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 response in the reply filed on 22 December 2025 are acknowledged and have been fully considered. Claims 1-14 and 17-20 are pending. Claims 1-10 are under consideration in the instant office action. Claims 11-14 and 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 15-16 are canceled.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08 December 2023 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's election without traverse of Group I (claims 1-10) in the reply filed on 22 December 2025 is acknowledged. Additionally, Applicant’s election without traverse of mannitol as the filler; colloidal anhydrous silica as glidant; and croscarmellose sodium as disintegrant type in the reply filed on 22 December 2025 is also acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
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 3 and 6 are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “wherein the ratio between said first amount of microcrystalline cellulose and said second amount of microcrystalline cellulose is in the range of 1:4 to 1:10 wt%/wt%”, and the claim also recites “preferably approximately 1:5 wt%/wt%”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “wherein said multiple portions are three portions, four portions, five portions, six portions, seven portions, or eight portions”, and the claim also recites “preferably five portions”, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Note: The claims are examined with respect to the elected species wherein sodium stearyl fumarate as the binder; sodium starch glycolate as the disintegrant; and colloidal silicon dioxide as the excipient.
Claims 1, 3-8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over NAYER et al. (EP 3127536) in view of Aurora et al. (US 2010/0204292) .
Applicants’ claims
Applicants claim a method for manufacture of a rapid release melatonin formulation in solid dosage form, said method comprising the steps as recited in claim 1. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
NAYER et al. teach a method for manufacturing formulation solid formulation comprising melatonin and a tablet produced from such solid formulation, as well as the medical use thereof (see abstract). NAYER et al. teach in FIG.1 as follows:
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NAYER et al. teach a method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intragranular excipients to form a melatonin blend, followed by a wet granulation step (see claim 1). Method according to claim 1, whereby said intragranular excipients in the dispersion step are chosen from fillers, binders, disintegrants, and/or glidants (see claim 2). Method according to any one of the claims 1 or 2, characterized in that a binder solution is granulated with said melatonin blend (see claim 3).
NAYER et al. teach in claim 10 tablet comprising melatonin, whereby said tablet is an immediate release formulation and whereby said tablet comprises:
- between 0.5 and 10% w/w of melatonin;
- between 75 and 99% w/w of one or more fillers;
- between 0.5 and 5% w/w of one or more binders;
- between 0.05 and 0.5% of one or more glidants; and
- between 0.25 and 1% w/w of one or more lubricants.
Tablet according to claim 10, characterized in that said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof (see claim 11). Tablet according to any one of the previous claims, whereby said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof (see claim 12). Tablet according to any one of the previous claims, whereby said glidant is selected from (colloidal) silicon dioxide, starch, talc, magnesium stearate and/or a mixture thereof (see claim 13).
Method according to claim 3, characterized in that said wet granulation occurs by means of a high shear granulator, fluidized bed granulator or twin screw granulator (see claim 4). Method according to any one of the previous claims, characterized in that said dispersion step comprises the formation of a premix, said premix comprises melatonin and one or more intragranular excipients, followed by a sieving step of said premix and further blending with one or more intragranular excipients to form said melatonin blend (see claim 5). Method according to claim 5, characterized in that said sieving is performed by use of a mesh with mesh size between 800 and 1200 micron (see claim 6) NAYER et al. in claim 7 teach method according to claim 6, comprising the following sequence of steps:
- dispersion of melatonin with one or more fillers and a glidant;
- providing a binder solution;
- wet granulation of said melatonin blend with said binder solution;
- drying the obtained granulate;
- addition of a lubricant to said granulate; and mixing of the final blend.
Method according to claim 7, whereby said final blend is tableted (see claim 8). Method according to claim 7 or 8, characterized in that said ratio between melatonin, glidant and filler is between 1:0.1:4 and 1:0.3:6 (see claim 9).
NAYER et al. teach the present invention provides for a method for the manufacturing of a solid formulation according to claim 1. The methodology ensures good uniformity of dosage units results, which is a key requirement according to the pharmaceutical guidelines. In a second aspect, the current invention provides a tablet according to claim 10 (paragraph 0008).
NAYER et al. teach on paragraph 0009 in particular, the current invention is characterized by the following embodiments, which should not be construed as limiting.
1. A method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intragranular excipients to form a melatonin blend, followed by a wet granulation step.
