solvent for printing inks and a catalog teaching the boiling point and vapor pressure characteristics of butyl carbitol.). Additionally, it should be noticed that Schobel et al. teach the use of HPMC and HPC as film former polymers (paragraph 0135). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Kadbhane et al., Myers et al., Bernardo et al., Schobel et al. because all of the references teach orally dissolvable films for the delivery of active agents. Furthermore, in the case where the claimed permeation rates "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955). It is within the purview of one of ordinary skill in the art to optimize the permeation rates etc., absent evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are 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 TIGABU KASSA whose telephone number is (571)270-5867. The examiner can normally be reached on 8 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on 571-272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TIGABU KASSA/Primary Examiner, Art Unit 1619
Prosecution Insights