2. Method according to embodiment 1, whereby said intragranular excipients in the dispersion step are chosen from fillers, binders, disintegrants, and/or glidants.
3. Method according to any one of the embodiments 1 or 2, characterized in that a binder solution is granulated with said melatonin blend.
4. Method according to embodiment 3, characterized in that said wet granulation occurs by means of a high shear granulator, fluidized bed granulator, twin screw granulator.
5. Method according to any one of the previous embodiments, characterized in that said dispersion step comprises the formation of a premix, said premix comprises melatonin and one or more intragranular excipients, followed by a sieving step of said premix and further blending with one or more intragranular excipients to form said melatonin blend.
6. Method according to embodiment 5, characterized in that said sieving is performed by use of a mesh with mesh size between 800 and 1200 micron.
7. Method according to embodiment 6, comprising the following sequence of steps:
dispersion of melatonin with one or more fillers and a glidant;
providing a binder solution;
wet granulation of said melatonin blend with said binder solution;
drying the granulate;
addition of a lubricant to said granulate; and mixing of the final blend.
8. Method according to embodiment 7, whereby said final blend is tableted.
9. Method according to embodiment 7 or 8, characterized in that said ratio between melatonin, glidant and filler is between 1:0.1:4 and 1:0.3:6.
10. Method according to any one of the previous embodiments, characterized in that said melatonin has a particle size distribution determined by laser-diffraction or comparable method as follows:
d(0.1) = 10 µm
d(0.5) = 50 µm
d(0.9) = 210 µm.
The examiner notes that the above teachings clearly met the steps recited i)-v) in claim 1.
11. Tablet comprising melatonin, whereby said tablet is an immediate release formulation and whereby said tablet comprises:
between 0.5 and 10% w/w of melatonin;
between 75 and 99% w/w of one or more fillers;
between 0.5 and 5% w/w of one or more binders;
between 0.05 and 0.5% of one or more glidants; and
between 0.25 and 1% w/w of one or more lubricants.
12. Tablet according to embodiment 11, characterized in that the formulation for the tablet is obtained via the method according to any of the embodiments 1 to 10.
13.Tablet according to any one of the previous embodiments, characterized in that said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof.
14. Tablet according to any one of the previous embodiments, whereby said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof.
15. Tablet according to any one of the previous embodiments, whereby said glidant is selected from (colloidal) silicon dioxide, starch, talc, magnesium stearate and/or a mixture thereof.
16. Tablet according to any one of the previous embodiments, comprising particulate melatonin, characterized in that said melatonin has a particle size distribution profile as follows:
d(0.1) = 10 µm
d(0.5) = 50 µm
d(0.9) = 210 µm.
17. Tablet according to any one of the previous embodiments, for use in the treatment of sleep problems chosen from delayed sleep phase disorders, primary insomnia for adults aged 55+ and general sleep disorders and treatment of difficulties in sleep initiation and maintenance that are not associated with a medical condition, substance use or concurrent psychological disorder.
18. Tablet according to any one of the previous embodiments 11 to 16, for use in the treatment of ADHD, concentration and/or attention problems and/or hyperactivity.
Diluents or fillers increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents suitable for tablets according to the current invention include, for example, cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc (paragraph 0056). In a preferred embodiment, said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof (paragraph 0057). Solid formulations that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to contain the active ingredient-and other excipients together after compression. Suitable binders include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®, pregelatinized starch, sodium alginate and starch (paragraph 0058). In a preferred embodiment, said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof (paragraph 0059). The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Suitable disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch (paragraph 0060). Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants in the current invention include colloidal silicon dioxide, magnesium trisilicate, magnesium stearate, powdered cellulose, starch, talc and tribasic calcium phosphate (paragraph 0061). In a preferred embodiment, said glidant is selected from (colloidal) silicon dioxide, starch or talc (paragraph 0062). When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl furmarate, stearic acid, talc and zinc stearate. Preferably, said lubricant is present in between 0.25 and 1% w/w by weight (paragraph 0063).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
NAYER et al. do not specifically teach wherein the final mixture comprises at least 3 wt% magnesium stearate with respect to the total weight of the solid dosage form as recited in claim 8. These deficiencies are cured by the teachings of Aurora et al.
Aurora et al. teach a pharmaceutical composition comprising i) an intra-granular fraction containing a pharmaceutically acceptable active component and a first excipient and ii) an extra-granular fraction containing a second excipient. The pharmaceutical composition is characterized by being substantially surfactant-free and by exhibiting a rapid-dissolution profile (see abstract). A pharmaceutical composition comprising an intra-granular fraction intermingled with an extra-granular fraction, said intra-granular fraction consisting of granules comprising a pharmaceutically acceptable active component and a first pharmaceutically acceptable excipient component said first pharmaceutically acceptable excipient component comprising a first binder element, a first disintegrant element and a first antiadherent element, said intra-granular fraction being at least substantially free of a diluent element and being at least substantially free of a surfactant element, said extra-granular fraction comprising a second pharmaceutically acceptable excipient component, said second pharmaceutically acceptable excipient component comprising a diluent element, a second disintegrant element, a second anti-adherent element and a lubricant element said extra-granular fraction being at least substantially free of a surfactant element (see claim 1). A pharmaceutical composition (e.g. tablet) of the present invention may suitably comprise high amounts of medicament so that a high proportion of medicament is present. For example, the pharmaceutically acceptable active component(s) or element(s) (e.g. irbesartan or a pharmaceutically acceptable salt thereof or a mixture thereof) may be present in an amount of at least 30% or more (e.g. up to 71%) of the total weight of the composition (or tablet), with the remainder comprising pharmaceutically acceptable excipient substance(s) or material(s)) present for example in an amount of from 70% or less (e.g. from 29% to 70%) of the total weight of the composition (or tablet). If desired or necessary, lower amounts of medicament may, of course, be present in the pharmaceutical composition, i.e. with correspondingly higher amounts of excipient substance(s) or material(s). Herein the amount of excipient substance(s) or material(s) will in the usual course be a function of the amount of medicament desired to be present in the composition (e.g. tablet), i.e. the amount of medicament in the usual course will take precedence over the amount(s) of excipient substance(s) or material(s), with the amount of the various excipient substance(s) or material(s) being adjusted as necessary or desired in view of the desired amount of medicament (paragraph 0025). The intra-granular fraction (i.e. granules) may for example comprise up to 75% of the total weight of the composition (or tablet), e.g. from 40% to 75% by weight of the composition (or tablet). The (first) binder element of the intra-granular fraction may for example comprise up to 20% of the total weight of the composition (or tablet), e.g. from 0.5% to 20% by weight of the composition (or tablet). The (first) disintegrant element of the intra-granular fraction may for example comprise up to 15% of the total weight of the composition (or tablet), e.g. from 0.1% to 15% by weight of the composition (or tablet). The (first) anti-adherent element of the intra-granular fraction may comprise up to 5% of the total weight of the composition (or tablet), e.g. from 0.01% to 5% by weight of the composition (or tablet) (paragraph 0026). The extra-granular fraction may for example comprise up to 60% of the total weight of the composition (or tablet), e.g. from 25% to 60% by weight of the composition (or tablet). The diluent element of the extra-granular fraction may for example comprise up to 59.6% of the total weight of the composition (or tablet), e.g. from 10% to 59.6% by weight of the composition (or tablet). The (second) disintegrant element of the extra-granular fraction may for example comprise up to 15% of the total weight of the composition (or tablet), e.g. from 0.1% to 15% by weight of the composition (or tablet). The (second) binder element, if present, of the extra-granular fraction, may be present per se or for the granulation of the diluent where required; the second binder element may thus, for example, be present in an amount of from 0 up to 10. % of the total weight of the composition (or tablet), e.g. from 0.5% to 10% by weight of the composition (or tablet). The (second) anti-adherent element of the extra-granular fraction may for example comprise up to 5% of the total weight of the composition (or tablet), e.g. from 0.1% to 5% by weight of the composition (or tablet). The lubricant element of the extra-granular fraction may for example comprise up to 7.5% of the total weight of the composition (or tablet), e.g. from 0.2% to 7.5% by weight of the composition (or tablet) (paragraph 0027). An example preparation process for the manufacture of a 300 mg Irbesartan tablet (referring to Table 3 for the Item number description) is described hereinafter; the process exploits various known types of equipment which are referred to (unless otherwise indicated) by their generic designations (paragraph 0050). The example process comprises the following (14) steps or stages: 1) Items 1 and 4 (Table 3) are mixed and sieved together using a comil. The comil consists of a rotating blade that forces the material through a screen that has perforations of specified size (i.e. 0.018 inch perforations).2) Items 2 and 3 (Table 3) are separately sieved using a vibratory sifter through a screen/mesh of specified opening 20 mesh screen (ASTM) (850 microns).3) The sieved items 1 and 4 (i.e. undersize material) are loaded, into a high shear granulator. (The granulator comprises a bowl fitted with impeller blades that mix the powders. This enables dry mixing of powders as well as granulating powders when a fluid such as water is admixed with the powders causing lumping or binding.)4) The sieved items 2 and 3 (i.e. undersize material) are dry mixed with items 1 and 4 in the high shear granulator.5) Purified water is then added at a fixed rate (600 gm per minute) while mixing with the impellers at fixed speed (200 rpm). After adequate addition of water (35% by weight) and mixing a mass of suitable consistency is obtained.6) The wet mass is then dried using a fluid bed dryer wherein the wet mass is fluidized using heated air for a predetermined time period.7) The partially dried material is then milled using the comil and a fixed screen (i.e. 0.187 inch perforations) to break the big lumps into smaller ones to facilitate faster and proper drying.8) The partially dried milled material is then further dried in the fluid bed dryer.9) The (completely) dried material is then screened to using a mesh of 850 microns. Any material retained over the mesh is sized to granule size by further milling using a comil.10) The dried sized granules are then loaded into a blender (i.e. a V or bin type blender).11) Item 6 (Table 3) is sieved through a mesh size of 850 micron opening. Item 7 (Table 3) and item 8 (Table 3) are mixed and then sieved through a mesh size of 425 micron opening. Item 9 (Table 3) is sieved through a mesh of 425 micron opening.12) The sieved items 6 to 8 (i.e. undersize material) are then loaded into the blender containing the granules (step 10 above) and the blender is rotated at a fixed speed (14 rpm) for a fixed time (5 minutes)*. *the fixed speed and fixed time may be varied as necessary or desired respectively for example from 10 to 20 rpm and from 1 to fifteen minutes;13) The sieved item 9 is then loaded into the blender after step 12) and the blender is again rotated at a fixed speed (14 rpm) for a fixed time (2 minute)** and the obtained blend comprising an intra-granular fraction and an extra-granular fraction (i.e. lubricated granules) is unloaded. the fixed speed and fixed time may be varied as necessary or desired respectively for example from 10 to 20 rpm, and from 1 to five minutes.14) The blend obtained from step 13) is then compressed into tablets using a tablet compression machine fitted with punches and dies of required dimensions.
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 NAYER et al. by including a lubricant such as magnesium stearate in amount as recited in claim 8 because Aurora et al. teach a pharmaceutical composition comprising i) an intra-granular fraction containing a pharmaceutically acceptable active component and a first excipient and ii) an extra-granular fraction containing a second excipient. The pharmaceutical composition is characterized by being substantially surfactant-free and by exhibiting a rapid-dissolution profile (see abstract). A pharmaceutical composition comprising an intra-granular fraction intermingled with an extra-granular fraction, said intra-granular fraction consisting of granules comprising a pharmaceutically acceptable active component and a first pharmaceutically acceptable excipient component said first pharmaceutically acceptable excipient component comprising a first binder element, a first disintegrant element and a first antiadherent element, said intra-granular fraction being at least substantially free of a diluent element and being at least substantially free of a surfactant element, said extra-granular fraction comprising a second pharmaceutically acceptable excipient component, said second pharmaceutically acceptable excipient component comprising a diluent element, a second disintegrant element, a second anti-adherent element and a lubricant element said extra-granular fraction being at least substantially free of a surfactant element (see claim 1). A pharmaceutical composition (e.g. tablet) of the present invention may suitably comprise high amounts of medicament so that a high proportion of medicament is present. For example, the pharmaceutically acceptable active component(s) or element(s) (e.g. irbesartan or a pharmaceutically acceptable salt thereof or a mixture thereof) may be present in an amount of at least 30% or more (e.g. up to 71%) of the total weight of the composition (or tablet), with the remainder comprising pharmaceutically acceptable excipient substance(s) or material(s)) present for example in an amount of from 70% or less (e.g. from 29% to 70%) of the total weight of the composition (or tablet). If desired or necessary, lower amounts of medicament may, of course, be present in the pharmaceutical composition, i.e. with correspondingly higher amounts of excipient substance(s) or material(s). Herein the amount of excipient substance(s) or material(s) will in the usual course be a function of the amount of medicament desired to be present in the composition (e.g. tablet), i.e. the amount of medicament in the usual course will take precedence over the amount(s) of excipient substance(s) or material(s), with the amount of the various excipient substance(s) or material(s) being adjusted as necessary or desired in view of the desired amount of medicament (paragraph 0025). The intra-granular fraction (i.e. granules) may for example comprise up to 75% of the total weight of the composition (or tablet), e.g. from 40% to 75% by weight of the composition (or tablet). The (first) binder element of the intra-granular fraction may for example comprise up to 20% of the total weight of the composition (or tablet), e.g. from 0.5% to 20% by weight of the composition (or tablet). The (first) disintegrant element of the intra-granular fraction may for example comprise up to 15% of the total weight of the composition (or tablet), e.g. from 0.1% to 15% by weight of the composition (or tablet). The (first) anti-adherent element of the intra-granular fraction may comprise up to 5% of the total weight of the composition (or tablet), e.g. from 0.01% to 5% by weight of the composition (or tablet) (paragraph 0026). The extra-granular fraction may for example comprise up to 60% of the total weight of the composition (or tablet), e.g. from 25% to 60% by weight of the composition (or tablet). The diluent element of the extra-granular fraction may for example comprise up to 59.6% of the total weight of the composition (or tablet), e.g. from 10% to 59.6% by weight of the composition (or tablet). The (second) disintegrant element of the extra-granular fraction may for example comprise up to 15% of the total weight of the composition (or tablet), e.g. from 0.1% to 15% by weight of the composition (or tablet). The (second) binder element, if present, of the extra-granular fraction, may be present per se or for the granulation of the diluent where required; the second binder element may thus, for example, be present in an amount of from 0 up to 10. % of the total weight of the composition (or tablet), e.g. from 0.5% to 10% by weight of the composition (or tablet). The (second) anti-adherent element of the extra-granular fraction may for example comprise up to 5% of the total weight of the composition (or tablet), e.g. from 0.1% to 5% by weight of the composition (or tablet). The lubricant element of the extra-granular fraction may for example comprise up to 7.5% of the total weight of the composition (or tablet), e.g. from 0.2% to 7.5% by weight of the composition (or tablet) (paragraph 0027). One of ordinary skill in the art would have been motivated to do so to improve powder flow, prevent materials from sticking to machinery, and reduce friction during compression and ejection. 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.) Furthermore, in the case where the claimed amounts of ingredients such as lubricants"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 or any measurable parameters 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of NAYER et al. and Aurora et al. because both references are drawn to an oral pharmaceutical composition comprising intragranular and extragranular excipients. With regard to adding mixtures or ingredients in portions or in different sequences it is prima facie obvious. See Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
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.
Claims 1-7 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over NAYER et al. (EP 3127536) in view of Yildirim et al. (WO2021071444)
Applicants’ claims
Applicants claim a method for manufacture of a rapid release melatonin formulation in solid dosage form, said method comprising the steps as recited in claim 1. Dependent claims thereof recite additional features.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
NAYER et al. teach a method for manufacturing formulation solid formulation comprising melatonin and a tablet produced from such solid formulation, as well as the medical use thereof (see abstract). NAYER et al. teach in FIG.1 as follows:
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NAYER et al. teach a method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intragranular excipients to form a melatonin blend, followed by a wet granulation step (see claim 1). Method according to claim 1, whereby said intragranular excipients in the dispersion step are chosen from fillers, binders, disintegrants, and/or glidants (see claim 2). Method according to any one of the claims 1 or 2, characterized in that a binder solution is granulated with said melatonin blend (see claim 3).
NAYER et al. teach in claim 10 tablet comprising melatonin, whereby said tablet is an immediate release formulation and whereby said tablet comprises:
- between 0.5 and 10% w/w of melatonin;
- between 75 and 99% w/w of one or more fillers;
- between 0.5 and 5% w/w of one or more binders;
- between 0.05 and 0.5% of one or more glidants; and
- between 0.25 and 1% w/w of one or more lubricants.
Tablet according to claim 10, characterized in that said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof (see claim 11). Tablet according to any one of the previous claims, whereby said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof (see claim 12). Tablet according to any one of the previous claims, whereby said glidant is selected from (colloidal) silicon dioxide, starch, talc, magnesium stearate and/or a mixture thereof (see claim 13).
Method according to claim 3, characterized in that said wet granulation occurs by means of a high shear granulator, fluidized bed granulator or twin screw granulator (see claim 4). Method according to any one of the previous claims, characterized in that said dispersion step comprises the formation of a premix, said premix comprises melatonin and one or more intragranular excipients, followed by a sieving step of said premix and further blending with one or more intragranular excipients to form said melatonin blend (see claim 5). Method according to claim 5, characterized in that said sieving is performed by use of a mesh with mesh size between 800 and 1200 micron (see claim 6) NAYER et al. in claim 7 teach method according to claim 6, comprising the following sequence of steps:
- dispersion of melatonin with one or more fillers and a glidant;
- providing a binder solution;
- wet granulation of said melatonin blend with said binder solution;
- drying the obtained granulate;
- addition of a lubricant to said granulate; and mixing of the final blend.
Method according to claim 7, whereby said final blend is tableted (see claim 8). Method according to claim 7 or 8, characterized in that said ratio between melatonin, glidant and filler is between 1:0.1:4 and 1:0.3:6 (see claim 9).
NAYER et al. teach the present invention provides for a method for the manufacturing of a solid formulation according to claim 1. The methodology ensures good uniformity of dosage units results, which is a key requirement according to the pharmaceutical guidelines. In a second aspect, the current invention provides a tablet according to claim 10 (paragraph 0008).
NAYER et al. teach on paragraph 0009 in particular, the current invention is characterized by the following embodiments, which should not be construed as limiting.
1. A method for the manufacturing of a solid formulation comprising melatonin as active pharmaceutical ingredient, said method comprises a melatonin dispersion step in one or more intragranular excipients to form a melatonin blend, followed by a wet granulation step.
2. Method according to embodiment 1, whereby said intragranular excipients in the dispersion step are chosen from fillers, binders, disintegrants, and/or glidants.
3. Method according to any one of the embodiments 1 or 2, characterized in that a binder solution is granulated with said melatonin blend.
4. Method according to embodiment 3, characterized in that said wet granulation occurs by means of a high shear granulator, fluidized bed granulator, twin screw granulator.
5. Method according to any one of the previous embodiments, characterized in that said dispersion step comprises the formation of a premix, said premix comprises melatonin and one or more intragranular excipients, followed by a sieving step of said premix and further blending with one or more intragranular excipients to form said melatonin blend.
6. Method according to embodiment 5, characterized in that said sieving is performed by use of a mesh with mesh size between 800 and 1200 micron.
7. Method according to embodiment 6, comprising the following sequence of steps:
dispersion of melatonin with one or more fillers and a glidant;
providing a binder solution;
wet granulation of said melatonin blend with said binder solution;
drying the granulate;
addition of a lubricant to said granulate; and mixing of the final blend.
8. Method according to embodiment 7, whereby said final blend is tableted.
9. Method according to embodiment 7 or 8, characterized in that said ratio between melatonin, glidant and filler is between 1:0.1:4 and 1:0.3:6.
10. Method according to any one of the previous embodiments, characterized in that said melatonin has a particle size distribution determined by laser-diffraction or comparable method as follows:
d(0.1) = 10 µm
d(0.5) = 50 µm
d(0.9) = 210 µm.
The examiner notes that the above teachings clearly met the steps recited i)-v) in claim 1.
11. Tablet comprising melatonin, whereby said tablet is an immediate release formulation and whereby said tablet comprises:
between 0.5 and 10% w/w of melatonin;
between 75 and 99% w/w of one or more fillers;
between 0.5 and 5% w/w of one or more binders;
between 0.05 and 0.5% of one or more glidants; and
between 0.25 and 1% w/w of one or more lubricants.
12. Tablet according to embodiment 11, characterized in that the formulation for the tablet is obtained via the method according to any of the embodiments 1 to 10.
13.Tablet according to any one of the previous embodiments, characterized in that said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof.
14. Tablet according to any one of the previous embodiments, whereby said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof.
15. Tablet according to any one of the previous embodiments, whereby said glidant is selected from (colloidal) silicon dioxide, starch, talc, magnesium stearate and/or a mixture thereof.
16. Tablet according to any one of the previous embodiments, comprising particulate melatonin, characterized in that said melatonin has a particle size distribution profile as follows:
d(0.1) = 10 µm
d(0.5) = 50 µm
d(0.9) = 210 µm.
17. Tablet according to any one of the previous embodiments, for use in the treatment of sleep problems chosen from delayed sleep phase disorders, primary insomnia for adults aged 55+ and general sleep disorders and treatment of difficulties in sleep initiation and maintenance that are not associated with a medical condition, substance use or concurrent psychological disorder.
18. Tablet according to any one of the previous embodiments 11 to 16, for use in the treatment of ADHD, concentration and/or attention problems and/or hyperactivity.
Diluents or fillers increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents suitable for tablets according to the current invention include, for example, cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc (paragraph 0056). In a preferred embodiment, said filler is selected from cellulose microcrystalline, lactose monohydrate, sucrose, glucose, polyols, calcium carbonate, and/or magnesium stearate, mixtures or derivatives thereof (paragraph 0057). Solid formulations that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to contain the active ingredient-and other excipients together after compression. Suitable binders include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®, pregelatinized starch, sodium alginate and starch (paragraph 0058). In a preferred embodiment, said binder is selected from cellulose or modified cellulose such as hydroxycellulose, microcrystalline cellulose; polyethylene glycol; polyvinylpyrrolidone; starch and/or mixtures thereof (paragraph 0059). The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Suitable disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch (paragraph 0060). Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants in the current invention include colloidal silicon dioxide, magnesium trisilicate, magnesium stearate, powdered cellulose, starch, talc and tribasic calcium phosphate (paragraph 0061). In a preferred embodiment, said glidant is selected from (colloidal) silicon dioxide, starch or talc (paragraph 0062). When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl furmarate, stearic acid, talc and zinc stearate. Preferably, said lubricant is present in between 0.25 and 1% w/w by weight (paragraph 0063).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
NAYER et al. do not specifically teach wherein the second adding step is followed by a first blending of the second mixture for a duration of 40-240 seconds as recited in claim 2; and wherein the third adding step is followed by a second blending of the final mixture for less than 120 seconds. These deficiencies are cured by the teachings of Yildirim et al.
Yildirim et al. teach an oral pharmaceutical formulation comprising rivaroxaban and pharmaceutically acceptable excipients wherein rivaroxaban is in non-hydrophilized form and the dosage form is manufactured by using high-shear granulation method in which the granulation solution comprising water content between 45% to 55% is given in a duration time range between 30 seconds to 2 minutes to the intragranular phase (see abstract). Different durations to give granulation solution were investigated: from 30 seconds to 3 minutes. Between these range, 1st minute, 1.5th minute, 2nd minute and 3rd minute intervals were applied (see page 11). Most proper dissolution results are obtained with a duration range to give granulation solution from 30 seconds to 2 minutes (see page 13).
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 NAYER et al. by making the second adding step to be followed by a first blending of the second mixture for a duration of 40-240 seconds as recited in claim 2; and wherein the third adding step is followed by a second blending of the final mixture for less than 120 seconds because Yildirim et al. teach an oral pharmaceutical formulation comprising rivaroxaban and pharmaceutically acceptable excipients wherein rivaroxaban is in non-hydrophilized form and the dosage form is manufactured by using high-shear granulation method in which the granulation solution comprising water content between 45% to 55% is given in a duration time range between 30 seconds to 2 minutes to the intragranular phase (see abstract). One of ordinary skill in the art would have been motivated to do so because Yildirim et al. teach that different durations to give granulation solution were investigated: from 30 seconds to 3 minutes. Between these range, 1st minute, 1.5th minute, 2nd minute and 3rd minute intervals were applied (see page 11). Most proper dissolution results are obtained with a duration range to give granulation solution from 30 seconds to 2 minutes (see page 13). Furthermore, in the case where the claimed amounts of ingredients and mixing times" 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 or any measurable parameters 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). One of ordinary skill in the art would have had a reasonable chance of success in combining the teachings of NAYER et al. and Aurora et al. because both references are drawn to an oral pharmaceutical composition comprising intragranular and extragranular excipients. With regard to adding mixtures or ingredients in portions or in different sequences it is prima facie obvious. See Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).
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.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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